International Journal of Molecular Sciences

17 pages, 2994 KiB

Open AccessArticle

Clinical, Genetic, and Histological Characterization of Patients with Rare Neuromuscular and Mitochondrial Diseases Presenting with Different Cardiomyopathy Phenotypes

by Emanuele Monda, Michele Lioncino, Martina Caiazza, Vincenzo Simonelli, Claudia Nesti, Marta Rubino, Alessia Perna, Alfredo Mauriello, Alberta Budillon, Vincenzo Pota, Giorgia Bruno, Antonio Varone, Vincenzo Nigro, Filippo Maria Santorelli, Giuseppe Pacileo, Maria Giovanna Russo, Giulia Frisso, Simone Sampaolo and Giuseppe Limongelli

Int. J. Mol. Sci. 2023, 24(10), 9108; https://doi.org/10.3390/ijms24109108 - 22 May 2023

Viewed by 1507

Abstract

Cardiomyopathies are mostly determined by genetic mutations affecting either cardiac muscle cell structure or function. Nevertheless, cardiomyopathies may also be part of complex clinical phenotypes in the spectrum of neuromuscular (NMD) or mitochondrial diseases (MD). The aim of this study is to describe [...] Read more.

Cardiomyopathies are mostly determined by genetic mutations affecting either cardiac muscle cell structure or function. Nevertheless, cardiomyopathies may also be part of complex clinical phenotypes in the spectrum of neuromuscular (NMD) or mitochondrial diseases (MD). The aim of this study is to describe the clinical, molecular, and histological characteristics of a consecutive cohort of patients with cardiomyopathy associated with NMDs or MDs referred to a tertiary cardiomyopathy clinic. Consecutive patients with a definitive diagnosis of NMDs and MDs presenting with a cardiomyopathy phenotype were described. Seven patients were identified: two patients with ACAD9 deficiency (Patient 1 carried the c.1240C>T (p.Arg414Cys) homozygous variant in ACAD9; Patient 2 carried the c.1240C>T (p.Arg414Cys) and the c.1646G>A (p.Ar549Gln) variants in ACAD9); two patients with MYH7-related myopathy (Patient 3 carried the c.1325G>A (p.Arg442His) variant in MYH7; Patient 4 carried the c.1357C>T (p.Arg453Cys) variant in MYH7); one patient with desminopathy (Patient 5 carried the c.46C>T (p.Arg16Cys) variant in DES); two patients with mitochondrial myopathy (Patient 6 carried the m.3243A>G variant in MT-TL1; Patient 7 carried the c.253G>A (p.Gly85Arg) and the c.1055C>T (p.Thr352Met) variants in MTO1). All patients underwent a comprehensive cardiovascular and neuromuscular evaluation, including muscle biopsy and genetic testing. This study described the clinical phenotype of rare NMDs and MDs presenting as cardiomyopathies. A multidisciplinary evaluation, combined with genetic testing, plays a main role in the diagnosis of these rare diseases, and provides information about clinical expectations, and guides management. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies 3.0)

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21 pages, 6194 KiB

Open AccessArticle

An Optimized Flow Cytometric Method to Demonstrate the Differentiation Stage-Dependent Ca²⁺ Flux Responses of Peripheral Human B Cells

by Anna Bajnok, Timea Serény-Litvai, Viktória Temesfői, Jasper Nörenberg, Róbert Herczeg, Ambrus Kaposi, Timea Berki and Emese Mezosi

Int. J. Mol. Sci. 2023, 24(10), 9107; https://doi.org/10.3390/ijms24109107 - 22 May 2023

Cited by 2 | Viewed by 2696

Abstract

Calcium (Ca²⁺) flux acts as a central signaling pathway in B cells, and its alterations are associated with autoimmune dysregulation and B-cell malignancies. We standardized a flow-cytometry-based method using various stimuli to investigate the Ca²⁺ flux characteristics of circulating human [...] Read more.

Calcium (Ca²⁺) flux acts as a central signaling pathway in B cells, and its alterations are associated with autoimmune dysregulation and B-cell malignancies. We standardized a flow-cytometry-based method using various stimuli to investigate the Ca²⁺ flux characteristics of circulating human B lymphocytes from healthy individuals. We found that different activating agents trigger distinct Ca²⁺ flux responses and that B-cell subsets show specific developmental-stage dependent Ca²⁺ flux response patterns. Naive B cells responded with a more substantial Ca²⁺ flux to B cell receptor (BCR) stimulation than memory B cells. Non-switched memory cells responded to anti-IgD stimulation with a naive-like Ca²⁺ flux pattern, whereas their anti-IgM response was memory-like. Peripheral antibody-secreting cells retained their IgG responsivity but showed reduced Ca²⁺ responses upon activation, indicating their loss of dependence on Ca²⁺ signaling. Ca²⁺ flux is a relevant functional test for B cells, and its alterations could provide insight into pathological B-cell activation development. Full article

(This article belongs to the Special Issue New Insight into B Cell Biology)

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13 pages, 2619 KiB

Open AccessArticle

Kidney-Related Function of Mitochondrial Protein Mitoregulin

by Olga A. Averina, Oleg A. Permyakov, Mariia A. Emelianova, Ekaterina A. Guseva, Olga O. Grigoryeva, Maxim L. Lovat, Anna E. Egorova, Andrei V. Grinchenko, Vadim V. Kumeiko, Maria V. Marey, Vasily N. Manskikh, Olga A. Dontsova, Mikhail Y. Vyssokikh and Petr V. Sergiev

Int. J. Mol. Sci. 2023, 24(10), 9106; https://doi.org/10.3390/ijms24109106 - 22 May 2023

Cited by 1 | Viewed by 1727

Abstract

A small protein, Mitoregulin (Mtln), localizes in mitochondria and contributes to oxidative phosphorylation and fatty acid metabolism. Mtln knockout mice develop obesity on a high-fat diet, demonstrating elevated cardiolipin damage and suboptimal creatine kinase oligomerization in muscle tissue. Kidneys heavily depend on the [...] Read more.

A small protein, Mitoregulin (Mtln), localizes in mitochondria and contributes to oxidative phosphorylation and fatty acid metabolism. Mtln knockout mice develop obesity on a high-fat diet, demonstrating elevated cardiolipin damage and suboptimal creatine kinase oligomerization in muscle tissue. Kidneys heavily depend on the oxidative phosphorylation in mitochondria. Here we report kidney-related phenotypes in aged Mtln knockout mice. Similar to Mtln knockout mice muscle mitochondria, those of the kidney demonstrate a decreased respiratory complex I activity and excessive cardiolipin damage. Aged male mice carrying Mtln knockout demonstrated an increased frequency of renal proximal tubules’ degeneration. At the same time, a decreased glomerular filtration rate has been more frequently detected in aged female mice devoid of Mtln. An amount of Mtln partner protein, Cyb5r3, is drastically decreased in the kidneys of Mtln knockout mice. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 3.0)

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17 pages, 3058 KiB

Open AccessArticle

Potential Binding Sites of Pharmacological Chaperone NCGC00241607 on Mutant β-Glucocerebrosidase and Its Efficacy on Patient-Derived Cell Cultures in Gaucher and Parkinson’s Disease

by Alena E. Kopytova, George N. Rychkov, Alexander A. Cheblokov, Elena V. Grigor’eva, Mikhail A. Nikolaev, Elena S. Yarkova, Diana A. Sorogina, Farid M. Ibatullin, Galina V. Baydakova, Artem D. Izyumchenko, Daria A. Bogdanova, Vitali M. Boitsov, Akim V. Rybakov, Irina V. Miliukhina, Vadim A. Bezrukikh, Galina N. Salogub, Ekaterina Y. Zakharova, Sofya N. Pchelina and Anton K. Emelyanov

Int. J. Mol. Sci. 2023, 24(10), 9105; https://doi.org/10.3390/ijms24109105 - 22 May 2023

Cited by 2 | Viewed by 1868

Abstract

Mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), cause Gaucher disease (GD) and are the most common genetic risk factor for Parkinson’s disease (PD). Pharmacological chaperones (PCs) are being developed as an alternative treatment approach for GD and PD. To [...] Read more.

Mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), cause Gaucher disease (GD) and are the most common genetic risk factor for Parkinson’s disease (PD). Pharmacological chaperones (PCs) are being developed as an alternative treatment approach for GD and PD. To date, NCGC00241607 (NCGC607) is one of the most promising PCs. Using molecular docking and molecular dynamics simulation we identified and characterized six allosteric binding sites on the GCase surface suitable for PCs. Two sites were energetically more preferable for NCGC607 and located nearby to the active site of the enzyme. We evaluated the effects of NCGC607 treatment on GCase activity and protein levels, glycolipids concentration in cultured macrophages from GD (n = 9) and GBA-PD (n = 5) patients as well as in induced human pluripotent stem cells (iPSC)—derived dopaminergic (DA) neurons from GBA-PD patient. The results showed that NCGC607 treatment increased GCase activity (by 1.3-fold) and protein levels (by 1.5-fold), decreased glycolipids concentration (by 4.0-fold) in cultured macrophages derived from GD patients and also enhanced GCase activity (by 1.5-fold) in cultured macrophages derived from GBA-PD patients with N370S mutation (p < 0.05). In iPSC-derived DA neurons from GBA-PD patients with N370S mutation NCGC607 treatment increased GCase activity and protein levels by 1.1-fold and 1.7-fold (p < 0.05). Thus, our results showed that NCGC607 could bind to allosteric sites on the GCase surface and confirmed its efficacy on cultured macrophages from GD and GBA-PD patients as well as on iPSC-derived DA neurons from GBA-PD patients. Full article

(This article belongs to the Special Issue Molecular Advances in Nervous System Disorders)

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25 pages, 4973 KiB

Open AccessArticle

Design, Synthesis, Antiproliferative Actions, and DFT Studies of New Bis–Pyrazoline Derivatives as Dual EGFR/BRAF^V600E Inhibitors

by Lamya H. Al-Wahaibi, Hesham A. Abou-Zied, Eman A. M. Beshr, Bahaa G. M. Youssif, Alaa M. Hayallah and Mohamed Abdel-Aziz

Int. J. Mol. Sci. 2023, 24(10), 9104; https://doi.org/10.3390/ijms24109104 - 22 May 2023

Cited by 4 | Viewed by 1494

Abstract

Some new Bis-pyrazoline hybrids 8–17 with dual EGFR and BRAF^V600E inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds 12, 15, and 17 demonstrated strong antiproliferative activity with GI₅₀ [...] Read more.

Some new Bis-pyrazoline hybrids 8–17 with dual EGFR and BRAF^V600E inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds 12, 15, and 17 demonstrated strong antiproliferative activity with GI₅₀ values of 1.05 µM, 1.50 µM, and 1.20 µM, respectively. Hybrids showed dual inhibition of EGFR and BRAF^V600E. Compounds 12, 15, and 17 inhibited EGFR-like erlotinib and exhibited promising anticancer activity. Compound 12 is the most potent inhibitor of cancer cell proliferation and BRAF^V600E. Compounds 12 and 17 induced apoptosis by increasing caspase 3, 8, and Bax levels, and resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that compounds 12, 15, and 17 have the potential to be dual EGFR/BRAF^V600E inhibitors. Additionally, in silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and adverse effects. DFT studies for the two most active compounds, 12 and 15, were also carried out. The values of the HOMO and LUMO energies, as well as softness and hardness, were computationally investigated using the DFT method. These findings agreed well with those of the in vitro research and molecular docking study. Full article

(This article belongs to the Special Issue Recent Advances: Heterocycles in Drugs and Drug Discovery)

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15 pages, 5504 KiB

Open AccessArticle

Translocation of Methionine Adenosyl Transferase MAT2A and Its Prognostic Relevance for Liver Hepatocellular Carcinoma

by Pei-Yi Chu, Dev-Aur Chou, Po-Ming Chen and En-Pei Isabel Chiang

Int. J. Mol. Sci. 2023, 24(10), 9103; https://doi.org/10.3390/ijms24109103 - 22 May 2023

Viewed by 1992

Abstract

Methionine adenosyl transferases (MATs) catalyze the synthesis of the biological methyl donor adenosylmethionine (SAM). Dysregulation of MATs has been associated with carcinogenesis in humans. We previously found that downregulation of the MAT1A gene enriches the protein-associated translation process and worsens liver hepatocellular carcinoma [...] Read more.

Methionine adenosyl transferases (MATs) catalyze the synthesis of the biological methyl donor adenosylmethionine (SAM). Dysregulation of MATs has been associated with carcinogenesis in humans. We previously found that downregulation of the MAT1A gene enriches the protein-associated translation process and worsens liver hepatocellular carcinoma (LIHC) prognosis. We also discovered that subcellular localization of the MAT2A protein has independently prognostic relevance in breast cancer patients. The present study aimed to examined the clinical relevance of MAT2A translocation in human LIHC. Essential methionine cycle gene expressions in TCGA LIHC datasets were analyzed using Gene Expression Profiling Interactive Analysis 2 (GEPIA2). The protein expression pattern of MAT2A was determined in the tissue array of our own LIHC cohort (n = 261) using immuno-histochemistry, and the prognostic relevance of MAT2A protein’s subcellular localization expression was examined using Kaplan–Meier survival curves. LIHC patients with higher MAT2A mRNA expression had a worse survival rate (p = 0.0083). MAT2A protein immunoreactivity was observed in both cytoplasm and nucleus fractions in the tissue array. Tumor tissues had elevated MAT2A protein expression in both cytoplasm and nucleus compared to their adjacent normal tissues. A higher cytoplasmic to nuclear MAT2A protein expression ratio (C/N) was found in female LIHC patients compared to that of male patients (p = 0.047). Kaplan–Meier survival curves showed that a lower MAT2A C/N correlated with poor overall survival in female LIHC patients (10-year survival rate: 29.2% vs. 68.8%, C/N ≤ 1.0 vs. C/N > 1.0, log-rank p = 0.004). Moreover, we found that specificity protein 1 (SP1) may have a potential interaction with nuclear MAT2A protein, using protein–protein interaction; this we found using the GeneMANIA algorithm. We explored the possible protective effects of the estrogen axis in LIHC using the Human Protein Atlas (HPA), and found evidence supporting a possible protective effect of estrogen-related protein ESSRG in LIHC. The localization of SP1 and MAT2 appeared to be inversely associated with ESRRG expression in LIHC. The present study demonstrated the translocation of MAT2A and its prognostic relevance in female LIHC patients. Our findings suggest the potential of estrogen in SP1 regulation and localization of MAT2A, as therapeutic modalities against in female LIHC patients. Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology)

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15 pages, 2393 KiB

Open AccessArticle

Unveiling the Stereoselectivity and Regioselectivity of the [3+2] Cycloaddition Reaction between N-methyl-C-4-methylphenyl-nitrone and 2-Propynamide from a MEDT Perspective

by Sabir A. Mohammed Salih, Huda A. Basheer, Jesus Vicente de Julián-Ortiz and Haydar A. Mohammad-Salim

Int. J. Mol. Sci. 2023, 24(10), 9102; https://doi.org/10.3390/ijms24109102 - 22 May 2023

Cited by 1 | Viewed by 1247

Abstract

[3+2] cycloaddition reactions play a crucial role in synthesizing complex organic molecules and have significant applications in drug discovery and materials science. In this study, the [3+2] cycloaddition (32CA) reactions of N-methyl-C-4-methyl phenyl-nitrone 1 and 2-propynamide 2, which have not been extensively [...] Read more.

[3+2] cycloaddition reactions play a crucial role in synthesizing complex organic molecules and have significant applications in drug discovery and materials science. In this study, the [3+2] cycloaddition (32CA) reactions of N-methyl-C-4-methyl phenyl-nitrone 1 and 2-propynamide 2, which have not been extensively studied before, were investigated using molecular electron density theory (MEDT) at the B3LYP/6–311++G(d,p) level of theory. According to an electron localization function (ELF) study, N-methyl-C-4-methyl phenyl-nitrone 1 is a zwitterionic species with no pseudoradical or carbenoid centers. Conceptual density functional theory (CDFT) indices were used to predict the global electronic flux from the strong nucleophilic N-methyl-C-4-methyl phenylnitrone 1 to the electrophilic 2-propynamide 2 functions. The 32CA reactions proceeded through two pairs of stereo- and regioisomeric reaction pathways to generate four different products: 3, 4, 5, and 6. The reaction pathways were irreversible owing to their exothermic characters: −136.48, −130.08, −130.99, and −140.81 kJ mol⁻¹, respectively. The enthalpy of the 32CA reaction leading to the formation of cycloadduct 6 was lower compared with the other path owing to a slight increase in its polar character, observed through the global electron density transfer (GEDT) during the transition states and along the reaction path. A bonding evolution theory (BET) analysis showed that these 32CA reactions proceed through the coupling of pseudoradical centers, and the formation of new C-C and C-O covalent bonds did not begin in the transition states. Full article

(This article belongs to the Topic Theoretical, Quantum and Computational Chemistry)

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24 pages, 4601 KiB

Open AccessArticle

Plasmatic MicroRNAs and Treatment Outcomes of Patients with Metastatic Castration-Resistant Prostate Cancer: A Hospital-Based Cohort Study and In Silico Analysis

by Jani Silva, Valéria Tavares, Ana Afonso, Juliana Garcia, Fátima Cerqueira and Rui Medeiros

Int. J. Mol. Sci. 2023, 24(10), 9101; https://doi.org/10.3390/ijms24109101 - 22 May 2023

Cited by 3 | Viewed by 1685

Abstract

Prostate cancer (PCa) is one of the most common malignancies among men worldwide. Inevitably, all advanced PCa patients develop metastatic castration-resistant prostate cancer (mCRPC), an aggressive phase of the disease. Treating mCRPC is challenging, and prognostic tools are needed for disease management. MicroRNA [...] Read more.

Prostate cancer (PCa) is one of the most common malignancies among men worldwide. Inevitably, all advanced PCa patients develop metastatic castration-resistant prostate cancer (mCRPC), an aggressive phase of the disease. Treating mCRPC is challenging, and prognostic tools are needed for disease management. MicroRNA (miRNA) deregulation has been reported in PCa, constituting potential non-invasive prognostic biomarkers. As such, this study aimed to evaluate the prognostic potential of nine miRNAs in the liquid biopsies (plasma) of mCRPC patients treated with second-generation androgen receptor axis-targeted (ARAT) agents, abiraterone acetate (AbA) and enzalutamide (ENZ). Low expression levels of miR-16-5p and miR-145-5p in mCRPC patients treated with AbA were significantly associated with lower progression-free survival (PFS). The two miRNAs were the only predictors of the risk of disease progression in AbA-stratified analyses. Low miR-20a-5p levels in mCRPC patients with Gleason scores of <8 were associated with worse overall survival (OS). The transcript seems to predict the risk of death regardless of the ARAT agent. According to the in silico analyses, miR-16-5p, miR-145-5p, and miR-20a-5p seem to be implicated in several processes, namely, cell cycle, proliferation, migration, survival, metabolism, and angiogenesis, suggesting an epigenetic mechanism related to treatment outcome. These miRNAs may represent attractive prognostic tools to be used in mCRPC management, as well as a step further in the identification of new potential therapeutic targets, to use in combination with ARAT for an improved treatment outcome. Despite the promising results, real-world validation is necessary. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment)

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25 pages, 6917 KiB

Open AccessArticle

Friunavirus Phage-Encoded Depolymerases Specific to Different Capsular Types of Acinetobacter baumannii

by Olga Y. Timoshina, Anastasia A. Kasimova, Mikhail M. Shneider, Ilya O. Matyuta, Alena Y. Nikolaeva, Peter V. Evseev, Nikolay P. Arbatsky, Alexander S. Shashkov, Alexander O. Chizhov, Andrey A. Shelenkov, Yulia V. Mikhaylova, Pavel V. Slukin, Nikolay V. Volozhantsev, Konstantin M. Boyko, Yuriy A. Knirel, Konstantin A. Miroshnikov and Anastasia V. Popova

Int. J. Mol. Sci. 2023, 24(10), 9100; https://doi.org/10.3390/ijms24109100 - 22 May 2023

Cited by 4 | Viewed by 1738

Abstract

Acinetobacter baumannii is a critical priority nosocomial pathogen that produces a variety of capsular polysaccharides (CPSs), the primary receptors for specific depolymerase-carrying phages. In this study, the tailspike depolymerases (TSDs) encoded in genomes of six novel Friunaviruses, APK09, APK14, APK16, APK86, APK127v, APK128, [...] Read more.

Acinetobacter baumannii is a critical priority nosocomial pathogen that produces a variety of capsular polysaccharides (CPSs), the primary receptors for specific depolymerase-carrying phages. In this study, the tailspike depolymerases (TSDs) encoded in genomes of six novel Friunaviruses, APK09, APK14, APK16, APK86, APK127v, APK128, and one previously described Friunavirus phage, APK37.1, were characterized. For all TSDs, the mechanism of specific cleavage of corresponding A. baumannii capsular polysaccharides (CPSs) was established. The structures of oligosaccharide fragments derived from K9, K14, K16, K37/K3-v1, K86, K127, and K128 CPSs degradation by the recombinant depolymerases have been determined. The crystal structures of three of the studied TSDs were obtained. A significant reduction in mortality of Galleria mellonella larvae infected with A. baumannii of K9 capsular type was shown in the example of recombinant TSD APK09_gp48. The data obtained will provide a better understanding of the interaction of phage–bacterial host systems and will contribute to the formation of principles of rational usage of lytic phages and phage-derived enzymes as antibacterial agents. Full article

(This article belongs to the Special Issue Bacteriophage: Molecular Ecology and Pharmacology)

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21 pages, 6019 KiB

Open AccessArticle

Metabolomic Analysis of the Response of Haloxylon ammodendron and Haloxylon persicum to Drought

by Fang Yang and Guanghui Lv

Int. J. Mol. Sci. 2023, 24(10), 9099; https://doi.org/10.3390/ijms24109099 - 22 May 2023

Cited by 4 | Viewed by 1145

Abstract

Haloxylon ammodendron and Haloxylon persicum, as typical desert plants in arid areas, show strong drought tolerance and environmental adaptability and are therefore ideal model plants for studying the molecular mechanisms of drought tolerance. A metabolomic analysis of H. ammodendron and H. persicum [...] Read more.

Haloxylon ammodendron and Haloxylon persicum, as typical desert plants in arid areas, show strong drought tolerance and environmental adaptability and are therefore ideal model plants for studying the molecular mechanisms of drought tolerance. A metabolomic analysis of H. ammodendron and H. persicum in their natural environment is lacking, and their metabolic response to drought therefore remains unclear. To elucidate the response of H. ammodendron and H. persicum to drought at the metabolic level, a non-targeted metabolomics analysis was carried out herein. Under a dry environment, H. ammodendron exhibited 296 and 252 differentially expressed metabolites (DEMs) in the positive and negative ion modes, respectively, whereas 452 and 354 DEMs were identified in the positive and negative ion modes in H. persicum, respectively. The results indicated that H. ammodendron responds to drought by increasing the content of organic nitrogen compounds and lignans, neolignans, and related compounds, and reducing the content of alkaloids and derivatives. By contrast, H. persicum adapts to the dry environment by increasing the content of organic acids and their derivatives and reducing the content of lignans, neolignans, and related compounds. In addition, H. ammodendron and H. persicum improved their osmoregulation ability, reactive oxygen species detoxification ability, and cell membrane stability by regulating the key metabolic pathways and anabolism of associated metabolites. This is the first metabolomics report on the response of H. ammodendron and H. persicum to drought in their natural environment, providing a foundation for the further study of their regulatory mechanisms under drought stress. Full article

(This article belongs to the Special Issue Drought Stress Tolerance in Plants in 2022)

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30 pages, 7929 KiB

Open AccessReview

“ThermoTRP” Channel Expression in Cancers: Implications for Diagnosis and Prognosis (Practical Approach by a Pathologist)

by Arpad Szallasi

Int. J. Mol. Sci. 2023, 24(10), 9098; https://doi.org/10.3390/ijms24109098 - 22 May 2023

Cited by 2 | Viewed by 1640

Abstract

Temperature-sensitive transient receptor potential (TRP) channels (so-called “thermoTRPs”) are multifunctional signaling molecules with important roles in cell growth and differentiation. Several “thermoTRP” channels show altered expression in cancers, though it is unclear if this is a cause or consequence of the disease. Regardless [...] Read more.

Temperature-sensitive transient receptor potential (TRP) channels (so-called “thermoTRPs”) are multifunctional signaling molecules with important roles in cell growth and differentiation. Several “thermoTRP” channels show altered expression in cancers, though it is unclear if this is a cause or consequence of the disease. Regardless of the underlying pathology, this altered expression may potentially be used for cancer diagnosis and prognostication. “ThermoTRP” expression may distinguish between benign and malignant lesions. For example, TRPV1 is expressed in benign gastric mucosa, but is absent in gastric adenocarcinoma. TRPV1 is also expressed both in normal urothelia and non-invasive papillary urothelial carcinoma, but no TRPV1 expression has been seen in invasive urothelial carcinoma. “ThermoTRP” expression can also be used to predict clinical outcomes. For instance, in prostate cancer, TRPM8 expression predicts aggressive behavior with early metastatic disease. Furthermore, TRPV1 expression can dissect a subset of pulmonary adenocarcinoma patients with bad prognosis and resistance to a number of commonly used chemotherapeutic agents. This review will explore the current state of this rapidly evolving field with special emphasis on immunostains that can already be added to the armoire of diagnostic pathologists. Full article

(This article belongs to the Special Issue TRP Channels in Cancer: New Avenues for Diagnosis, Prognostication, and Therapy)

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49 pages, 15227 KiB

Open AccessReview

Heterocyclic Compounds as Synthetic Tyrosinase Inhibitors: Recent Advances

by Serena Vittorio, Christian Dank and Laura Ielo

Int. J. Mol. Sci. 2023, 24(10), 9097; https://doi.org/10.3390/ijms24109097 - 22 May 2023

Cited by 7 | Viewed by 1765

Abstract

Tyrosinase is a copper-containing enzyme which is widely distributed in nature (e.g., bacteria, mammals, fungi) and involved in two consecutive steps of melanin biosynthesis. In humans, an excessive production of melanin can determine hyperpigmentation disorders as well as neurodegenerative processes in Parkinson’s disease. [...] Read more.

Tyrosinase is a copper-containing enzyme which is widely distributed in nature (e.g., bacteria, mammals, fungi) and involved in two consecutive steps of melanin biosynthesis. In humans, an excessive production of melanin can determine hyperpigmentation disorders as well as neurodegenerative processes in Parkinson’s disease. The development of molecules able to inhibit the high activity of the enzyme remain a current topic in medicinal chemistry, because the inhibitors reported so far present several side effects. Heterocycle-bearing molecules are largely diffuse in this sense. Due to their importance as biologically active compounds, we decided to report a comprehensive review of synthetic tyrosinase inhibitors possessing heterocyclic moieties reported within the last five years. For the reader’s convenience, we classified them as inhibitors of mushroom tyrosinase (Agaricus bisporus) and human tyrosinase. Full article

(This article belongs to the Special Issue The Role of Tyrosinase in Human Health and Disease)

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18 pages, 2451 KiB

Open AccessReview

Markers of Restenosis after Percutaneous Transluminal Balloon Angioplasty in Patients with Critical Limb Ischemia

by Elvira V. Sobolevskaya, Oleg A. Shumkov, Mikhail A. Smagin, Andrey E. Guskov, Alexandra V. Malysheva, Victor V. Atuchin and Vadim V. Nimaev

Int. J. Mol. Sci. 2023, 24(10), 9096; https://doi.org/10.3390/ijms24109096 - 22 May 2023

Cited by 1 | Viewed by 1699

Abstract

Among cardiovascular diseases, chronic obliterating lesions of the arteries of lower extremities, which are one of the important problems of modern healthcare, are distinguished. In most cases, the cause of damage to the arteries of lower extremities is atherosclerosis. The most severe form [...] Read more.

Among cardiovascular diseases, chronic obliterating lesions of the arteries of lower extremities, which are one of the important problems of modern healthcare, are distinguished. In most cases, the cause of damage to the arteries of lower extremities is atherosclerosis. The most severe form is chronic ischemia, characterized by pain at rest and ischemic ulcers, ultimately increasing the risk of limb loss and cardiovascular mortality. Therefore, patients with critical limb ischemia need limb revascularization. Percutaneous transluminal balloon angioplasty is one of the least invasive and safe approaches, with advantages for patients with comorbidities. However, after this procedure, restenosis is still possible. Early detection of changes in the composition of some molecules as markers of restenosis will help screen patients at the risk of restenosis, as well as find ways to apply efforts for further directions of inhibition of this process. The purpose of this review is to provide the most important and up-to-date information on the mechanisms of restenosis development, as well as possible predictors of their occurrence. The information collected in this publication may be useful in predicting outcomes after surgical treatment and will also find new ways for the target implication to the mechanisms of development of restenosis and atherosclerosis. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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18 pages, 2968 KiB

Open AccessArticle

Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of Drosophila melanogaster

by Yulia S. Vershinina, George S. Krasnov, David G. Garbuz, Mikhail V. Shaposhnikov, Maria S. Fedorova, Elena A. Pudova, Irina V. Katunina, Alexey B. Kornev, Nadezhda V. Zemskaya, Alexander A. Kudryavtsev, Elizaveta V. Bulavkina, Anna A. Matveeva, Natalia S. Ulyasheva, Zulfiya G. Guvatova, Artemiy A. Anurov, Alexey A. Moskalev and Anna V. Kudryavtseva

Int. J. Mol. Sci. 2023, 24(10), 9095; https://doi.org/10.3390/ijms24109095 - 22 May 2023

Viewed by 1763

Abstract

Torin-2, a synthetic compound, is a highly selective inhibitor of both TORC1 and TORC2 (target of rapamycin) complexes as an alternative to the well-known immunosuppressor, geroprotector, and potential anti-cancer natural compound rapamycin. Torin-2 is effective at hundreds of times lower concentrations and prevents [...] Read more.

Torin-2, a synthetic compound, is a highly selective inhibitor of both TORC1 and TORC2 (target of rapamycin) complexes as an alternative to the well-known immunosuppressor, geroprotector, and potential anti-cancer natural compound rapamycin. Torin-2 is effective at hundreds of times lower concentrations and prevents some negative side effects of rapamycin. Moreover, it inhibits the rapamycin-resistant TORC2 complex. In this work, we evaluated transcriptomic changes in D. melanogaster heads induced with lifetime diets containing Torin-2 and suggested possible neuroprotective mechanisms of Torin-2. The analysis included D. melanogaster of three ages (2, 4, and 6 weeks old), separately for males and females. Torin-2, taken at the lowest concentration being tested (0.5 μM per 1 L of nutrient paste), had a slight positive effect on the lifespan of D. melanogaster males (+4% on the average) and no positive effect on females. At the same time, RNA-Seq analysis revealed interesting and previously undiscussed effects of Torin-2, which differed between sexes as well as in flies of different ages. Among the cellular pathways mostly altered by Torin-2 at the gene expression level, we identified immune response, protein folding (heat shock proteins), histone modification, actin cytoskeleton organization, phototransduction and sexual behavior. Additionally, we revealed that Torin-2 predominantly reduced the expression of Srr gene responsible for the conversion of L-serine to D-serine and thus regulating activity of NMDA receptor. Via western blot analysis, we showed than in old males Torin-2 tends to increase the ratio of the active phosphorylated form of ERK, the lowest node of the MAPK cascade, which may play a significant role in neuroprotection. Thus, the complex effect of Torin-2 may be due to the interplay of the immune system, hormonal background, and metabolism. Our work is of interest for further research in the field of NMDA-mediated neurodegeneration. Full article

(This article belongs to the Section Molecular Neurobiology)

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15 pages, 3044 KiB

Open AccessReview

A Promising Needle-Free Pyro-Drive Jet Injector for Augmentation of Immunity by Intradermal Injection as a Physical Adjuvant

by Jukito Sonoda, Izuru Mizoguchi, Shinya Inoue, Aruma Watanabe, Ami Sekine, Miu Yamagishi, Satomi Miyakawa, Natsuki Yamaguchi, Eri Horio, Yasuhiro Katahira, Hideaki Hasegawa, Takashi Hasegawa, Kunihiko Yamashita and Takayuki Yoshimoto

Int. J. Mol. Sci. 2023, 24(10), 9094; https://doi.org/10.3390/ijms24109094 - 22 May 2023

Cited by 2 | Viewed by 2723

Abstract

Current worldwide mRNA vaccination against SARS-CoV-2 by intramuscular injection using a needled syringe has greatly protected numerous people from COVID-19. An intramuscular injection is generally well tolerated, safer and easier to perform on a large scale, whereas the skin has the benefit of [...] Read more.

Current worldwide mRNA vaccination against SARS-CoV-2 by intramuscular injection using a needled syringe has greatly protected numerous people from COVID-19. An intramuscular injection is generally well tolerated, safer and easier to perform on a large scale, whereas the skin has the benefit of the presence of numerous immune cells, such as professional antigen-presenting dendritic cells. Therefore, intradermal injection is considered superior to intramuscular injection for the induction of protective immunity, but more proficiency is required for the injection. To improve these issues, several different types of more versatile jet injectors have been developed to deliver DNAs, proteins or drugs by high jet velocity through the skin without a needle. Among them, a new needle-free pyro-drive jet injector has a unique characteristic that utilizes gunpower as a mechanical driving force, in particular, bi-phasic pyrotechnics to provoke high jet velocity and consequently the wide dispersion of the injected DNA solution in the skin. A significant amount of evidence has revealed that it is highly effective as a vaccinating tool to induce potent protective cellular and humoral immunity against cancers and infectious diseases. This is presumably explained by the fact that shear stress generated by the high jet velocity facilitates the uptake of DNA in the cells and, consequently, its protein expression. The shear stress also possibly elicits danger signals which, together with the plasmid DNA, subsequently induces the activation of innate immunity including dendritic cell maturation, leading to the establishment of adaptive immunity. This review summarizes the recent advances in needle-free jet injectors to augment the cellular and humoral immunity by intradermal injection and the possible mechanism of action. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Immunotherapies)

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14 pages, 1492 KiB

Open AccessReview

Molecular and Genetics-Based Systems for Tracing the Evolution and Exploring the Mechanisms of Human Norovirus Infections

by Sheng-Chieh Lin, Geng-Hao Bai, Pei-Chun Lin, Chung-Yung Chen, Yi-Hsiang Hsu, Yuan-Chang Lee and Shih-Yen Chen

Int. J. Mol. Sci. 2023, 24(10), 9093; https://doi.org/10.3390/ijms24109093 - 22 May 2023

Viewed by 1791

Abstract

Human noroviruses (HuNoV) are major causes of acute gastroenteritis around the world. The high mutation rate and recombination potential of noroviruses are significant challenges in studying the genetic diversity and evolution pattern of novel strains. In this review, we describe recent advances in [...] Read more.

Human noroviruses (HuNoV) are major causes of acute gastroenteritis around the world. The high mutation rate and recombination potential of noroviruses are significant challenges in studying the genetic diversity and evolution pattern of novel strains. In this review, we describe recent advances in the development of technologies for not only the detection but also the analysis of complete genome sequences of noroviruses and the future prospects of detection methods for tracing the evolution and genetic diversity of human noroviruses. The mechanisms of HuNoV infection and the development of antiviral drugs have been hampered by failure to develop the infectious virus in a cell model. However, recent studies have demonstrated the potential of reverse genetics for the recovery and generation of infectious viral particles, suggesting the utility of this genetics-based system as an alternative for studying the mechanisms of viral infection, such as cell entry and replication. Full article

(This article belongs to the Special Issue Molecular Advances in Infectious Disease)

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25 pages, 7140 KiB

Open AccessArticle

Single-Cell RNA-Seq Analysis Reveals Ferroptosis in the Tumor Microenvironment of Clear Cell Renal Cell Carcinoma

by Jing Zhang, Yun Deng, Hui Zhang, Zhiyuan Zhang, Xin Jin, Yan Xuan, Zhen Zhang and Xuejun Ma

Int. J. Mol. Sci. 2023, 24(10), 9092; https://doi.org/10.3390/ijms24109092 - 22 May 2023

Viewed by 1932

Abstract

In this study, we investigated the role of ferroptosis in the tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC), the leading cause of renal cancer-related death. We analyzed single-cell data from seven ccRCC cases to determine cell types most correlated with [...] Read more.

In this study, we investigated the role of ferroptosis in the tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC), the leading cause of renal cancer-related death. We analyzed single-cell data from seven ccRCC cases to determine cell types most correlated with ferroptosis and performed pseudotime analysis on three myeloid subtypes. We identified 16 immune-related ferroptosis genes (IRFGs) by analyzing differentially expressed genes between cell subgroups and between high and low immune infiltration groups in the TCGA-KIRC dataset and the FerrDb V2 database. Using univariate and multivariate Cox regression, we identified two independent prognostic genes, AMN and PDK4, and constructed an IRFG score model immune-related ferroptosis genes risk score (IRFGRs) to evaluate its prognostic value in ccRCC. The IRFGRs demonstrated excellent and stable performance for predicting ccRCC patient survival in both the TCGA training set and the ArrayExpress validation set, with an AUC range of 0.690–0.754, outperforming other commonly used clinicopathological indicators. Our findings enhance the understanding of TME infiltration with ferroptosis and identify immune-mediated ferroptosis genes associated with prognosis in ccRCC. Full article

(This article belongs to the Special Issue Tumor Microenvironment: Molecular Mechanism and Signaling Pathway Involved in Cancer Metastasis)

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17 pages, 1913 KiB

Open AccessArticle

Eosinophil Granule Proteins Involvement in Acute Appendicitis—An Allergic Disease?

by Nuno Carvalho, Elisabete Carolino, Hélder Coelho, Ana Lúcia Barreira, Luísa Moreira, Margarida André, Susana Henriques, Carlos Cardoso, Luis Moita and Paulo Matos Costa

Int. J. Mol. Sci. 2023, 24(10), 9091; https://doi.org/10.3390/ijms24109091 - 22 May 2023

Cited by 2 | Viewed by 1369

Abstract

Several pieces of evidence point to an allergic component as a trigger of acute appendicitis. As the Th2 immune response is characterized by eosinophil mobilization to the target organ and release of their cationic granule proteins, it is reasonable to investigate if the [...] Read more.

Several pieces of evidence point to an allergic component as a trigger of acute appendicitis. As the Th2 immune response is characterized by eosinophil mobilization to the target organ and release of their cationic granule proteins, it is reasonable to investigate if the degranulation of eosinophils could be associated with the local injury. The primary aim of this study is to evaluate the participation of eosinophils granules proteins in acute appendicitis, both at local and systemic levels and the secondary aim is to evaluate the diagnostic accuracy of eosinophils granules proteins for the detection of acute appendicitis, as well as for distinguishing between complicated and uncomplicated acute appendicitis. Eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP) and eosinophil peroxidase (EP) are the most well-known eosinophil granule proteins. From August 2021 to April 2022, we present a prospective single-center study to evaluate the EDN, ECP, and EP concentrations simultaneously in appendicular lavage fluid (ALF) and the serum of 22 patients with acute phlegmonous appendicitis (APA), 24 with acute gangrenous appendicitis (AGA), and 14 normal controls. Concerning EDN, no differences were found between groups. ECP concentrations in ALF and serum were significantly higher in the histologically confirmed acute appendicitis compared to the control groups (p < 0.0001 and p < 0.0001, respectively). In ALF, no differences were found between ECP levels in APA: 38.85 ng/mL (IQR 26.50–51.77) and AGA 51.55 ng/mL (IQR 39.55–70.09) groups (p = 0.176). In the serum, no difference was found between ECP levels at APA: 39 ng/mL (IQR 21.30–56.90) and AGA: 51.30 ng/mL (IQR 20.25–62.59) (p = 0.100). For EP, the concentrations in ALF (p < 0.001) and serum (p < 0.001) were both higher in acute appendicitis compared to the control. In ALF, no difference was found between APA: 240.28 ng/mL (IQR 191.2–341.3) and AGA: 302.5 (IQR 227.7–535.85) (p = 0.236). In the serum, no differences were found between APA: 158.4 ng/mL (IQR 111.09–222.1) and AGA: 235.27 (IQR 192.33–262.51) (p = 0.179). Globally, the ALF concentrations were higher than serum concentrations, reflecting an intense inflammatory local reaction in AA. The optimal ECP cut-off for discriminating between acute appendicitis and the controls was >11.41 ng/mL, with a sensitivity of 93.5%, but with a specificity for identifying appendicitis of 21.4%, good discriminative power (AUC = 0.880). For EP, the optimal cut-off was >93.20 ng/mL, with a sensitivity of 87%, but with a specificity of 14.3% (AUC = 0.901), excellent discriminative power. For the diagnosis of perforated AA, the discriminative power of ECP and EP serum concentrations are weak (AUC = 0.562 and AUC = 0.664, respectively). Concerning the presence of peritonitis, the discriminative power of ECP and EP serum concentrations is acceptable, respectively: AUC = 0.724 and AUC = 0.735. Serum levels of EDN (p = 0.119), ECP (p = 0.586) and EP (p = 0.08) in complicated appendicitis were similar to uncomplicated appendicitis. Serum concentrations of ECP and EP can be added to decision-making AA diagnosis. A Th2-type immune response is present in AA. These data bring forward the role of an allergic reaction in the pathogenesis of acute appendicitis. Full article

(This article belongs to the Collection Feature Papers in “Molecular Biology”)

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16 pages, 4598 KiB

Open AccessArticle

Stability of Human Telomeric G-Quadruplexes Complexed with Photosensitive Ligands and Irradiated with Visible Light

by Valeria Libera, Francesca Ripanti, Caterina Petrillo, Francesco Sacchetti, Javier Ramos-Soriano, Maria Carmen Galan, Giorgio Schirò, Alessandro Paciaroni and Lucia Comez

Int. J. Mol. Sci. 2023, 24(10), 9090; https://doi.org/10.3390/ijms24109090 - 22 May 2023

Cited by 1 | Viewed by 1368

Abstract

Guanine-rich DNA sequences can fold into non-canonical nucleic acid structures called G-quadruplexes (G4s). These nanostructures have strong implications in many fields, from medical science to bottom-up nanotechnologies. As a result, ligands interacting with G4s have attracted great attention as candidates in medical therapies, [...] Read more.

Guanine-rich DNA sequences can fold into non-canonical nucleic acid structures called G-quadruplexes (G4s). These nanostructures have strong implications in many fields, from medical science to bottom-up nanotechnologies. As a result, ligands interacting with G4s have attracted great attention as candidates in medical therapies, molecular probe applications, and biosensing. In recent years, the use of G4-ligand complexes as photopharmacological targets has shown significant promise for developing novel therapeutic strategies and nanodevices. Here, we studied the possibility of manipulating the secondary structure of a human telomeric G4 sequence through the interaction with two photosensitive ligands, DTE and TMPyP4, whose response to visible light is different. The effect of these two ligands on G4 thermal unfolding was also considered, revealing the occurrence of peculiar multi-step melting pathways and the different attitudes of the two molecules on the quadruplex stabilization. Full article

(This article belongs to the Special Issue The Polymorphic World of G-Quadruplexes: From Structural Insights to Functional Activity 3.0)

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18 pages, 5120 KiB

Open AccessArticle

Citric Acid Confers Broad Antibiotic Tolerance through Alteration of Bacterial Metabolism and Oxidative Stress

by Xue-Song Li, Jun-Ze Xue, Yu Qi, Inam Muhammad, Hao Wang, Xuan-Yu Li, Yi-Jia Luo, Dao-Mi Zhu, Yun-Hang Gao, Ling-Cong Kong and Hong-Xia Ma

Int. J. Mol. Sci. 2023, 24(10), 9089; https://doi.org/10.3390/ijms24109089 - 22 May 2023

Cited by 3 | Viewed by 2715

Abstract

Antibiotic tolerance has become an increasingly serious crisis that has seriously threatened global public health. However, little is known about the exogenous factors that can trigger the development of antibiotic tolerance, both in vivo and in vitro. Herein, we found that the addition [...] Read more.

Antibiotic tolerance has become an increasingly serious crisis that has seriously threatened global public health. However, little is known about the exogenous factors that can trigger the development of antibiotic tolerance, both in vivo and in vitro. Herein, we found that the addition of citric acid, which is used in many fields, obviously weakened the bactericidal activity of antibiotics against various bacterial pathogens. This mechanistic study shows that citric acid activated the glyoxylate cycle by inhibiting ATP production in bacteria, reduced cell respiration levels, and inhibited the bacterial tricarboxylic acid cycle (TCA cycle). In addition, citric acid reduced the oxidative stress ability of bacteria, which led to an imbalance in the bacterial oxidation–antioxidant system. These effects together induced the bacteria to produce antibiotic tolerance. Surprisingly, the addition of succinic acid and xanthine could reverse the antibiotic tolerance induced by citric acid in vitro and in animal infection models. In conclusion, these findings provide new insights into the potential risks of citric acid usage and the relationship between antibiotic tolerance and bacterial metabolism. Full article

(This article belongs to the Section Molecular Microbiology)

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24 pages, 772 KiB

Open AccessReview

Parkinson’s Disease: Exploring Different Animal Model Systems

by Engila Khan, Ikramul Hasan and M. Emdadul Haque

Int. J. Mol. Sci. 2023, 24(10), 9088; https://doi.org/10.3390/ijms24109088 - 22 May 2023

Cited by 4 | Viewed by 2003

Abstract

Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease, experimental models are required to replicate the disease process. Due to the huge diversity in pathophysiology and prognosis [...] Read more.

Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease, experimental models are required to replicate the disease process. Due to the huge diversity in pathophysiology and prognosis in different diseases, animal modeling is customized and specific accordingly. As in other neurodegenerative diseases, Parkinson’s disease is a progressive disorder coupled with varying forms of physical and mental disabilities. The pathological hallmarks of Parkinson’s disease are associated with the accumulation of misfolded protein called α-synuclein as Lewy body, and degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) area affecting the patient’s motor activity. Extensive research has already been conducted regarding animal modeling of Parkinson’s diseases. These include animal systems with induction of Parkinson’s, either pharmacologically or via genetic manipulation. In this review, we will be summarizing and discussing some of the commonly employed Parkinson’s disease animal model systems and their applications and limitations. Full article

(This article belongs to the Special Issue Model Animals in Human Diseases)

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20 pages, 819 KiB

Open AccessReview

Gut Microbiota and Cardiovascular Disease: Evidence on the Metabolic and Inflammatory Background of a Complex Relationship

by Antonio Nesci, Claudia Carnuccio, Vittorio Ruggieri, Alessia D’Alessandro, Angela Di Giorgio, Luca Santoro, Antonio Gasbarrini, Angelo Santoliquido and Francesca Romana Ponziani

Int. J. Mol. Sci. 2023, 24(10), 9087; https://doi.org/10.3390/ijms24109087 - 22 May 2023

Cited by 14 | Viewed by 3365

Abstract

Several studies in recent years have demonstrated that gut microbiota–host interactions play an important role in human health and disease, including inflammatory and cardiovascular diseases. Dysbiosis has been linked to not only well-known inflammatory diseases, such as inflammatory bowel diseases, rheumatoid arthritis, and [...] Read more.

Several studies in recent years have demonstrated that gut microbiota–host interactions play an important role in human health and disease, including inflammatory and cardiovascular diseases. Dysbiosis has been linked to not only well-known inflammatory diseases, such as inflammatory bowel diseases, rheumatoid arthritis, and systemic lupus erythematous, but also to cardiovascular risk factors, such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. The ways the microbiota is involved in modulating cardiovascular risk are multiple and not only related to inflammatory mechanisms. Indeed, human and the gut microbiome cooperate as a metabolically active superorganism, and this affects host physiology through metabolic pathways. In turn, congestion of the splanchnic circulation associated with heart failure, edema of the intestinal wall, and altered function and permeability of the intestinal barrier result in the translocation of bacteria and their products into the systemic circulation, further enhancing the pro-inflammatory conditions underlying cardiovascular disorders. The aim of the present review is to describe the complex interplay between gut microbiota, its metabolites, and the development and evolution of cardiovascular diseases. We also discuss the possible interventions intended to modulate the gut microbiota to reduce cardiovascular risk. Full article

(This article belongs to the Special Issue Gut Microbiota–Host Interactions: From Symbiosis to Dysbiosis 2.0)

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20 pages, 2063 KiB

Open AccessArticle

Modulation of Gut Microbiome in Ecstasy/MDMA-Induced Behavioral and Biochemical Impairment in Rats and Potential of Post-Treatment with Anacyclus pyrethrum L. Aqueous Extract to Mitigate Adverse Effects

by Abdelmounaim Baslam, Abdelfatah Aitbaba, Asmae Lamrani Hanchi, Zakaria Tazart, Rachida Aboufatima, Nabila Soraa, Mohamed Ait-El-Mokhtar, Samia Boussaa, Marouane Baslam and Abderrahman Chait

Int. J. Mol. Sci. 2023, 24(10), 9086; https://doi.org/10.3390/ijms24109086 - 22 May 2023

Cited by 8 | Viewed by 2660

Abstract

The use of illicit substances continues to pose a substantial threat to global health, affecting millions of individuals annually. Evidence suggests the existence of a ‘brain–gut axis’ as the involving connection between the central nervous system and gut microbiome (GM). Dysbiosis of the [...] Read more.

The use of illicit substances continues to pose a substantial threat to global health, affecting millions of individuals annually. Evidence suggests the existence of a ‘brain–gut axis’ as the involving connection between the central nervous system and gut microbiome (GM). Dysbiosis of the GM has been associated with the pathogenesis of various chronic diseases, including metabolic, malignant, and inflammatory conditions. However, little is currently known about the involvement of this axis in modulating the GM in response to psychoactive substances. In this study, we investigated the effect of MDMA (3,4-methylenedioxymethamphetamine, “Ecstasy”)-dependence on the behavioral and biochemical responses, and the diversity and abundance of the gut microbiome in rats post-treated (or not) with aqueous extract of Anacyclus pyrethrum (AEAP), which has been reported to exhibit anticonvulsant activity. The dependency was validated using the conditioned place preference (CPP) paradigm, behavioral, and biochemical tests, while the gut microbiota was identified using matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). The CPP and behavioral tests confirmed the presence of MDMA withdrawal syndrome. Interestingly, treatment with AEAP led to a compositional shift in the GM compared to the MDMA-treated rats. Specifically, the AEAP group yielded a higher relative abundance of Lactobacillus and Bifidobacter, while animals receiving MDMA had higher levels of E. coli. These findings suggest that A. pyrethrum therapy may directly modulate the gut microbiome, highlighting a potential target for regulating and treating substance use disorders. Full article

(This article belongs to the Special Issue Recent Research of Gut Microbiota-Brain Axis and Neurons in Psychiatric Disorders)

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14 pages, 2225 KiB

Open AccessReview

The Management of Diabetes Mellitus Using Medicinal Plants and Vitamins

by Clement G. Yedjou, Jameka Grigsby, Ariane Mbemi, Daryllynn Nelson, Bryan Mildort, Lekan Latinwo and Paul B. Tchounwou

Int. J. Mol. Sci. 2023, 24(10), 9085; https://doi.org/10.3390/ijms24109085 - 22 May 2023

Cited by 18 | Viewed by 9815

Abstract

Diabetes mellitus (DM) is a serious chronic metabolic disease that is associated with hyperglycemia and several complications including cardiovascular disease and chronic kidney disease. DM is caused by high levels of blood sugar in the body associated with the disruption of insulin metabolism [...] Read more.

Diabetes mellitus (DM) is a serious chronic metabolic disease that is associated with hyperglycemia and several complications including cardiovascular disease and chronic kidney disease. DM is caused by high levels of blood sugar in the body associated with the disruption of insulin metabolism and homeostasis. Over time, DM can induce life-threatening health problems such as blindness, heart disease, kidney damage, and stroke. Although the cure of DM has improved over the past decades, its morbidity and mortality rates remain high. Hence, new therapeutic strategies are needed to overcome the burden of this disease. One such prevention and treatment strategy that is easily accessible to diabetic patients at low cost is the use of medicinal plants, vitamins, and essential elements. The research objective of this review article is to study DM and explore its treatment modalities based on medicinal plants and vitamins. To achieve our objective, we searched scientific databases of ongoing trials in PubMed Central, Medline databases, and Google Scholar websites. We also searched databases on World Health Organization International Clinical Trials Registry Platform to collect relevant papers. Results of numerous scientific investigations revealed that phytochemicals present in medicinal plants (Allium sativum, Momordica charantia, Hibiscus sabdariffa L., and Zingiber officinale) possess anti-hypoglycemic activities and show promise for the prevention and/or control of DM. Results also revealed that intake of vitamins C, D, E, or their combination improves the health of diabetes patients by reducing blood glucose, inflammation, lipid peroxidation, and blood pressure levels. However, very limited studies have addressed the health benefits of medicinal plants and vitamins as chemo-therapeutic/preventive agents for the management of DM. This review paper aims at addressing this knowledge gap by studying DM and highlighting the biomedical significance of the most potent medicinal plants and vitamins with hypoglycemic properties that show a great potential to prevent and/or treat DM. Full article

(This article belongs to the Special Issue Bioactive Compounds and Proteins/Peptides, Biosynthesis, and Applications)

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13 pages, 1461 KiB

Open AccessArticle

Serum microRNA Levels as a Biomarker for Diagnosing Non-Alcoholic Fatty Liver Disease in Chinese Colorectal Polyp Patients

by Lui Ng, Ryan Wai-Yan Sin, David Him Cheung, Wai-Keung Leung, Abraham Tak-Ka Man, Oswens Siu-Hung Lo, Wai-Lun Law and Dominic Chi-Chung Foo

Int. J. Mol. Sci. 2023, 24(10), 9084; https://doi.org/10.3390/ijms24109084 - 22 May 2023

Cited by 1 | Viewed by 1225

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and its prevalence is increasing worldwide. It is reported that NAFLD is associated with colorectal polyps. Since identifying NAFLD in its early stages could prevent possible disease progression to [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and its prevalence is increasing worldwide. It is reported that NAFLD is associated with colorectal polyps. Since identifying NAFLD in its early stages could prevent possible disease progression to cirrhosis and decrease the risk of HCC by early intervention, patients with colorectal polyp may thus be considered a target group for screening NAFLD. This study aimed to investigate the potential of serum microRNAs (miRNAs) in identifying NAFLD for colorectal polyp patients. Serum samples were collected from 141 colorectal polyp patients, of which 38 had NAFLD. The serum level of eight miRNAs was determined by quantitative PCR and delta Ct values of different miRNA pairs which were compared between NAFLD and control groups. A miRNA panel was formulated from candidate miRNA pairs by multiple linear regression model and ROC analysis was performed to evaluate its diagnostic potential for NAFLD. Compared to the control group, the NAFLD group showed significantly lower delta Ct values of miR-18a/miR-16 (6.141 vs. 7.374, p = 0.009), miR-25-3p/miR-16 (2.311 vs. 2.978, p = 0.003), miR-18a/miR-21-5p (4.367 vs. 5.081, p = 0.021) and miR-18a/miR-92a-3p (8.807 vs. 9.582, p = 0.020). A serum miRNA panel composed of these four miRNA pairs significantly identified NAFLD in colorectal polyp patients with an AUC value of 0.6584 (p = 0.004). The performance of the miRNA panel was further improved to an AUC value of 0.8337 (p < 0.0001) when polyp patients with other concurrent metabolic disorders were removed from the analysis. The serum miRNA panel is a potential diagnostic biomarker for screening NAFLD in colorectal polyp patients. This serum miRNA test could be performed for colorectal polyp patients for early diagnosis and for prevention of the disease from progressing into more advanced stages. Full article

(This article belongs to the Special Issue Circulating Non-coding RNAs as Diagnostic and Prognostic Markers of Human Diseases)

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22 pages, 929 KiB

Open AccessReview

Connecting Circuits with Networks in Addiction Neuroscience: A Salience Network Perspective

by Adriana K. Cushnie, Wei Tang and Sarah R. Heilbronner

Int. J. Mol. Sci. 2023, 24(10), 9083; https://doi.org/10.3390/ijms24109083 - 22 May 2023

Cited by 2 | Viewed by 2184

Abstract

Human neuroimaging has demonstrated the existence of large-scale functional networks in the cerebral cortex consisting of topographically distant brain regions with functionally correlated activity. The salience network (SN), which is involved in detecting salient stimuli and mediating inter-network communication, is a crucial functional [...] Read more.

Human neuroimaging has demonstrated the existence of large-scale functional networks in the cerebral cortex consisting of topographically distant brain regions with functionally correlated activity. The salience network (SN), which is involved in detecting salient stimuli and mediating inter-network communication, is a crucial functional network that is disrupted in addiction. Individuals with addiction display dysfunctional structural and functional connectivity of the SN. Furthermore, while there is a growing body of evidence regarding the SN, addiction, and the relationship between the two, there are still many unknowns, and there are fundamental limitations to human neuroimaging studies. At the same time, advances in molecular and systems neuroscience techniques allow researchers to manipulate neural circuits in nonhuman animals with increasing precision. Here, we describe attempts to translate human functional networks to nonhuman animals to uncover circuit-level mechanisms. To do this, we review the structural and functional connections of the salience network and its homology across species. We then describe the existing literature in which circuit-specific perturbation of the SN sheds light on how functional cortical networks operate, both within and outside the context of addiction. Finally, we highlight key outstanding opportunities for mechanistic studies of the SN. Full article

(This article belongs to the Special Issue The Neurobiology of Substance Addiction)

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25 pages, 5078 KiB

Open AccessReview

RNAi Technology: A New Path for the Research and Management of Obligate Biotrophic Phytopathogenic Fungi

by Isabel Padilla-Roji, Laura Ruiz-Jiménez, Nisrine Bakhat, Alejandra Vielba-Fernández, Alejandro Pérez-García and Dolores Fernández-Ortuño

Int. J. Mol. Sci. 2023, 24(10), 9082; https://doi.org/10.3390/ijms24109082 - 22 May 2023

Cited by 3 | Viewed by 2404

Abstract

Powdery mildew and rust fungi are major agricultural problems affecting many economically important crops and causing significant yield losses. These fungi are obligate biotrophic parasites that are completely dependent on their hosts for growth and reproduction. Biotrophy in these fungi is determined by [...] Read more.

Powdery mildew and rust fungi are major agricultural problems affecting many economically important crops and causing significant yield losses. These fungi are obligate biotrophic parasites that are completely dependent on their hosts for growth and reproduction. Biotrophy in these fungi is determined by the presence of haustoria, specialized fungal cells that are responsible for nutrient uptake and molecular dialogue with the host, a fact that undoubtedly complicates their study under laboratory conditions, especially in terms of genetic manipulation. RNA interference (RNAi) is the biological process of suppressing the expression of a target gene through double-stranded RNA that induces mRNA degradation. RNAi technology has revolutionized the study of these obligate biotrophic fungi by enabling the analysis of gene function in these fungal. More importantly, RNAi technology has opened new perspectives for the management of powdery mildew and rust diseases, first through the stable expression of RNAi constructs in transgenic plants and, more recently, through the non-transgenic approach called spray-induced gene silencing (SIGS). In this review, the impact of RNAi technology on the research and management of powdery mildew and rust fungi will be addressed. Full article

(This article belongs to the Special Issue RNA Interference-Based Tools for Plant Improvement and Protection 2.0)

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3 pages, 156 KiB

Open AccessEditorial

Targeted Radionuclide Therapy of Cancer and Infections

by Bart C. H. van der Wal and Ekaterina Dadachova

Int. J. Mol. Sci. 2023, 24(10), 9081; https://doi.org/10.3390/ijms24109081 - 22 May 2023

Cited by 1 | Viewed by 957

Abstract

Targeted radionuclide therapy (TRT) has been burgeoning worldwide, with several radiopharmaceuticals for the treatment of metastatic cancers being approved for clinical use [...] Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy of Cancer and Infections)

17 pages, 4836 KiB

Open AccessArticle

Modulation of Membrane Trafficking of AQP5 in the Lens in Response to Changes in Zonular Tension Is Mediated by the Mechanosensitive Channel TRPV1

by Rosica S. Petrova, Nikhil Nair, Nandini Bavana, Yadi Chen, Kevin L. Schey and Paul J. Donaldson

Int. J. Mol. Sci. 2023, 24(10), 9080; https://doi.org/10.3390/ijms24109080 - 22 May 2023

Cited by 2 | Viewed by 1115

Abstract

In mice, the contraction of the ciliary muscle via the administration of pilocarpine reduces the zonular tension applied to the lens and activates the TRPV1-mediated arm of a dual feedback system that regulates the lens’ hydrostatic pressure gradient. In the rat lens, this [...] Read more.

In mice, the contraction of the ciliary muscle via the administration of pilocarpine reduces the zonular tension applied to the lens and activates the TRPV1-mediated arm of a dual feedback system that regulates the lens’ hydrostatic pressure gradient. In the rat lens, this pilocarpine-induced reduction in zonular tension also causes the water channel AQP5 to be removed from the membranes of fiber cells located in the anterior influx and equatorial efflux zones. Here, we determined whether this pilocarpine-induced membrane trafficking of AQP5 is also regulated by the activation of TRPV1. Using microelectrode-based methods to measure surface pressure, we found that pilocarpine also increased pressure in the rat lenses via the activation of TRPV1, while pilocarpine-induced removal of AQP5 from the membrane observed using immunolabelling was abolished by pre-incubation of the lenses with a TRPV1 inhibitor. In contrast, mimicking the actions of pilocarpine by blocking TRPV4 and then activating TRPV1 resulted in sustained increase in pressure and the removal of AQP5 from the anterior influx and equatorial efflux zones. These results show that the removal of AQP5 in response to a decrease in zonular tension is mediated by TRPV1 and suggest that regional changes to P_H2O contribute to lens hydrostatic pressure gradient regulation. Full article

(This article belongs to the Special Issue Aquaporins: Dynamic Role and Regulations)

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13 pages, 1781 KiB

Open AccessArticle

Toxic Determination of Cry11 Mutated Proteins Obtained Using Rational Design and Its Computational Analysis

by Miguel O. Suárez-Barrera, Diego F. Herrera-Pineda, Paola Rondón-Villarreal, Efraín Hernando Pinzón-Reyes, Rodrigo Ochoa, Lydia Visser and Nohora Juliana Rueda-Forero

Int. J. Mol. Sci. 2023, 24(10), 9079; https://doi.org/10.3390/ijms24109079 - 22 May 2023

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Abstract

Cry11 proteins are toxic to Aedes aegypti, the vector of dengue, chikungunya, and Zika viruses. Cry11Aa and Cry11Bb are protoxins, which when activated present their active-toxin form in two fragments between 30 and 35 kDa respectively. Previous studies conducted with Cry11Aa and [...] Read more.

Cry11 proteins are toxic to Aedes aegypti, the vector of dengue, chikungunya, and Zika viruses. Cry11Aa and Cry11Bb are protoxins, which when activated present their active-toxin form in two fragments between 30 and 35 kDa respectively. Previous studies conducted with Cry11Aa and Cry11Bb genes using DNA shuffling generated variant 8, which presented a deletion in the first 73 amino acids and one at position 572 and 9 substitutions including L553F and L556W. In this study, variant 8 mutants were constructed using site-directed mutagenesis, resulting in conversion of phenylalanine (F) and tryptophan (W) to leucine (L) at positions 553 and 556, respectively, producing the mutants 8F553L, 8W556L, and 8F553L/8W556L. Additionally, two mutants, A92D and C157R, derived from Cry11Bb were also generated. The proteins were expressed in the non-crystal strain BMB171 of Bacillus thuringiensis and subjected to median-lethal concentration (LC₅₀) tests on first-instar larvae of A. aegypti. LC₅₀ analysis showed that the 8F553L, 8W556L, 8F553L/8W556L, and C157R variants lost their toxic activity (>500 ng·mL⁻¹), whereas the A92D protein presented a loss of toxicity of 11.4 times that of Cry11Bb. Cytotoxicity assays performed using variant 8, 8W556L and the controls Cry11Aa, Cry11Bb, and Cry-negative BMB171 on the colorectal cancer cell line SW480 reported 30–50% of cellular viability except for BMB171. Molecular dynamic simulations performed to identify whether the mutations at positions 553 and 556 were related to the stability and rigidity of the functional tertiary structure (domain III) of the Cry11Aa protein and variant 8 showed the importance of these mutations in specific regions for the toxic activity of Cry11 against A. aegypti. This generates pertinent knowledge for the design of Cry11 proteins and their biotechnological applications in vector-borne disease control and cancer cell lines. Full article

(This article belongs to the Special Issue Investigating the Molecular Mechanism of Action of Natural Bioactive Molecules)

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Int. J. Mol. Sci., Volume 24, Issue 10 (May-2 2023) – 649 articles

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