International Journal of Molecular Sciences

14 pages, 2284 KiB

Open AccessArticle

Characterization of Two-Component System CitB Family in Salmonella Pullorum

by Xiamei Kang, Xiao Zhou, Yanting Tang, Zhijie Jiang, Jiaqi Chen, Muhammad Mohsin and Min Yue

Int. J. Mol. Sci. 2022, 23(17), 10201; https://doi.org/10.3390/ijms231710201 - 05 Sep 2022

Cited by 7 | Viewed by 2171

Abstract

Salmonella enterica, serovar Gallinarum, biovar Pullorum, is an avian-specific pathogen which has caused considerable economic losses to the poultry industry worldwide. Two-component systems (TCSs) play an essential role in obtaining nutrients, detecting the presence of neighboring bacteria and regulating the expression of virulence [...] Read more.

Salmonella enterica, serovar Gallinarum, biovar Pullorum, is an avian-specific pathogen which has caused considerable economic losses to the poultry industry worldwide. Two-component systems (TCSs) play an essential role in obtaining nutrients, detecting the presence of neighboring bacteria and regulating the expression of virulence factors. The genome analysis of S. Pullorum strain S06004 suggesting the carriage of 22 pairs of TCSs, which belong to five families named CitB, OmpR, NarL, Chemotaxis and LuxR. In the CitB family, three pairs of TCSs, namely CitA-CitB, DcuS-DcuR and DpiB-DpiA, remain unaddressed in S. Pullorum. To systematically investigate the function of the CitB family in S. Pullorum, four mutants, ΔcitAB (abbreviated as Δcit), ΔdcuSR (Δdcu), ΔdpiBA (Δdpi) and ΔcitABΔdcuSRΔdpiBA (Δ3), were made using the CRISPR/Cas9 system. The results demonstrated that the CitB family did not affect the growth of bacteria, the results of biochemical tests, invasion and proliferation in chicken macrophage HD-11 cells and the expression of fimbrial protein. But the mutants showed thicker biofilm formation, higher resistance to antimicrobial agents, enhanced tolerance to inhibition by egg albumen and increased virulence in chicken embryos. Moreover, the deletion of Dpi TCS was detrimental to survival after exposure to hyperosmotic and oxidative environments, as well as the long-term colonization of the small intestine of chickens. Collectively, we provided new knowledge regarding the possible role of the CitB family involved in the pathogenic processes of S. Pullorum. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Bacterial Communication and Their Control)

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18 pages, 3544 KiB

Open AccessArticle

Proteomics Profiling of Osteoporosis and Osteopenia Patients and Associated Network Analysis

by Mysoon M. Al-Ansari, Shereen M. Aleidi, Afshan Masood, Eman A. Alnehmi, Mai Abdel Jabar, Maha Almogren, Mohammed Alshaker, Hicham Benabdelkamel and Anas M. Abdel Rahman

Int. J. Mol. Sci. 2022, 23(17), 10200; https://doi.org/10.3390/ijms231710200 - 05 Sep 2022

Cited by 9 | Viewed by 2815

Abstract

Bone mass reduction due to an imbalance in osteogenesis and osteolysis is characterized by low bone mineral density (LBMD) and is clinically classified as osteopenia (ON) or osteoporosis (OP), which is more severe. Multiple biomarkers for diagnosing OP and its progression have been [...] Read more.

Bone mass reduction due to an imbalance in osteogenesis and osteolysis is characterized by low bone mineral density (LBMD) and is clinically classified as osteopenia (ON) or osteoporosis (OP), which is more severe. Multiple biomarkers for diagnosing OP and its progression have been reported; however, most of these lack specificity. This cohort study aimed to investigate sensitive and specific LBMD-associated protein biomarkers in patients diagnosed with ON and OP. A label-free liquid chromatography-mass spectrometry (LC-MS) proteomics approach was used to analyze serum samples. Patients’ proteomics profiles were filtered for potential confounding effects, such as age, sex, chronic diseases, and medication. A distinctive proteomics profile between the control, ON, and OP groups (Q² = 0.7295, R² = 0.9180) was identified, and significant dysregulation in a panel of proteins (n = 20) was common among the three groups. A comparison of these proteins showed that the levels of eight proteins were upregulated in ON, compared to those in the control and the OP groups, while the levels of eleven proteins were downregulated in the ON group compared to those in the control group. Interestingly, only one protein, myosin heavy chain 14 (MYH14), showed a linear increase from the control to the ON group, with the highest abundance in the OP group. A significant separation in the proteomics profile between the ON and OP groups (Q² = 0.8760, R² = 0.991) was also noted. Furthermore, a total of twenty-six proteins were found to be dysregulated between the ON and the OP groups, with fourteen upregulated and twelve downregulated proteins in the OP, compared to that in the ON group. Most of the identified dysregulated proteins were immunoglobulins, complement proteins, cytoskeletal proteins, coagulation factors, and various enzymes. Of these identified proteins, the highest area under the curve (AUC) in the receiver operating characteristic (ROC) analysis was related to three proteins (immunoglobulin Lambda constant 1 (IGLC1), RNA binding protein (MEX3B), and fibulin 1 (FBLN1)). Multiple reaction monitoring (MRM), LC-MS, was used to validate some of the identified proteins. A network pathway analysis of the differentially abundant proteins demonstrated dysregulation of inflammatory signaling pathways in the LBMD patients, including the tumor necrosis factor (TNF), toll-like receptor (TL4), and interferon-γ (IFNG) signaling pathways. These results reveal the existence of potentially sensitive protein biomarkers that could be used in further investigations of bone health and OP progression. Full article

(This article belongs to the Special Issue Molecular Advances in Osteoporosis Research)

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18 pages, 3103 KiB

Open AccessArticle

Tubular IKKβ Deletion Alleviates Acute Ischemic Kidney Injury and Facilitates Tissue Regeneration

by Eileen Dahlke, Toni Engmann, Yaman Anan, Robert Häsler, Giovanni Solinas and Franziska Theilig

Int. J. Mol. Sci. 2022, 23(17), 10199; https://doi.org/10.3390/ijms231710199 - 05 Sep 2022

Viewed by 1828

Abstract

Acute kidney injury (AKI) is a common renal injury leading to relevant morbidity and mortality worldwide. Most of the clinical cases of AKI are caused by ischemia reperfusion (I/R) injury with renal ischemia injury followed by reperfusion injury and activation of the innate [...] Read more.

Acute kidney injury (AKI) is a common renal injury leading to relevant morbidity and mortality worldwide. Most of the clinical cases of AKI are caused by ischemia reperfusion (I/R) injury with renal ischemia injury followed by reperfusion injury and activation of the innate immune response converging to NF-ĸB pathway induction. Despite the clear role of NF-ĸB in inflammation, it has recently been acknowledged that NF-ĸB may impact other cell functions. To identify NF-ĸB function with respect to metabolism, vascular function and oxidative stress after I/R injury and to decipher in detail the underlying mechanism, we generated a transgenic mouse model with targeted deletion of IKKβ along the tubule and applied I/R injury followed by its analysis after 2 and 14 days after I/R injury. Tubular IKKβ deletion ameliorated renal function and reduced tissue damage. RNAseq data together with immunohistochemical, biochemical and morphometric analysis demonstrated an ameliorated vascular organization and mRNA expression profile for increased angiogenesis in mice with tubular IKKβ deletion at 2 days after I/R injury. RNAseq and protein analysis indicate an ameliorated metabolism, oxidative species handling and timely-adapted cell proliferation and apoptosis as well as reduced fibrosis in mice with tubular IKKβ deletion at 14 days after I/R injury. In conclusion, mice with tubular IKKβ deletion upon I/R injury display improved renal function and reduced tissue damage and fibrosis in association with improved vascularization, metabolism, reactive species disposal and fine-tuned cell proliferation. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Kidney Injury and Repair)

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27 pages, 6311 KiB

Open AccessReview

BODIPYs in PDT: A Journey through the Most Interesting Molecules Produced in the Last 10 Years

by Miryam Chiara Malacarne, Marzia Bruna Gariboldi and Enrico Caruso

Int. J. Mol. Sci. 2022, 23(17), 10198; https://doi.org/10.3390/ijms231710198 - 05 Sep 2022

Cited by 19 | Viewed by 2722

Abstract

Over the past 30 years, photodynamic therapy (PDT) has shown great development. In the clinical setting the few approved molecules belong almost exclusively to the porphyrin family; but in the scientific field, in recent years many researchers have been interested in other families [...] Read more.

Over the past 30 years, photodynamic therapy (PDT) has shown great development. In the clinical setting the few approved molecules belong almost exclusively to the porphyrin family; but in the scientific field, in recent years many researchers have been interested in other families of photosensitizers, among which BODIPY has shown particular interest. BODIPY is the acronym for 4,4-difluoro-4-bora-3a, 4a-diaza-s-indacene, and is a family of molecules well-known for their properties in the field of imaging. In order for these molecules to be used in PDT, a structural modification is necessary which involves the introduction of heavy atoms, such as bromine and iodine, in the beta positions of the pyrrole ring; this change favors the intersystem crossing, and increases the ¹O₂ yield. This mini review focused on a series of structural changes made to BODIPYs to further increase ¹O₂ production and bioavailability by improving cell targeting or photoactivity efficiency. Full article

(This article belongs to the Special Issue Materials for Photobiology)

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13 pages, 1544 KiB

Open AccessArticle

The Ambivalence of Connexin43 Gap Peptides in Cardioprotection of the Isolated Heart against Ischemic Injury

by Aleksander Tank Falck, Bjarte Aarmo Lund, David Johansen, Trine Lund and Kirsti Ytrehus

Int. J. Mol. Sci. 2022, 23(17), 10197; https://doi.org/10.3390/ijms231710197 - 05 Sep 2022

Cited by 1 | Viewed by 1595

Abstract

The present study investigates infarct-reducing effects of blocking ischemia-induced opening of connexin43 hemichannels using peptides Gap19, Gap26 or Gap27. Cardioprotection by ischemic preconditioning (IPC) and Gap peptides was compared, and combined treatment was tested in isolated, perfused male rat hearts using function and [...] Read more.

The present study investigates infarct-reducing effects of blocking ischemia-induced opening of connexin43 hemichannels using peptides Gap19, Gap26 or Gap27. Cardioprotection by ischemic preconditioning (IPC) and Gap peptides was compared, and combined treatment was tested in isolated, perfused male rat hearts using function and infarct size after global ischemia, high-resolution respirometry of isolated mitochondrial and peptide binding kinetics as endpoints. The Gap peptides reduced infarct size significantly when given prior to ischemia plus at reperfusion (Gap19 76.2 ± 2.7, Gap26 72.9 ± 5.8 and Gap27 71.9 ± 5.8% of untreated control infarcts, mean ± SEM). Cardioprotection was lost when Gap26, but not Gap27 or Gap19, was combined with triggering IPC (IPC 73.4 ± 5.5, Gap19-IPC 60.9 ± 5.1, Gap26-IPC 109.6 ± 7.8, Gap27-IPC 56.3 ± 8.0% of untreated control infarct). Binding stability of peptide Gap26 to its specific extracellular loop sequence (EL2) of connexin43 was stronger than Gap27 to its corresponding loop EL1 (dissociation rate constant K_d 0.061 ± 0.004 vs. 0.0043 ± 0.0001 s⁻¹, mean ± SD). Mitochondria from IPC hearts showed slightly but significantly reduced respiratory control ratio (RCR). In vitro addition of Gap peptides did not significantly alter respiration. If transient hemichannel activity is part of the IPC triggering event, inhibition of IPC triggering stimuli might limit the use of cardioprotective Gap peptides. Full article

(This article belongs to the Special Issue Novel Molecular Targets in Cardiovascular Diseases 2.0)

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16 pages, 3451 KiB

Open AccessArticle

Osteogenic Efficacy of Human Trophoblasts-Derived Conditioned Medium on Mesenchymal Stem Cells

by Yoon-Young Go, Chan-Mi Lee, Sung-Won Chae and Jae-Jun Song

Int. J. Mol. Sci. 2022, 23(17), 10196; https://doi.org/10.3390/ijms231710196 - 05 Sep 2022

Cited by 2 | Viewed by 1839

Abstract

Trophoblasts play an important role in the regulation of the development and function of the placenta. Our recent study demonstrated the skin regeneration capacity of trophoblast-derived extracellular vesicles (EV). Here, we aimed to determine the potential of trophoblast-derived conditioned medium (TB-CM) in enhancing [...] Read more.

Trophoblasts play an important role in the regulation of the development and function of the placenta. Our recent study demonstrated the skin regeneration capacity of trophoblast-derived extracellular vesicles (EV). Here, we aimed to determine the potential of trophoblast-derived conditioned medium (TB-CM) in enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs). We found that TB-CM promoted the osteogenic differentiation of MSCs in a dose-dependent manner. Furthermore, it inhibited adipogenesis of MSCs. We also found that the primary trophoblast-derived conditioned medium (PTB-CM) significantly enhanced the proliferation and osteogenic differentiation of human MSCs. Our study demonstrated the regulatory mechanisms underlying the TB-CM-induced osteogenesis in MSCs. An upregulation of genes associated with cytokines/chemokines was observed. The treatment of MSCs with TB-CM stimulated osteogenesis by activating several biological processes, such as mitogen-activated protein kinase (MAPK) and bone morphogenetic protein 2 (BMP2) signaling. This study demonstrated the proliferative and osteogenic efficacies of the trophoblast-derived secretomes, suggesting their potential for use in clinical interventions for bone regeneration and treatment. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism 2023)

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11 pages, 1428 KiB

Open AccessArticle

Circulating Ageing Neutrophils as a Marker of Asymptomatic Polyvascular Atherosclerosis in Statin-Naïve Patients without Established Cardiovascular Disease

by Vadim Genkel, Ilya Dolgushin, Irina Baturina, Albina Savochkina, Karina Nikushkina, Anna Minasova, Lubov Pykhova, Veronika Sumerkina, Alla Kuznetsova and Igor Shaposhnik

Int. J. Mol. Sci. 2022, 23(17), 10195; https://doi.org/10.3390/ijms231710195 - 05 Sep 2022

Cited by 1 | Viewed by 1640

Abstract

Background: Current data on the possible involvement of aging neutrophils in atherogenesis are limited. This study aimed to research the diagnostic value of aging neutrophils in their relation to subclinical atherosclerosis in statin-naïve patients without established atherosclerotic cardiovascular diseases (ASCVD). Methods: The study [...] Read more.

Background: Current data on the possible involvement of aging neutrophils in atherogenesis are limited. This study aimed to research the diagnostic value of aging neutrophils in their relation to subclinical atherosclerosis in statin-naïve patients without established atherosclerotic cardiovascular diseases (ASCVD). Methods: The study was carried out on 151 statin-naïve patients aged 40–64 years old without ASCVD. All patients underwent duplex scanning of the carotid arteries, lower limb arteries and abdominal aorta. Phenotyping and differentiation of neutrophil subpopulations were performed through flow cytometry (Navios 6/2, Beckman Coulter, USA). Results: The number of CD62L^loCXCR4^hi-neutrophils is known to be significantly higher in patients with subclinical atherosclerosis compared with patients without atherosclerosis (p = 0.006). An increase in the number of CD62L^loCXCR4^hi-neutrophils above cut-off values makes it possible to predict atherosclerosis in at least one vascular bed with sensitivity of 35.4–50.5% and specificity of 80.0–92.1%, in two vascular beds with sensitivity of 44.7–84.4% and specificity of 80.8–33.3%. Conclusion: In statin-naïve patients 40–64 years old without established ASCVD with subclinical atherosclerosis, there is an increase in circulating CD62L^loCXCR4^hi-neutrophils. It was also concluded that the increase in the number of circulating CD62L^loCXCR4^hi-neutrophils demonstrated moderate diagnostic efficiency (AUC 0.617–0.656) in relation to the detection of subclinical atherosclerosis, including polyvascular atherosclerosis. Full article

(This article belongs to the Special Issue Neutrophil in Cell Biology and Diseases)

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21 pages, 6661 KiB

Open AccessArticle

Proteomic Analysis of HCC-1954 and MCF-7 Cell Lines Highlights Crosstalk between αv and β1 Integrins, E-Cadherin and HER-2

by Denise de Abreu Pereira, Vanessa Sandim, Thais F. B. Fernandes, Vitor Hugo Almeida, Murilo Ramos Rocha, Ronaldo J. F. C. do Amaral, Maria Isabel D. Rossi, Dário Eluan Kalume and Russolina B. Zingali

Int. J. Mol. Sci. 2022, 23(17), 10194; https://doi.org/10.3390/ijms231710194 - 05 Sep 2022

Cited by 4 | Viewed by 2858

Abstract

Overexpression of human epidermal growth factor receptor-2 (HER-2) occurs in 20% of all breast cancer subtypes, especially those that present the worst prognostic outcome through a very invasive and aggressive tumour. HCC-1954 (HER-2+) is a highly invasive, metastatic cell line, whereas MCF-7 is [...] Read more.

Overexpression of human epidermal growth factor receptor-2 (HER-2) occurs in 20% of all breast cancer subtypes, especially those that present the worst prognostic outcome through a very invasive and aggressive tumour. HCC-1954 (HER-2+) is a highly invasive, metastatic cell line, whereas MCF-7 is mildly aggressive and non-invasive. We investigated membrane proteins from both cell lines that could have a pivotal biological significance in metastasis. Membrane protein enrichment for HCC-1954 and MCF-7 proteomic analysis was performed. The samples were analysed and quantified by mass spectrometry. High abundance membrane proteins were confirmed by Western blot, immunofluorescence, and flow cytometry. Protein interaction prediction and correlations with the Cancer Genome Atlas (TCGA) patient data were conducted by bioinformatic analysis. In addition, β1 integrin expression was analysed by Western blot in cells upon trastuzumab treatment. The comparison between HCC-1954 and MCF-7 membrane-enriched proteins revealed that proteins involved in cytoskeleton organisation, such as HER-2, αv and β1 integrins, E-cadherin, and CD166 were more abundant in HCC-1954. β1 integrin membrane expression was higher in the HCC-1954 cell line resistant after trastuzumab treatment. TCGA data analysis showed a trend toward a positive correlation between HER-2 and β1 integrin in HER-2+ breast cancer patients. Differences in protein profile and abundance reflected distinctive capabilities for aggressiveness and invasiveness between HCC-1954 and MCF-7 cell line phenotypes. The higher membrane β1 integrin expression after trastuzumab treatment in the HCC-1954 cell line emphasised the need for investigating the contribution of β1 integrin modulation and its effect on the mechanism of trastuzumab resistance. Full article

(This article belongs to the Section Molecular Oncology)

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19 pages, 3869 KiB

Open AccessArticle

From Double-Strand Break Recognition to Cell-Cycle Checkpoint Activation: High Content and Resolution Image Cytometry Unmasks 53BP1 Multiple Roles in DNA Damage Response and p53 Action

by Laura Furia, Simone Pelicci, Mirco Scanarini, Pier Giuseppe Pelicci and Mario Faretta

Int. J. Mol. Sci. 2022, 23(17), 10193; https://doi.org/10.3390/ijms231710193 - 05 Sep 2022

Cited by 3 | Viewed by 1840

Abstract

53BP1 protein has been isolated in-vitro as a putative p53 interactor. From the discovery of its engagement in the DNA-Damage Response (DDR), its role in sustaining the activity of the p53-regulated transcriptional program has been frequently under-evaluated, even in the case of a [...] Read more.

53BP1 protein has been isolated in-vitro as a putative p53 interactor. From the discovery of its engagement in the DNA-Damage Response (DDR), its role in sustaining the activity of the p53-regulated transcriptional program has been frequently under-evaluated, even in the case of a specific response to numerous DNA Double-Strand Breaks (DSBs), i.e., exposure to ionizing radiation. The localization of 53BP1 protein constitutes a key to decipher the network of activities exerted in response to stress. We present here an automated-microscopy for image cytometry protocol to analyze the evolution of the DDR, and to demonstrate how 53BP1 moved from damaged sites, where the well-known interaction with the DSB marker γH2A.X takes place, to nucleoplasm, interacting with p53, and enhancing the transcriptional regulation of the guardian of the genome protein. Molecular interactions have been quantitatively described and spatiotemporally localized at the highest spatial resolution by a simultaneous analysis of the impairment of the cell-cycle progression. Thanks to the high statistical sampling of the presented protocol, we provide a detailed quantitative description of the molecular events following the DSBs formation. Single-Molecule Localization Microscopy (SMLM) Analysis finally confirmed the p53–53BP1 interaction on the tens of nanometers scale during the distinct phases of the response. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells 2.0)

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18 pages, 4938 KiB

Open AccessArticle

Advantage of Dimethyl Sulfoxide in the Fabrication of Binder-Free Layered Double Hydroxides Electrodes: Impacts of Physical Parameters on the Crystalline Domain and Electrochemical Performance

by Gayi Nyongombe, Guy L. Kabongo, Luyanda L. Noto and Mokhotjwa S. Dhlamini

Int. J. Mol. Sci. 2022, 23(17), 10192; https://doi.org/10.3390/ijms231710192 - 05 Sep 2022

Cited by 1 | Viewed by 1222

Abstract

The electrode fabrication stage is a crucial step in the design of supercapacitors. The latter involves the binder generally for adhesive purposes. The binder is electrochemically dormant and has weak interactions, leading to isolating the active material and conductive additive and then compromising [...] Read more.

The electrode fabrication stage is a crucial step in the design of supercapacitors. The latter involves the binder generally for adhesive purposes. The binder is electrochemically dormant and has weak interactions, leading to isolating the active material and conductive additive and then compromising the electrochemical performance. Designing binder-free electrodes is a practical way to improve the electrochemical performance of supercapacitors. However, most of the methods developed for the fabrication of binder-free LDH electrodes do not accommodate LDH materials prepared via the co-precipitation or ions exchange routes. Herein, we developed a novel method to fabricate binder-free LDH electrodes which accommodates LDH materials from other synthesis routes. The induced impacts of various physical parameters such as the temperature and time applied during the fabrication process on the crystalline domain and electrochemical performances of all the binder-free LDH electrodes were studied. The electrochemical analysis showed that the electrode prepared at 200 °C-1 h exhibited the best electrochemical performance compared to its counterparts. A specific capacitance of 3050.95 Fg⁻¹ at 10 mVs⁻¹ was achieved by it, while its Rct value was 0.68 Ω. Moreover, it retained 97% of capacitance after 5000 cycles at 120 mVs⁻¹. The XRD and FTIR studies demonstrated that its excellent electrochemical performance was due to its crystalline domain which had held an important amount of water than other electrodes. The as-developed method proved to be reliable and advantageous due to its simplicity and cost-effectiveness. Full article

(This article belongs to the Special Issue Polymeric Hybrid Nanomaterials for Biomedical and Energy Applications)

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13 pages, 1015 KiB

Open AccessReview

Targeting Persistent Neuroinflammation after Hypoxic-Ischemic Encephalopathy—Is Exendin-4 the Answer?

by Kelly Q. Zhou, Simerdeep K. Dhillon, Laura Bennet, Alistair J. Gunn and Joanne O. Davidson

Int. J. Mol. Sci. 2022, 23(17), 10191; https://doi.org/10.3390/ijms231710191 - 05 Sep 2022

Cited by 6 | Viewed by 2263

Abstract

Hypoxic-ischemic encephalopathy is brain injury resulting from the loss of oxygen and blood supply around the time of birth. It is associated with a high risk of death or disability. The only approved treatment is therapeutic hypothermia. Therapeutic hypothermia has consistently been shown [...] Read more.

Hypoxic-ischemic encephalopathy is brain injury resulting from the loss of oxygen and blood supply around the time of birth. It is associated with a high risk of death or disability. The only approved treatment is therapeutic hypothermia. Therapeutic hypothermia has consistently been shown to significantly reduce the risk of death and disability in infants with hypoxic-ischemic encephalopathy. However, approximately 29% of infants treated with therapeutic hypothermia still develop disability. Recent preclinical and clinical studies have shown that there is still persistent neuroinflammation even after treating with therapeutic hypothermia, which may contribute to the deficits seen in infants despite treatment. This suggests that potentially targeting this persistent neuroinflammation would have an additive benefit in addition to therapeutic hypothermia. A potential additive treatment is Exendin-4, which is a glucagon-like peptide 1 receptor agonist. Preclinical data from various in vitro and in vivo disease models have shown that Exendin-4 has anti-inflammatory, mitochondrial protective, anti-apoptotic, anti-oxidative and neurotrophic effects. Although preclinical studies of the effect of Exendin-4 in perinatal hypoxic-ischemic brain injury are limited, a seminal study in neonatal mice showed that Exendin-4 had promising neuroprotective effects. Further studies on Exendin-4 neuroprotection for perinatal hypoxic-ischemic brain injury, including in large animal translational models are warranted to better understand its safety, window of opportunity and effectiveness as an adjunct with therapeutic hypothermia. Full article

(This article belongs to the Special Issue Novel Anti-inflammatory Molecules)

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19 pages, 590 KiB

Open AccessArticle

Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200 + Water) Cosolvent Mixtures from 278.15 K to 318.15 K

by Daniela Baracaldo-Santamaría, Carlos Alberto Calderon-Ospina, Claudia Patricia Ortiz, Rossember Edén Cardenas-Torres, Fleming Martinez and Daniel Ricardo Delgado

Int. J. Mol. Sci. 2022, 23(17), 10190; https://doi.org/10.3390/ijms231710190 - 05 Sep 2022

Cited by 3 | Viewed by 1715

Abstract

The solubility of drugs in cosolvent systems of pharmaceutical interest is of great importance for understanding and optimizing a large number of processes. Here, we report the solubility of isoniazid in nine (PEG 200 + water) cosolvent mixtures at nine temperatures (278.15, 283.15, [...] Read more.

The solubility of drugs in cosolvent systems of pharmaceutical interest is of great importance for understanding and optimizing a large number of processes. Here, we report the solubility of isoniazid in nine (PEG 200 + water) cosolvent mixtures at nine temperatures (278.15, 283.15, 288.15, 293.15, 298.15, 303.15, 308.15, and 318.15 K) determined by UV–vis spectrophotometry. From the solubility data, the thermodynamic solution, mixing, and transfer functions were calculated in addition to performing the enthalpy–entropy compensation analysis. The solubility of isoniazid depends on the concentration of PEG 200 (positive cosolvent effect) and temperature (endothermic process) reaching its maximum solubility in pure PEG 200 at 318.15 K and the lowest solubility in pure water at 278.15 K. The solution process is favored by the solution entropy and according to the enthalpy–entropy compensation analysis it is driven by entropy in mixtures rich in water and by enthalpy in mixtures rich in PEG 200. Full article

(This article belongs to the Collection Feature Papers in Molecular Pharmacology)

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17 pages, 1045 KiB

Open AccessReview

Thalassemia Intermedia: Chelator or Not?

by Yen-Chien Lee, Chi-Tai Yen, Yen-Ling Lee and Rong-Jane Chen

Int. J. Mol. Sci. 2022, 23(17), 10189; https://doi.org/10.3390/ijms231710189 - 05 Sep 2022

Cited by 2 | Viewed by 3853

Abstract

Thalassemia is the most common genetic disorder worldwide. Thalassemia intermedia (TI) is non-transfusion-dependent thalassemia (NTDT), which includes β-TI hemoglobin, E/β-thalassemia and hemoglobin H (HbH) disease. Due to the availability of iron chelation therapy, the life expectancy of thalassemia major (TM) patients is now [...] Read more.

Thalassemia is the most common genetic disorder worldwide. Thalassemia intermedia (TI) is non-transfusion-dependent thalassemia (NTDT), which includes β-TI hemoglobin, E/β-thalassemia and hemoglobin H (HbH) disease. Due to the availability of iron chelation therapy, the life expectancy of thalassemia major (TM) patients is now close to that of TI patients. Iron overload is noted in TI due to the increasing iron absorption from the intestine. Questions are raised regarding the relationship between iron chelation therapy and decreased patient morbidity/mortality, as well as the starting threshold for chelation therapy. Searching all the available articles up to 12 August 2022, iron-chelation-related TI was reviewed. In addition to splenectomized patients, osteoporosis was the most common morbidity among TI cases. Most study designs related to ferritin level and morbidities were cross-sectional and most were from the same Italian study groups. Intervention studies of iron chelation therapy included a subgroup of TI that required regular transfusion. Liver iron concentration (LIC) ≥ 5 mg/g/dw measured by MRI and ferritin level > 300 ng/mL were suggested as indicators to start iron chelation therapy, and iron chelation therapy was suggested to be stopped at a ferritin level ≤ 300 ng/mL. No studies showed improved overall survival rates by iron chelation therapy. TI morbidities and mortalities cannot be explained by iron overload alone. Hypoxemia and hemolysis may play a role. Head-to-head studies comparing different treatment methods, including hydroxyurea, fetal hemoglobin-inducing agents, hypertransfusion as well as iron chelation therapy are needed for TI, hopefully separating β-TI and HbH disease. In addition, the target hemoglobin level should be determined for β-TI and HbH disease. Full article

(This article belongs to the Collection Feature Papers in Molecular Genetics and Genomics)

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18 pages, 4148 KiB

Open AccessArticle

Leonurine Reduces Oxidative Stress and Provides Neuroprotection against Ischemic Injury via Modulating Oxidative and NO/NOS Pathway

by Ziteng Deng, Jiao Li, Xiaoquan Tang, Dan Li, Yazhou Wang, Shengxi Wu, Kai Fan and Yunfei Ma

Int. J. Mol. Sci. 2022, 23(17), 10188; https://doi.org/10.3390/ijms231710188 - 05 Sep 2022

Cited by 14 | Viewed by 2167

Abstract

Leonurine (Leo) has been found to have neuroprotective effects against cerebral ischemic injury. However, the exact molecular mechanism underlying its neuroprotective ability remains unclear. The aim of the present study was to investigate whether Leo could provide protection through the nitric oxide (NO)/nitric [...] Read more.

Leonurine (Leo) has been found to have neuroprotective effects against cerebral ischemic injury. However, the exact molecular mechanism underlying its neuroprotective ability remains unclear. The aim of the present study was to investigate whether Leo could provide protection through the nitric oxide (NO)/nitric oxide synthase (NOS) pathway. We firstly explored the effects of NO/NOS signaling on oxidative stress and apoptosis in in vivo and in vitro models of cerebral ischemia. Further, we evaluated the protective effects of Leo against oxygen and glucose deprivation (OGD)-induced oxidative stress and apoptosis in PC12 cells. We found that the rats showed anxiety-like behavior, and the morphology and number of neurons were changed in a model of photochemically induced cerebral ischemia. Both in vivo and in vitro results show that the activity of superoxide dismutase (SOD) and glutathione (GSH) contents were decreased after ischemia, and reactive oxygen species (ROS) and malondialdehyde (MDA) levels were increased, indicating that cerebral ischemia induced oxidative stress and neuronal damage. Moreover, the contents of NO, total NOS, constitutive NOS (cNOS) and inducible NOS (iNOS) were increased after ischemia in rat and PC12 cells. Treatment with L-nitroarginine methyl ester (L-NAME), a nonselective NOS inhibitor, could reverse the change in NO/NOS expression and abolish these detrimental effects of ischemia. Leo treatment decreased ROS and MDA levels and increased the activity of SOD and GSH contents in PC12 cells exposed to OGD. Furthermore, Leo reduced NO/NOS production and cell apoptosis, decreased Bax expression and increased Bcl-2 levels in OGD-treated PC12 cells. All the data suggest that Leo protected against oxidative stress and neuronal apoptosis in cerebral ischemia by inhibiting the NO/NOS system. Our findings indicate that Leo could be a potential agent for the intervention of ischemic stroke and highlighted the NO/NOS-mediated oxidative stress signaling. Full article

(This article belongs to the Topic Antioxidants and Oxidative Stress in Brain Health)

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12 pages, 4155 KiB

Open AccessArticle

Quantitative Chemical Exchange Saturation Transfer Imaging of Amide Proton Transfer Differentiates between Cerebellopontine Angle Schwannoma and Meningioma: Preliminary Results

by Hirofumi Koike, Minoru Morikawa, Hideki Ishimaru, Reiko Ideguchi, Masataka Uetani, Takeshi Hiu, Takayuki Matsuo and Mitsuharu Miyoshi

Int. J. Mol. Sci. 2022, 23(17), 10187; https://doi.org/10.3390/ijms231710187 - 05 Sep 2022

Cited by 5 | Viewed by 1896

Abstract

Vestibular schwannomas are the most common tumor at the common cerebellopontine angle, followed by meningiomas. Differentiation of these tumors is critical because of the different surgical approaches required for treatment. Recent studies have demonstrated the utility of amide proton transfer (APT)-chemical exchange saturation [...] Read more.

Vestibular schwannomas are the most common tumor at the common cerebellopontine angle, followed by meningiomas. Differentiation of these tumors is critical because of the different surgical approaches required for treatment. Recent studies have demonstrated the utility of amide proton transfer (APT)-chemical exchange saturation transfer (CEST) imaging in evaluating malignant brain tumors. However, APT imaging has not been applied in benign tumors. Here, we explored the potential of APT in differentiating between schwannomas and meningiomas at the cerebellopontine angle. We retrospectively evaluated nine patients with schwannoma and nine patients with meningioma who underwent APT-CEST MRI from November 2020 to April 2022 pre-operation. All 18 tumors were histologically diagnosed. There was a significant difference in magnetization transfer ratio asymmetry (MTR_asym) values (0.033 ± 0.012 vs. 0.021 ± 0.004; p = 0.007) between the schwannoma and meningioma groups. Receiver operative curve analysis showed that MTR_asym values clearly differentiated between the schwannoma and meningioma groups. At an MTR_asym value threshold of 0.024, the diagnostic sensitivity, specificity, positive predictive value, and negative predictive values for MTR_asym were 88.9%, 77.8%, 80.0%, and 87.5%, respectively. Our results demonstrated the ability of MTR_asym values on APT-CEST imaging to discriminate patients with schwannomas from patients with meningiomas. Full article

(This article belongs to the Section Molecular Oncology)

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12 pages, 945 KiB

Open AccessReview

Antenatal Glucocorticoid Administration Promotes Cardiac Structure and Energy Metabolism Maturation in Preterm Fetuses

by Kenzo Sakurai, Yuko Takeba, Yosuke Osada, Masanori Mizuno, Yoshimitsu Tsuzuki, Kentaro Aso, Keisuke Kida, Yuki Ohta, Masanori Ootaki, Taroh Iiri, Isamu Hokuto, Naoki Shimizu and Naoki Matsumoto

Int. J. Mol. Sci. 2022, 23(17), 10186; https://doi.org/10.3390/ijms231710186 - 05 Sep 2022

Cited by 2 | Viewed by 2214

Abstract

Although the rate of preterm birth has increased in recent decades, a number of preterm infants have escaped death due to improvements in perinatal and neonatal care. Antenatal glucocorticoid (GC) therapy has significantly contributed to progression in lung maturation; however, its potential effects [...] Read more.

Although the rate of preterm birth has increased in recent decades, a number of preterm infants have escaped death due to improvements in perinatal and neonatal care. Antenatal glucocorticoid (GC) therapy has significantly contributed to progression in lung maturation; however, its potential effects on other organs remain controversial. Furthermore, the effects of antenatal GC therapy on the fetal heart show both pros and cons. Translational research in animal models indicates that constant fetal exposure to antenatal GC administration is sufficient for lung maturation. We have established a premature fetal rat model to investigate immature cardiopulmonary functions in the lungs and heart, including the effects of antenatal GC administration. In this review, we explain the mechanisms of antenatal GC actions on the heart in the fetus compared to those in the neonate. Antenatal GCs may contribute to premature heart maturation by accelerating cardiomyocyte proliferation, angiogenesis, energy production, and sarcoplasmic reticulum function. Additionally, this review specifically focuses on fetal heart growth with antenatal GC administration in experimental animal models. Moreover, knowledge regarding antenatal GC administration in experimental animal models can be coupled with that from developmental biology, with the potential for the generation of functional cells and tissues that could be used for regenerative medical purposes in the future. Full article

(This article belongs to the Special Issue Post-transcriptional Gene Expression Regulation in Eukaryotic Energy Metabolism)

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15 pages, 3971 KiB

Open AccessArticle

The MKK2a Gene Involved in the MAPK Signaling Cascades Enhances Populus Salt Tolerance

by Jiali Wang, Zimou Sun, Caihui Chen and Meng Xu

Int. J. Mol. Sci. 2022, 23(17), 10185; https://doi.org/10.3390/ijms231710185 - 05 Sep 2022

Cited by 7 | Viewed by 1545

Abstract

Mitogen-activated protein kinase (MAPK) cascades are highly conserved signal transduction modules, which transmit environmental signals in plant cells through stepwise phosphorylation and play indispensable roles in a wide range of physiological and biochemical processes. Here, we isolated and characterized a gene encoding MKK2 [...] Read more.

Mitogen-activated protein kinase (MAPK) cascades are highly conserved signal transduction modules, which transmit environmental signals in plant cells through stepwise phosphorylation and play indispensable roles in a wide range of physiological and biochemical processes. Here, we isolated and characterized a gene encoding MKK2 protein from poplar through the rapid amplification of cDNA ends (RACE). The full-length PeMKK2a gene was 1571 bp, including a 1068 bp open reading frame (ORF) encoding 355 amino acids, and the putative PeMKK2a protein belongs to the PKc_like (protein kinase domain) family (70–336 amino acids) in the PKc_MAPKK_plant subfamily and contains 62 sites of possible phosphorylation and two conserved domains, DLK and S/T-xxxxx-S/T. Detailed information about its gene structure, sequence similarities, subcellular localization, and transcript profiles under salt-stress conditions was revealed. Transgenic poplar lines overexpressing PeMKK2a exhibited higher activities of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) than non-transgenic poplar under salt stress conditions. These results will provide insight into the roles of MAPK signaling cascades in poplar response to salt stress. Full article

(This article belongs to the Special Issue Advanced Research in Plant Responses to Environmental Stresses 2.0)

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15 pages, 2323 KiB

Open AccessArticle

Systemic Beta-Hydroxybutyrate Affects BDNF and Autophagy into the Retina of Diabetic Mice

by Maria Consiglia Trotta, Carlo Gesualdo, Hildegard Herman, Sami Gharbia, Cornel Balta, Caterina Claudia Lepre, Marina Russo, Annalisa Itro, Giovanbattista D’Amico, Luisa Peluso, Iacopo Panarese, Gorizio Pieretti, Giuseppe Ferraro, Francesca Simonelli, Michele D’Amico, Settimio Rossi and Anca Hermenean

Int. J. Mol. Sci. 2022, 23(17), 10184; https://doi.org/10.3390/ijms231710184 - 05 Sep 2022

Cited by 10 | Viewed by 2442

Abstract

Background: Diabetic retinopathy (DR) is a neurovascular disease, characterized by a deficiency of brain-derived neurotrophic factor (BDNF), a regulator of autophagy. Beta-hydroxybutyrate (BHB), previously reported as a protective agent in DR, has been associated with BDNF promotion. Here, we investigated whether systemic BHB [...] Read more.

Background: Diabetic retinopathy (DR) is a neurovascular disease, characterized by a deficiency of brain-derived neurotrophic factor (BDNF), a regulator of autophagy. Beta-hydroxybutyrate (BHB), previously reported as a protective agent in DR, has been associated with BDNF promotion. Here, we investigated whether systemic BHB affects the retinal levels of BDNF and local autophagy in diabetic mice with retinopathy; Methods: C57BL/6J mice were administered with intraperitoneal (i.p.) streptozotocin (STZ) (75 mg/kg) injection to develop diabetes. After 2 weeks, they received i.p. injections of BHB (25–50–100 mg/kg) twice a week for 10 weeks. Retinal samples were collected in order to perform immunofluorescence, Western blotting, and ELISA analysis; Results: BHB 50 mg/kg and 100 mg/kg significantly improved retinal BDNF levels (p < 0.01) in diabetic mice. This improvement was negatively associated with autophagosome–lysosome formations (marked by LC3B and ATG14) and to higher levels of connexin 43 (p < 0.01), a marker of cell integrity. Moreover, BHB administration significantly reduced M1 microglial activation and autophagy (p < 0.01); Conclusions: The systemic administration of BHB in mice with DR improves the retinal levels of BDNF, with the consequent reduction of the abnormal microglial autophagy. This leads to retinal cell safety through connexin 43 restoration. Full article

(This article belongs to the Special Issue Novel Insights in Retinal Diseases Pathophysiology and Therapies)

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19 pages, 6621 KiB

Open AccessArticle

Genome-Wide Characterization of PIN Auxin Efflux Carrier Gene Family in Mikania micrantha

by Lihua Chen, Minling Cai, Minghao Chen, Weiqian Ke, Yanru Pan, Jundong Huang, Junjie Zhang and Changlian Peng

Int. J. Mol. Sci. 2022, 23(17), 10183; https://doi.org/10.3390/ijms231710183 - 05 Sep 2022

Cited by 3 | Viewed by 1694

Abstract

Mikania micrantha, recognized as one of the world’s top 10 pernicious weeds, is a rapidly spreading tropical vine that has invaded the coastal areas of South China, causing serious economic losses and environmental damage. Rapid stem growth is an important feature of [...] Read more.

Mikania micrantha, recognized as one of the world’s top 10 pernicious weeds, is a rapidly spreading tropical vine that has invaded the coastal areas of South China, causing serious economic losses and environmental damage. Rapid stem growth is an important feature of M. micrantha which may be related to its greater number of genes involved in auxin signaling and transport pathways and its ability to synthesize more auxin under adverse conditions to promote or maintain stem growth. Plant growth and development is closely connected to the regulation of endogenous hormones, especially the polar transport and asymmetric distribution of auxin. The PIN-FORMED (PIN) auxin efflux carrier gene family plays a key role in the polar transport of auxin and then regulates the growth of different plant tissues, which could indicate that the rapid growth of M. micrantha is closely related to this PIN-dependent auxin regulation. In this study, 11 PIN genes were identified and the phylogenetic relationship and structural compositions of the gene family in M. micrantha were analyzed by employing multiple bioinformatic methods. The phylogenetic analysis indicated that the PIN proteins could be divided into five distinct clades. The structural analysis revealed that three putative types of PIN (canonical, noncanonical and semi-canonical) exist among the proteins according to the length and the composition of the hydrophilic domain. The majority of the PINs were involved in the process of axillary bud differentiation and stem response under abiotic stress, indicating that M. micrantha may regulate its growth, development and stress response by regulating PIN expression in the axillary bud and stem, which may help explain its strong growth ability and environmental adaptability. Our study emphasized the structural features and stress response patterns of the PIN gene family and provided useful insights for further study into the molecular mechanism of auxin-regulated growth and control in M. micrantha. Full article

(This article belongs to the Special Issue Environmental Stress and Plants 2.0)

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18 pages, 8859 KiB

Open AccessArticle

Ectopic Expression of AeNAC83, a NAC Transcription Factor from Abelmoschus esculentus, Inhibits Growth and Confers Tolerance to Salt Stress in Arabidopsis

by Xuan Zhao, Tingting Wu, Shixian Guo, Junling Hu and Yihua Zhan

Int. J. Mol. Sci. 2022, 23(17), 10182; https://doi.org/10.3390/ijms231710182 - 05 Sep 2022

Cited by 6 | Viewed by 1597

Abstract

NAC transcription factors play crucial roles in plant growth, development and stress responses. Previously, we preliminarily identified that the transcription factor AeNAC83 gene was significantly up-regulated under salt stress in okra (Abelmoschus esculentus). Herein, we cloned the nuclear-localized AeNAC83 from okra [...] Read more.

NAC transcription factors play crucial roles in plant growth, development and stress responses. Previously, we preliminarily identified that the transcription factor AeNAC83 gene was significantly up-regulated under salt stress in okra (Abelmoschus esculentus). Herein, we cloned the nuclear-localized AeNAC83 from okra and identified its possible role in salt stress response and plant growth. The down-regulation of AeNAC83 caused by virus-induced gene silencing enhanced plant sensitivity to salt stress and increased the biomass accumulation of okra seedlings. Meanwhile, AeNAC83-overexpression Arabidopsis lines improved salt tolerance and exhibited many altered phenotypes, including small rosette, short primary roots, and promoted crown roots and root hairs. RNA-seq showed numerous genes at the transcriptional level that changed significantly in the AeNAC83-overexpression transgenic and the wild Arabidopsis with or without NaCl treatment, respectively. The expression of most phenylpropanoid and flavonoid biosynthesis-related genes was largely induced by salt stress. While genes encoding key proteins involved in photosynthesis were almost declined dramatically in AeNAC83-overexpression transgenic plants, and NaCl treatment further resulted in the down-regulation of these genes. Furthermore, DEGs encoding various plant hormone signal pathways were also identified. These results indicate that AeNAC83 is involved in resistance to salt stress and plant growth. Full article

(This article belongs to the Special Issue Research on Plant Genomics and Breeding)

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13 pages, 1634 KiB

Open AccessArticle

Imidacloprid Impairs Glutamatergic Synaptic Plasticity and Desensitizes Mechanosensitive, Nociceptive, and Photogenic Response of Drosophila melanogaster by Mediating Oxidative Stress, Which Could Be Rescued by Osthole

by Chuan-Hsiu Liu, Mei-Ying Chen, Jack Cheng, Tsai-Ni Chuang, Hsin-Ping Liu and Wei-Yong Lin

Int. J. Mol. Sci. 2022, 23(17), 10181; https://doi.org/10.3390/ijms231710181 - 05 Sep 2022

Viewed by 1580

Abstract

Background: Imidacloprid (IMD) is a widely used neonicotinoid-targeting insect nicotine acetylcholine receptors (nAChRs). However, off-target effects raise environmental concerns, including the IMD’s impairment of the memory of honeybees and rodents. Although the down-regulation of inotropic glutamate receptor (iGluR) was proposed as the cause, [...] Read more.

Background: Imidacloprid (IMD) is a widely used neonicotinoid-targeting insect nicotine acetylcholine receptors (nAChRs). However, off-target effects raise environmental concerns, including the IMD’s impairment of the memory of honeybees and rodents. Although the down-regulation of inotropic glutamate receptor (iGluR) was proposed as the cause, whether IMD directly manipulates the activation or inhibition of iGluR is unknown. Using electrophysiological recording on fruit fly neuromuscular junction (NMJ), we found that IMD of 0.125 and 12.5 mg/L did not activate glutamate receptors nor inhibit the glutamate-triggered depolarization of the glutamatergic synapse. However, chronic IMD treatment attenuated short-term facilitation (STF) of NMJ by more than 20%. Moreover, by behavioral assays, we found that IMD desensitized the fruit flies’ response to mechanosensitive, nociceptive, and photogenic stimuli. Finally, the treatment of the antioxidant osthole rescued the chronic IMD-induced phenotypes. We clarified that IMD is neither agonist nor antagonist of glutamate receptors, but chronic treatment with environmental-relevant concentrations impairs glutamatergic plasticity of the NMJ of fruit flies and interferes with the sensory response by mediating oxidative stress. Full article

(This article belongs to the Special Issue Pesticides Exposure and Toxicity)

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20 pages, 42635 KiB

Open AccessArticle

Mechano-Transduction Boosts the Aging Effects in Human Erythrocytes Submitted to Mechanical Stimulation

by Simone Dinarelli, Giovanni Longo, Antonio Francioso, Luciana Mosca and Marco Girasole

Int. J. Mol. Sci. 2022, 23(17), 10180; https://doi.org/10.3390/ijms231710180 - 05 Sep 2022

Cited by 4 | Viewed by 1325

Abstract

Erythrocytes’ aging and mechano-transduction are fundamental cellular pathways that determine the red blood cells’ (RBCs) behavior and function. The aging pattern can be influenced, in morphological, biochemical, and metabolic terms by the environmental conditions. In this paper, we studied the effect of a [...] Read more.

Erythrocytes’ aging and mechano-transduction are fundamental cellular pathways that determine the red blood cells’ (RBCs) behavior and function. The aging pattern can be influenced, in morphological, biochemical, and metabolic terms by the environmental conditions. In this paper, we studied the effect of a moderate mechanical stimulation applied through external shaking during the RBCs aging and revealed a strong acceleration of the aging pattern induced by such stimulation. Moreover, we evaluated the behavior of the main cellular effectors and resources in the presence of drugs (diamide) or of specific inhibitors of the mechano-transduction (probenecid, carbenoxolone, and glibenclamide). This approach provided the first evidence of a direct cross-correlation between aging and mechano-transduction and permitted an evaluation of the overall metabolic regulation and of the insurgence of specific morphological features, such as micro-vesicles and roughness alterations. Overall, for the first time the present data provided a schematic to understand the integration of distinct complex patterns in a comprehensive view of the cell and of its interactions with the environment. Mechano-transduction produces structural effects that are correlated with the stimulation and the strength of the environmental stimulation is paramount to effectively activate and trigger the biological cascades initiated by the mechano-sensing. Full article

(This article belongs to the Special Issue Roles of Erythrocytes in Human Health and Disease)

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16 pages, 5517 KiB

Open AccessReview

Retinal Ganglion Cell Survival and Axon Regeneration after Optic Nerve Injury: Role of Inflammation and Other Factors

by Kimberly A. Wong and Larry I. Benowitz

Int. J. Mol. Sci. 2022, 23(17), 10179; https://doi.org/10.3390/ijms231710179 - 05 Sep 2022

Cited by 18 | Viewed by 3454

Abstract

The optic nerve, like most pathways in the mature central nervous system, cannot regenerate if injured, and within days, retinal ganglion cells (RGCs), the neurons that extend axons through the optic nerve, begin to die. Thus, there are few clinical options to improve [...] Read more.

The optic nerve, like most pathways in the mature central nervous system, cannot regenerate if injured, and within days, retinal ganglion cells (RGCs), the neurons that extend axons through the optic nerve, begin to die. Thus, there are few clinical options to improve vision after traumatic or ischemic optic nerve injury or in neurodegenerative diseases such as glaucoma, dominant optic neuropathy, or optic pathway gliomas. Research over the past two decades has identified several strategies to enable RGCs to regenerate axons the entire length of the optic nerve, in some cases leading to modest reinnervation of di- and mesencephalic visual relay centers. This review primarily focuses on the role of the innate immune system in improving RGC survival and axon regeneration, and its synergy with manipulations of signal transduction pathways, transcription factors, and cell-extrinsic suppressors of axon growth. Research in this field provides hope that clinically effective strategies to improve vision in patients with currently untreatable losses could become a reality in 5–10 years. Full article

(This article belongs to the Special Issue Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair)

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15 pages, 2373 KiB

Open AccessArticle

DNA Motifs and an Accessory CRISPR Factor Determine Cas1 Binding and Integration Activity in Sulfolobus islandicus

by Tao Liu, Ying Xu, Xiaojie Wang, Qing Ye, Zhenzhen Liu, Zhufeng Zhang, Jilin Liu, Yudong Yang, Xu Peng and Nan Peng

Int. J. Mol. Sci. 2022, 23(17), 10178; https://doi.org/10.3390/ijms231710178 - 05 Sep 2022

Cited by 1 | Viewed by 1476

Abstract

CRISPR-Cas systems empower prokaryotes with adaptive immunity against invasive mobile genetic elements. At the first step of CRISPR immunity adaptation, short DNA fragments from the invaders are integrated into CRISPR arrays at the leader-proximal end. To date, the mechanism of recognition of the [...] Read more.

CRISPR-Cas systems empower prokaryotes with adaptive immunity against invasive mobile genetic elements. At the first step of CRISPR immunity adaptation, short DNA fragments from the invaders are integrated into CRISPR arrays at the leader-proximal end. To date, the mechanism of recognition of the leader-proximal end remains largely unknown. Here, in the Sulfolobus islandicus subtype I-A system, we show that mutations destroying the proximal region reduce CRISPR adaptation in vivo. We identify that a stem-loop structure is present on the leader-proximal end, and we demonstrate that Cas1 preferentially binds the stem-loop structure in vitro. Moreover, we demonstrate that the integrase activity of Cas1 is modulated by interacting with a CRISPR-associated factor Csa3a. When translocated to the CRISPR array, the Csa3a-Cas1 complex is separated by Csa3a binding to the leader-distal motif and Cas1 binding to the leader-proximal end. Mutation at the leader-distal motif reduces CRISPR adaptation efficiency, further confirming the in vivo function of leader-distal motif. Together, our results suggest a general model for binding of Cas1 protein to a leader motif and modulation of integrase activity by an accessory factor. Full article

(This article belongs to the Special Issue CRISPR-Cas in Genomic Manipulation and Antimicrobial Resistance)

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23 pages, 6658 KiB

Open AccessArticle

In Vitro Characterization of Renal Drug Transporter Activity in Kidney Cancer

by Pedro Caetano-Pinto, Nathanil Justian, Maria Dib, Jana Fischer, Maryna Somova, Martin Burchardt and Ingmar Wolff

Int. J. Mol. Sci. 2022, 23(17), 10177; https://doi.org/10.3390/ijms231710177 - 05 Sep 2022

Cited by 3 | Viewed by 2642

Abstract

The activity of drug transporters is central to the secretory function of the kidneys and a defining feature of renal proximal tubule epithelial cells (RPTECs). The expression, regulation, and function of these membrane-bound proteins is well understood under normal renal physiological conditions. However, [...] Read more.

The activity of drug transporters is central to the secretory function of the kidneys and a defining feature of renal proximal tubule epithelial cells (RPTECs). The expression, regulation, and function of these membrane-bound proteins is well understood under normal renal physiological conditions. However, the impact of drug transporters on the pathophysiology of kidney cancer is still elusive. In the present study, we employed different renal cell carcinoma (RCC) cell lines and a prototypical non-malignant RPTEC cell line to characterize the activity, expression, and potential regulatory mechanisms of relevant renal drug transporters in RCC in vitro. An analysis of the uptake and efflux activity, the expression of drug transporters, and the evaluation of cisplatin cytotoxicity under the effects of methylation or epidermal growth factor receptor (EGFR) inhibition showed that the RCC cells retained substantial drug transport activity. In RCC cells, P-glycoprotein was localized in the nucleus and its pharmacological inhibition enhanced cisplatin toxicity in non-malignant RPTECs. On the other hand, methylation inhibition enhanced cisplatin toxicity by upregulating the organic cation uptake activity in RCC cells. Differential effects of methylation and EGFR were observed in transporter expression, showing regulatory heterogeneity in these cells. Interestingly, the non-malignant RPTEC cell line that was used lacked the machinery responsible for organic cation transport, which reiterates the functional losses that renal cells undergo in vitro. Full article

(This article belongs to the Special Issue Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment)

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14 pages, 3211 KiB

Open AccessArticle

Increased Lipids in Chlamydomonas reinhardtii by Multiple Regulations of DOF, LACS2, and CIS1

by Bin Jia, Jianbo Yin, Xiaolian Li, Yingling Li, Xingcai Yang, Chengxiang Lan and Ying Huang

Int. J. Mol. Sci. 2022, 23(17), 10176; https://doi.org/10.3390/ijms231710176 - 05 Sep 2022

Cited by 5 | Viewed by 1914

Abstract

Microalgal lipids are essential for biofuel and dietary supplement production. Lipid engineering for higher production has been studied for years. However, due to the complexity of lipid metabolism, single-gene engineering gradually encounters bottlenecks. Multiple gene regulation is more beneficial to boosting lipid accumulation [...] Read more.

Microalgal lipids are essential for biofuel and dietary supplement production. Lipid engineering for higher production has been studied for years. However, due to the complexity of lipid metabolism, single-gene engineering gradually encounters bottlenecks. Multiple gene regulation is more beneficial to boosting lipid accumulation and further clarifying the complex regulatory mechanism of lipid biosynthesis in the homeostasis of lipids, carbohydrates, and protein metabolism. Here, three lipid-related genes, DOF, LACS2, and CIS, were co-regulated in Chlamydomonas reinhartii by two circles of transformation to overexpress DOF and knock down LACS2 and CIS simultaneously. With the multiple regulations of these genes, the intracellular lipids and FA content increased by 142% and 52%, respectively, compared with CC849, whereas the starch and protein contents decreased by 45% and 24%. Transcriptomic analysis showed that genes in TAG and FA biosynthesis were up-regulated, and genes in starch and protein metabolism were down-regulated. This revealed that more carbon precursor fluxes from starch and protein metabolism were redirected towards lipid synthesis pathways. These results showed that regulating genes in various metabolisms contributed to carbon flux redirection and significantly improved intracellular lipids, demonstrating the potential of multiple gene regulation strategies and providing possible candidates for lipid overproduction in microalgae. Full article

(This article belongs to the Section Molecular Biology)

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17 pages, 1853 KiB

Open AccessReview

CRISPR-Based Genome Editing and Its Applications in Woody Plants

by Tian Min, Delight Hwarari, Dong’ao Li, Ali Movahedi and Liming Yang

Int. J. Mol. Sci. 2022, 23(17), 10175; https://doi.org/10.3390/ijms231710175 - 05 Sep 2022

Cited by 13 | Viewed by 3519

Abstract

CRISPR/Cas-based genome editing technology provides straightforward, proficient, and multifunctional ways for the site-directed modification of organism genomes and genes. The application of CRISPR-based technology in plants has a vast potential value in gene function research, germplasm innovation, and genetic improvement. The complexity of [...] Read more.

CRISPR/Cas-based genome editing technology provides straightforward, proficient, and multifunctional ways for the site-directed modification of organism genomes and genes. The application of CRISPR-based technology in plants has a vast potential value in gene function research, germplasm innovation, and genetic improvement. The complexity of woody plants genome may pose significant challenges in the application and expansion of various new editing techniques, such as Cas9, 12, 13, and 14 effectors, base editing, particularly for timberland species with a long life span, huge genome, and ploidy. Therefore, many novel optimisms have been drawn to molecular breeding research based on woody plants. This review summarizes the recent development of CRISPR/Cas applications for essential traits, including wood properties, flowering, biological stress, abiotic stress, growth, and development in woody plants. We outlined the current problems and future development trends of this technology in germplasm and the improvement of products in woody plants. Full article

(This article belongs to the Special Issue New Advance on Functional Genomics and Genome Editing in Plant)

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18 pages, 4594 KiB

Open AccessArticle

Distress-Mediated Remodeling of Cardiac Connexin-43 in a Novel Cell Model for Arrhythmogenic Heart Diseases

by Carl-Mattheis Wahl, Constanze Schmidt, Markus Hecker and Nina D. Ullrich

Int. J. Mol. Sci. 2022, 23(17), 10174; https://doi.org/10.3390/ijms231710174 - 05 Sep 2022

Cited by 8 | Viewed by 4152

Abstract

Gap junctions and their expression pattern are essential to robust function of intercellular communication and electrical propagation in cardiomyocytes. In healthy myocytes, the main cardiac gap junction protein connexin-43 (Cx43) is located at the intercalated disc providing a clear direction of signal spreading [...] Read more.

Gap junctions and their expression pattern are essential to robust function of intercellular communication and electrical propagation in cardiomyocytes. In healthy myocytes, the main cardiac gap junction protein connexin-43 (Cx43) is located at the intercalated disc providing a clear direction of signal spreading across the cardiac tissue. Dislocation of Cx43 to lateral membranes has been detected in numerous cardiac diseases leading to slowed conduction and high propensity for the development of arrhythmias. At the cellular level, arrhythmogenic diseases are associated with elevated levels of oxidative distress and gap junction remodeling affecting especially the amount and sarcolemmal distribution of Cx43 expression. So far, a mechanistic link between sustained oxidative distress and altered Cx43 expression has not yet been identified. Here, we propose a novel cell model based on murine induced-pluripotent stem cell-derived cardiomyocytes to investigate subcellular signaling pathways linking cardiomyocyte distress with gap junction remodeling. We tested the new hypothesis that chronic distress, induced by rapid pacing, leads to increased reactive oxygen species, which promotes expression of a micro-RNA, miR-1, specific for the control of Cx43. Our data demonstrate that Cx43 expression is highly sensitive to oxidative distress, leading to reduced expression. This effect can be efficiently prevented by the glutathione peroxidase mimetic ebselen. Moreover, Cx43 expression is tightly regulated by miR-1, which is activated by tachypacing-induced oxidative distress. In light of the high arrhythmogenic potential of altered Cx43 expression, we propose miR-1 as a novel target for pharmacological interventions to prevent the maladaptive remodeling processes during chronic distress in the heart. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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21 pages, 1663 KiB

Open AccessReview

Maternal Supplementation of Probiotics, Prebiotics or Postbiotics to Prevent Offspring Metabolic Syndrome: The Gap between Preclinical Results and Clinical Translation

by Ying-Hua Huang, You-Lin Tain and Chien-Ning Hsu

Int. J. Mol. Sci. 2022, 23(17), 10173; https://doi.org/10.3390/ijms231710173 - 05 Sep 2022

Cited by 2 | Viewed by 3616

Abstract

Metabolic syndrome (MetS) is an extremely prevalent complex trait and it can originate in early life. This concept is now being termed the developmental origins of health and disease (DOHaD). Increasing evidence supports that disturbance of gut microbiota influences various risk factors of [...] Read more.

Metabolic syndrome (MetS) is an extremely prevalent complex trait and it can originate in early life. This concept is now being termed the developmental origins of health and disease (DOHaD). Increasing evidence supports that disturbance of gut microbiota influences various risk factors of MetS. The DOHaD theory provides an innovative strategy to prevent MetS through early intervention (i.e., reprogramming). In this review, we summarize the existing literature that supports how environmental cues induced MetS of developmental origins and the interplay between gut microbiota and other fundamental underlying mechanisms. We also present an overview of experimental animal models addressing implementation of gut microbiota-targeted reprogramming interventions to avert the programming of MetS. Even with growing evidence from animal studies supporting the uses of gut microbiota-targeted therapies start before birth to protect against MetS of developmental origins, their effects on pregnant women are still unknown and these results require further clinical translation. Full article

(This article belongs to the Special Issue New Approaches for the Management of Metabolic Syndrome and Related Health Alterations: A Focus in Probiotics, Parabiotics and Postbiotics)

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27 pages, 1836 KiB

Open AccessReview

Connexins and Glucose Metabolism in Cancer

by Jennifer C. Jones and Thomas M. Bodenstine

Int. J. Mol. Sci. 2022, 23(17), 10172; https://doi.org/10.3390/ijms231710172 - 05 Sep 2022

Cited by 4 | Viewed by 3567

Abstract

Connexins are a family of transmembrane proteins that regulate diverse cellular functions. Originally characterized for their ability to mediate direct intercellular communication through the formation of highly regulated membrane channels, their functions have been extended to the exchange of molecules with the extracellular [...] Read more.

Connexins are a family of transmembrane proteins that regulate diverse cellular functions. Originally characterized for their ability to mediate direct intercellular communication through the formation of highly regulated membrane channels, their functions have been extended to the exchange of molecules with the extracellular environment, and the ability to modulate numerous channel-independent effects on processes such as motility and survival. Notably, connexins have been implicated in cancer biology for their context-dependent roles that can both promote or suppress cancer cell function. Moreover, connexins are able to mediate many aspects of cellular metabolism including the intercellular coupling of nutrients and signaling molecules. During cancer progression, changes to substrate utilization occur to support energy production and biomass accumulation. This results in metabolic plasticity that promotes cell survival and proliferation, and can impact therapeutic resistance. Significant progress has been made in our understanding of connexin and cancer biology, however, delineating the roles these multi-faceted proteins play in metabolic adaptation of cancer cells is just beginning. Glucose represents a major carbon substrate for energy production, nucleotide synthesis, carbohydrate modifications and generation of biosynthetic intermediates. While cancer cells often exhibit a dependence on glycolytic metabolism for survival, cellular reprogramming of metabolic pathways is common when blood perfusion is limited in growing tumors. These metabolic changes drive aggressive phenotypes through the acquisition of functional traits. Connections between glucose metabolism and connexin function in cancer cells and the surrounding stroma are now apparent, however much remains to be discovered regarding these relationships. This review discusses the existing evidence in this area and highlights directions for continued investigation. Full article

(This article belongs to the Special Issue Metabolism Signaling and Gene Regulation in Human Health)

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