Current Issues in Molecular Biology

23 pages, 433 KiB

Open AccessReview

Immune Response and Immune Checkpoint Molecules in Patients with Rectal Cancer Undergoing Neoadjuvant Chemoradiotherapy: A Review

by Ioannis M. Koukourakis, Kalliopi Platoni, Dina Tiniakos, Vassilis Kouloulias and Anna Zygogianni

Curr. Issues Mol. Biol. 2023, 45(5), 4495-4517; https://doi.org/10.3390/cimb45050285 - 22 May 2023

Cited by 1 | Viewed by 1340

Abstract

It is well-established that tumor antigens and molecules expressed and secreted by cancer cells trigger innate and adaptive immune responses. These two types of anti-tumor immunity lead to the infiltration of the tumor’s microenvironment by immune cells with either regulatory or cytotoxic properties. [...] Read more.

It is well-established that tumor antigens and molecules expressed and secreted by cancer cells trigger innate and adaptive immune responses. These two types of anti-tumor immunity lead to the infiltration of the tumor’s microenvironment by immune cells with either regulatory or cytotoxic properties. Whether this response is associated with tumor eradication after radiotherapy and chemotherapy or regrowth has been a matter of extensive research through the years, mainly focusing on tumor-infiltrating lymphocytes and monocytes and their subtypes, and the expression of immune checkpoint and other immune-related molecules by both immune and cancer cells in the tumor microenvironment. A literature search has been conducted on studies dealing with the immune response in patients with rectal cancer treated with neoadjuvant radiotherapy or chemoradiotherapy, assessing its impact on locoregional control and survival and underlying the potential role of immunotherapy in the treatment of this cancer subtype. Here, we provide an overview of the interactions between local/systemic anti-tumor immunity, cancer-related immune checkpoint, and other immunological pathways and radiotherapy, and how these affect the prognosis of rectal cancer patients. Chemoradiotherapy induces critical immunological changes in the tumor microenvironment and cancer cells that can be exploited for therapeutic interventions in rectal cancer. Full article

(This article belongs to the Special Issue Understanding Cellular Radiation Responses for Radiation Therapy)

15 pages, 1064 KiB

Open AccessReview

Insights into Advanced Neurological Dysfunction Mechanisms Following DBS Surgery in Parkinson’s Patients: Neuroinflammation and Pyroptosis

by Hao Meng, Jia-Hang Wei, Peng-Zheng Yu, Jia-Xin Ren, Meng-Yao Tang, Jun-Yi Sun, Xiao-Yu Yan and Jing Su

Curr. Issues Mol. Biol. 2023, 45(5), 4480-4494; https://doi.org/10.3390/cimb45050284 - 20 May 2023

Cited by 1 | Viewed by 1672

Abstract

Parkinson’s disease is a severe neurodegenerative disorder. Currently, deep brain electrical stimulation (DBS) is the first line of surgical treatment. However, serious neurological impairments such as speech disorders, disturbances of consciousness, and depression after surgery limit the efficacy of treatment. In this review, [...] Read more.

Parkinson’s disease is a severe neurodegenerative disorder. Currently, deep brain electrical stimulation (DBS) is the first line of surgical treatment. However, serious neurological impairments such as speech disorders, disturbances of consciousness, and depression after surgery limit the efficacy of treatment. In this review, we summarize the recent experimental and clinical studies that have explored the possible causes of neurological deficits after DBS. Furthermore, we tried to identify clues from oxidative stress and pathological changes in patients that could lead to the activation of microglia and astrocytes in DBS surgical injury. Notably, reliable evidence supports the idea that neuroinflammation is caused by microglia and astrocytes, which may contribute to caspase-1 pathway-mediated neuronal pyroptosis. Finally, existing drugs and treatments may partially ameliorate the loss of neurological function in patients following DBS surgery by exerting neuroprotective effects. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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29 pages, 1777 KiB

Open AccessReview

Mitochondria Have Made a Long Evolutionary Path from Ancient Bacteria Immigrants within Eukaryotic Cells to Essential Cellular Hosts and Key Players in Human Health and Disease

by Anna Atlante and Daniela Valenti

Curr. Issues Mol. Biol. 2023, 45(5), 4451-4479; https://doi.org/10.3390/cimb45050283 - 19 May 2023

Cited by 3 | Viewed by 4055

Abstract

Mitochondria have made a long evolutionary path from ancient bacteria immigrants within the eukaryotic cell to become key players for the cell, assuming crucial multitasking skills critical for human health and disease. Traditionally identified as the powerhouses of eukaryotic cells due to their [...] Read more.

Mitochondria have made a long evolutionary path from ancient bacteria immigrants within the eukaryotic cell to become key players for the cell, assuming crucial multitasking skills critical for human health and disease. Traditionally identified as the powerhouses of eukaryotic cells due to their central role in energy metabolism, these chemiosmotic machines that synthesize ATP are known as the only maternally inherited organelles with their own genome, where mutations can cause diseases, opening up the field of mitochondrial medicine. More recently, the omics era has highlighted mitochondria as biosynthetic and signaling organelles influencing the behaviors of cells and organisms, making mitochondria the most studied organelles in the biomedical sciences. In this review, we will especially focus on certain ‘novelties’ in mitochondrial biology “left in the shadows” because, although they have been discovered for some time, they are still not taken with due consideration. We will focus on certain particularities of these organelles, for example, those relating to their metabolism and energy efficiency. In particular, some of their functions that reflect the type of cell in which they reside will be critically discussed, for example, the role of some carriers that are strictly functional to the typical metabolism of the cell or to the tissue specialization. Furthermore, some diseases in whose pathogenesis, surprisingly, mitochondria are involved will be mentioned. Full article

(This article belongs to the Special Issue Mitochondrial Function and Dysfunction)

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20 pages, 714 KiB

Open AccessReview

Brassica napus Haploid and Double Haploid Production and Its Latest Applications

by Ewa Starosta, Justyna Szwarc, Janetta Niemann, Katarzyna Szewczyk and Dorota Weigt

Curr. Issues Mol. Biol. 2023, 45(5), 4431-4450; https://doi.org/10.3390/cimb45050282 - 18 May 2023

Cited by 1 | Viewed by 2188

Abstract

Rapeseed is one of the most important oil crops in the world. Increasing demand for oil and limited agronomic capabilities of present-day rapeseed result in the need for rapid development of new, superior cultivars. Double haploid (DH) technology is a fast and convenient [...] Read more.

Rapeseed is one of the most important oil crops in the world. Increasing demand for oil and limited agronomic capabilities of present-day rapeseed result in the need for rapid development of new, superior cultivars. Double haploid (DH) technology is a fast and convenient approach in plant breeding as well as genetic research. Brassica napus is considered a model species for DH production based on microspore embryogenesis; however, the molecular mechanisms underlying microspore reprogramming are still vague. It is known that morphological changes are accompanied by gene and protein expression patterns, alongside carbohydrate and lipid metabolism. Novel, more efficient methods for DH rapeseed production have been reported. This review covers new findings and advances in Brassica napus DH production as well as the latest reports related to agronomically important traits in molecular studies employing the double haploid rapeseed lines. Full article

(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)

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15 pages, 1696 KiB

Open AccessArticle

Mapping and Functional Analysis of QTL for Kernel Number per Row in Tropical and Temperate–Tropical Introgression Lines of Maize (Zea mays L.)

by Yuling Wang, Yaqi Bi, Fuyan Jiang, Ranjan Kumar Shaw, Jiachen Sun, Can Hu, Ruijia Guo and Xingming Fan

Curr. Issues Mol. Biol. 2023, 45(5), 4416-4430; https://doi.org/10.3390/cimb45050281 - 18 May 2023

Cited by 6 | Viewed by 1507

Abstract

Kernel number per row (KNR) is an essential component of maize (Zea mays L.) grain yield (GY), and understanding its genetic mechanism is crucial to improve GY. In this study, two F₇ recombinant inbred line (RIL) populations were created using a [...] Read more.

Kernel number per row (KNR) is an essential component of maize (Zea mays L.) grain yield (GY), and understanding its genetic mechanism is crucial to improve GY. In this study, two F₇ recombinant inbred line (RIL) populations were created using a temperate–tropical introgression line TML418 and a tropical inbred line CML312 as female parents and a backbone maize inbred line Ye107 as the common male parent. Bi-parental quantitative trait locus (QTL) mapping and genome-wide association analysis (GWAS) were then performed on 399 lines of the two maize RIL populations for KNR in two different environments using 4118 validated single nucleotide polymorphism (SNP) markers. This study aimed to: (1) detect molecular markers and/or the genomic regions associated with KNR; (2) identify the candidate genes controlling KNR; and (3) analyze whether the candidate genes are useful in improving GY. The authors reported a total of 7 QTLs tightly linked to KNR through bi-parental QTL mapping and identified 21 SNPs significantly associated with KNR through GWAS. Among these, a highly confident locus qKNR7-1 was detected at two locations, Dehong and Baoshan, with both mapping approaches. At this locus, three novel candidate genes (Zm00001d022202, Zm00001d022168, Zm00001d022169) were identified to be associated with KNR. These candidate genes were primarily involved in the processes related to compound metabolism, biosynthesis, protein modification, degradation, and denaturation, all of which were related to the inflorescence development affecting KNR. These three candidate genes were not reported previously and are considered new candidate genes for KNR. The progeny of the hybrid Ye107 × TML418 exhibited strong heterosis for KNR, which the authors believe might be related to qKNR7-1. This study provides a theoretical foundation for future research on the genetic mechanism underlying KNR in maize and the use of heterotic patterns to develop high-yielding hybrids. Full article

(This article belongs to the Special Issue Functional Genomics and Comparative Genomics Analysis in Plants)

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16 pages, 619 KiB

Open AccessReview

Hidradenitis Suppurativa: Molecular Etiology, Pathophysiology, and Management—A Systematic Review

by Michael Joseph Diaz, Shaliz Aflatooni, Parsa Abdi, Rina Li, Michelle Robert Anthony, Sphurti Neelam, Chris Farkouh, Jasmine Thuy Tran, Steven Svoboda, Mahtab Forouzandeh and Rodrigo H. Valdes Rodriguez

Curr. Issues Mol. Biol. 2023, 45(5), 4400-4415; https://doi.org/10.3390/cimb45050280 - 17 May 2023

Cited by 1 | Viewed by 2501

Abstract

Hidradenitis suppurativa is a chronic inflammatory skin condition that affects the hair follicles in areas of the body with apocrine glands. The condition is characterized by recurrent, painful nodules, abscesses, and draining sinuses that can lead to scarring and disfigurement. In this present [...] Read more.

Hidradenitis suppurativa is a chronic inflammatory skin condition that affects the hair follicles in areas of the body with apocrine glands. The condition is characterized by recurrent, painful nodules, abscesses, and draining sinuses that can lead to scarring and disfigurement. In this present study, we provide a focused evaluation of recent developments in hidradenitis suppurativa research, including novel therapeutics and promising biomarkers that may facilitate clinical diagnosis and treatment. We conducted a systematic review of controlled trials, randomized controlled trials, meta-analyses, case reports, and Cochrane Review articles in accordance with the PRISMA guidelines. The Cochrane Library, PubMed, EMBASE, and Epistemonikos databases were queried via Title/Abstract screen. Eligibility criteria included the following: (1) has a primary focus on hidradenitis suppurativa, (2) includes measurable outcomes data with robust comparators, (3) details the sample population, (4) English language, and (5) archived as full-text journal articles. A total of 42 eligible articles were selected for review. Qualitative evaluation identified numerous developments in our understanding of the disease’s multiple potential etiologies, pathophysiology, and treatment options. It is important for individuals with hidradenitis suppurativa to work closely with a healthcare provider to develop a comprehensive treatment plan that addresses their individual needs and goals. To meet this objective, providers must keep current with developments in the genetic, immunological, microbiological, and environmental factors contributing to the disease’s development and progression. Full article

(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)

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11 pages, 5550 KiB

Open AccessCommunication

Protective Effects of Apamin on Acetaminophen-Induced Hepatotoxicity in Mice

by Hyo-Jeong Jang, Jaechan Leem and Gyun Moo Kim

Curr. Issues Mol. Biol. 2023, 45(5), 4389-4399; https://doi.org/10.3390/cimb45050279 - 17 May 2023

Cited by 2 | Viewed by 1614

Abstract

Acetaminophen (APAP) overdose can cause severe liver damage, but therapeutic options are limited. Apamin is a natural peptide present in bee venom and has antioxidant and anti-inflammatory properties. Accumulating evidence suggests that apamin has favorable actions in rodent models of inflammatory disorders. Here, [...] Read more.

Acetaminophen (APAP) overdose can cause severe liver damage, but therapeutic options are limited. Apamin is a natural peptide present in bee venom and has antioxidant and anti-inflammatory properties. Accumulating evidence suggests that apamin has favorable actions in rodent models of inflammatory disorders. Here, we examined the effect of apamin on APAP-evoked hepatotoxicity. Intraperitoneal administration of apamin (0.1 mg/kg) alleviated histological abnormalities and reduced serum levels of liver enzymes in mice injected with APAP. Apamin inhibited oxidative stress through an increase in the amount of glutathione and activation of the antioxidant system. Apamin also attenuated apoptosis with inhibition of caspase-3 activation. Moreover, apamin reduced serum and hepatic levels of cytokines in APAP-injected mice. These effects were accompanied by suppression of NF-κB activation. Furthermore, apamin inhibited chemokine expression and inflammatory cell infiltration. Our results suggest that apamin dampens APAP-evoked hepatotoxicity through inhibiting oxidative stress, apoptosis, and inflammation. Full article

(This article belongs to the Special Issue Natural Products in Biomedicine and Pharmacotherapy)

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14 pages, 3647 KiB

Open AccessArticle

A Novel Approach to Reducing Lung Metastasis in Osteosarcoma: Increasing Cell Stiffness with Carbenoxolone

by Kouji Kita, Kunihiro Asanuma, Takayuki Okamoto, Eiji Kawamoto, Koichi Nakamura, Tomohito Hagi, Tomoki Nakamura, Motomu Shimaoka and Akihiro Sudo

Curr. Issues Mol. Biol. 2023, 45(5), 4375-4388; https://doi.org/10.3390/cimb45050278 - 17 May 2023

Viewed by 1278

Abstract

Aim: Primary malignant bone tumor osteosarcoma can metastasize to the lung. Diminishing lung metastasis would positively affect the prognosis of patients. Our previous studies demonstrated that highly metastatic osteosarcoma cell lines are significantly softer than low-metastasis cell lines. We therefore hypothesized that increasing [...] Read more.

Aim: Primary malignant bone tumor osteosarcoma can metastasize to the lung. Diminishing lung metastasis would positively affect the prognosis of patients. Our previous studies demonstrated that highly metastatic osteosarcoma cell lines are significantly softer than low-metastasis cell lines. We therefore hypothesized that increasing cell stiffness would suppress metastasis by reducing cell motility. In this study, we tested whether carbenoxolone (CBX) increases the stiffness of LM8 osteosarcoma cells and prevents lung metastasis in vivo. Methods: We evaluated the actin cytoskeletal structure and polymerization of CBX-treated LM8 cells using actin staining. Cell stiffness was measured using atomic force microscopy. Metastasis-related cell functions were analyzed using cell proliferation, wound healing, invasion, and cell adhesion assays. Furthermore, lung metastasis was examined in LM8-bearing mice administered with CBX. Results: Treatment with CBX significantly increased actin staining intensity and stiffness of LM8 cells compared with vehicle-treated LM8 cells (p < 0.01). In Young’s modulus images, compared with the control group, rigid fibrillate structures were observed in the CBX treatment group. CBX suppressed cell migration, invasion, and adhesion but not cell proliferation. The number of LM8 lung metastases were significantly reduced in the CBX administration group compared with the control group (p < 0.01). Conclusion: In this study, we demonstrated that CBX increases tumor cell stiffness and significantly reduces lung metastasis. Our study is the first to provide evidence that reducing cell motility by increasing cell stiffness might be effective as a novel anti-metastasis approach in vivo. Full article

(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)

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16 pages, 626 KiB

Open AccessArticle

Clinicopathological Characteristics and Mutational Landscape of APC, HOXB13, and KRAS among Rwandan Patients with Colorectal Cancer

by Felix Manirakiza, Eric Rutaganda, Hidetaka Yamada, Yuji Iwashita, Belson Rugwizangoga, Benoit Seminega, Vincent Dusabejambo, Gervais Ntakirutimana, Deogratias Ruhangaza, Annette Uwineza, Kazuya Shinmura and Haruhiko Sugimura

Curr. Issues Mol. Biol. 2023, 45(5), 4359-4374; https://doi.org/10.3390/cimb45050277 - 16 May 2023

Cited by 2 | Viewed by 1578

Abstract

Cancer research in Rwanda is estimated to be less than 1% of the total African cancer research output with limited research on colorectal cancer (CRC). Rwandan patients with CRC are young, with more females being affected than males, and most patients present with [...] Read more.

Cancer research in Rwanda is estimated to be less than 1% of the total African cancer research output with limited research on colorectal cancer (CRC). Rwandan patients with CRC are young, with more females being affected than males, and most patients present with advanced disease. Considering the paucity of oncological genetic studies in this population, we investigated the mutational status of CRC tissues, focusing on the Adenomatous polyposis coli (APC), Kirsten rat sarcoma (KRAS), and Homeobox B13 (HOXB13) genes. Our aim was to determine whether there were any differences between Rwandan patients and other populations. To do so, we performed Sanger sequencing of the DNA extracted from formalin-fixed paraffin-embedded adenocarcinoma samples from 54 patients (mean age: 60 years). Most tumors were located in the rectum (83.3%), and 92.6% of the tumors were low-grade. Most patients (70.4%) reported never smoking, and 61.1% of patients had consumed alcohol. We identified 27 variants of APC, including 3 novel mutations (c.4310_4319delAAACACCTCC, c.4463_4470delinsA, and c.4506_4507delT). All three novel mutations are classified as deleterious by MutationTaster2021. We found four synonymous variants (c.330C>A, c.366C>T, c.513T>C, and c.735G>A) of HOXB13. For KRAS, we found six variants (Asp173, Gly13Asp, Gly12Ala, Gly12Asp, Gly12Val, and Gln61His), the last four of which are pathogenic. In conclusion, here we contribute new genetic variation data and provide clinicopathological information pertinent to CRC in Rwanda. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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15 pages, 1019 KiB

Open AccessReview

Cellular and Genetic Background of Osteosarcoma

by Inga Urlić, Marijana Šimić Jovičić, Karla Ostojić and Alan Ivković

Curr. Issues Mol. Biol. 2023, 45(5), 4344-4358; https://doi.org/10.3390/cimb45050276 - 15 May 2023

Cited by 5 | Viewed by 1619

Abstract

Osteosarcoma describes a tumor of mesenchymal origin with an annual incidence rate of four to five people per million. Even though chemotherapy treatment has shown success in non-metastatic osteosarcoma, metastatic disease still has a low survival rate of 20%. A targeted therapy approach [...] Read more.

Osteosarcoma describes a tumor of mesenchymal origin with an annual incidence rate of four to five people per million. Even though chemotherapy treatment has shown success in non-metastatic osteosarcoma, metastatic disease still has a low survival rate of 20%. A targeted therapy approach is limited due to high heterogeneity of tumors, and different underlying mutations. In this review, we will summarize new advances obtained by new technologies, such as next generation sequencing and single-cell sequencing. These new techniques have enabled better assessment of cell populations within osteosarcoma, as well as an understanding of the molecular pathogenesis. We also discuss the presence and properties of osteosarcoma stem cells—the cell population within the tumor that is responsible for metastasis, recurrence, and drug resistance. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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13 pages, 879 KiB

Open AccessReview

Is Th17-Targeted Therapy Effective in Systemic Lupus Erythematosus?

by Marin Petrić and Mislav Radić

Curr. Issues Mol. Biol. 2023, 45(5), 4331-4343; https://doi.org/10.3390/cimb45050275 - 15 May 2023

Cited by 9 | Viewed by 2052

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical manifestations. The proposed pathophysiological hypotheses of SLE are numerous, involving both innate and adaptive abnormal immune responses. SLE is characterized by the overproduction of different autoantibodies that form [...] Read more.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical manifestations. The proposed pathophysiological hypotheses of SLE are numerous, involving both innate and adaptive abnormal immune responses. SLE is characterized by the overproduction of different autoantibodies that form immune complexes, which cause damage in different organs. Current therapeutic modalities are anti-inflammatory and immunosuppressive. In the last decade, we have witnessed the development of many biologicals targeting different cytokines and other molecules. One of them is interleukin-17 (IL-17), a central cytokine of a proinflammatory process that is mediated by a group of helper T cells called Th17. Direct inhibitors of IL-17 are used in psoriatic arthritis, spondyloarthritis, and other diseases. Evidence about the therapeutic potential of Th17-targeted therapies in SLE is scarce, and probably the most promising is related to lupus nephritis. As SLE is a complex heterogeneous disease with different cytokines involved in its pathogenesis, it is highly unlikely that inhibition of only one molecule, such as IL-17, will be effective in the treatment of all clinical manifestations. Future studies should identify SLE patients that are eligible for Th17-targeted therapy. Full article

(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)

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14 pages, 1764 KiB

Open AccessArticle

Influence of Auditory Integrative Training on Casein Kinase 2 and Its Impact on Behavioral and Social Interaction in Children with Autism Spectrum Disorder

by Laila Al-Ayadhi, Ramesa Shafi Bhat, Farah Ali Alghamdi, Abdulmalik S. Alhadlaq and Afaf El-Ansary

Curr. Issues Mol. Biol. 2023, 45(5), 4317-4330; https://doi.org/10.3390/cimb45050274 - 15 May 2023

Viewed by 1670

Abstract

Considerable disturbances in post-translational protein phosphorylation have recently been discovered in multiple neurological disorders. Casein kinase-2 (CK2) is a tetrameric Ser/Thr protein kinase that phosphorylates a large number of substrates and contributes in several cellular physiological and pathological processes. CK2 is highly expressed [...] Read more.

Considerable disturbances in post-translational protein phosphorylation have recently been discovered in multiple neurological disorders. Casein kinase-2 (CK2) is a tetrameric Ser/Thr protein kinase that phosphorylates a large number of substrates and contributes in several cellular physiological and pathological processes. CK2 is highly expressed in the mammalian brain and catalyzes the phosphorylation of a large number of substrates that are crucial in neuronal or glial homeostasis and inflammatory signaling processes across synapses. In this study, we investigated the impact of auditory integration therapy (AIT) for the treatment of sensory processing abnormalities in autism on plasma CK2 levels. A total of 25 ASD children, aged between 5 and 12 years, were enrolled and participated in the present research study. AIT was performed for two weeks, for a period of 30 min, twice a day, with a 3 h interval between sessions. Before and after AIT, the Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), and Short Sensory Profile (SSP) scores were calculated, and plasma CK2 levels were assayed using an ELISA test. The CARS and SRS indices of autism severity improved as a result of AIT, which could be related to the decreased level of plasma CK2. However, the mean value of the SSP scores was not significantly increased after AIT. The relationship between CK2 downregulation and glutamate excitotoxicity, neuro-inflammation, and leaky gut, as etiological mechanisms in ASD, was proposed and discussed. Further research, conducted on a larger scale and with a longer study duration, are required to assess whether the cognitive improvement in ASD children after AIT is related to the downregulation of CK2. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies)

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16 pages, 1075 KiB

Open AccessReview

Pharmacological Significance of Heme Oxygenase 1 in Prostate Cancer

by Mohamed Ben-Eltriki, Erysa J. Gayle, Noah Walker and Subrata Deb

Curr. Issues Mol. Biol. 2023, 45(5), 4301-4316; https://doi.org/10.3390/cimb45050273 - 15 May 2023

Cited by 2 | Viewed by 1893

Abstract

Heme oxygenase 1 (HO-1) is a detoxifying antioxidant microsomal enzyme that regulates inflammation, apoptosis, cell proliferation, and angiogenesis in prostate cancer (PCa). This makes HO-1 a promising target for therapeutic prevention and treatment due to its anti-inflammatory properties and ability to control redox [...] Read more.

Heme oxygenase 1 (HO-1) is a detoxifying antioxidant microsomal enzyme that regulates inflammation, apoptosis, cell proliferation, and angiogenesis in prostate cancer (PCa). This makes HO-1 a promising target for therapeutic prevention and treatment due to its anti-inflammatory properties and ability to control redox homeostasis. Clinical evidence highlights the possible correlation between HO-1 expression and PCa growth, aggressiveness, metastasized tumors, resistance to therapy, and poor clinical outcomes. Interestingly, studies have reported anticancer benefits mediated by both HO-1 induction and inhibition in PCa models. Contrasting evidence exists on the role of HO-1 in PCa progression and possible treatment targets. Herein, we provide an overview of available evidence on the clinical significance of HO-1 signaling in PCa. It appears that the beneficial effects of HO-1 induction or inhibition are dependent on whether it is a normal versus malignant cell as well as the intensity (major vs. minor) of the increase in HO-1 enzymatic activity. The current literature evidence indicates that HO-1 has dual effects in PCa. The amount of cellular iron and reactive oxygen species (ROS) can determine the role of HO-1 in PCa. A major increase in ROS enforces HO-1 to a protective role. HO-1 overexpression may provide cryoprotection to normal cells against oxidative stress via suppressing the expression of proinflammatory genes, and thus offer therapeutic prevention. In contrast, a moderate increase in ROS can lead to the perpetrator role of HO-1, which is associated with PCa progression and metastasis. HO-1 inhibition by xenobiotics in DNA-damaged cells tilts the balance to promote apoptosis and inhibit PCa proliferation and metastasis. Overall, the totality of the evidence revealed that HO-1 may play a dual role in the therapeutic prevention and treatment of PCa. Full article

(This article belongs to the Special Issue Drugs: Mechanisms of Action, Molecular Targets and Biological Activities)

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16 pages, 895 KiB

Open AccessReview

CNS Border-Associated Macrophages: Ontogeny and Potential Implication in Disease

by Iasonas Dermitzakis, Paschalis Theotokis, Paschalis Evangelidis, Efthymia Delilampou, Nikolaos Evangelidis, Anastasia Chatzisavvidou, Eleni Avramidou and Maria Eleni Manthou

Curr. Issues Mol. Biol. 2023, 45(5), 4285-4300; https://doi.org/10.3390/cimb45050272 - 13 May 2023

Cited by 11 | Viewed by 2426

Abstract

Being immune privileged, the central nervous system (CNS) is constituted by unique parenchymal and non-parenchymal tissue-resident macrophages, namely, microglia and border-associated macrophages (BAMs), respectively. BAMs are found in the choroid plexus, meningeal and perivascular spaces, playing critical roles in maintaining CNS homeostasis while [...] Read more.

Being immune privileged, the central nervous system (CNS) is constituted by unique parenchymal and non-parenchymal tissue-resident macrophages, namely, microglia and border-associated macrophages (BAMs), respectively. BAMs are found in the choroid plexus, meningeal and perivascular spaces, playing critical roles in maintaining CNS homeostasis while being phenotypically and functionally distinct from microglial cells. Although the ontogeny of microglia has been largely determined, BAMs need comparable scrutiny as they have been recently discovered and have not been thoroughly explored. Newly developed techniques have transformed our understanding of BAMs, revealing their cellular heterogeneity and diversity. Recent data showed that BAMs also originate from yolk sac progenitors instead of bone marrow-derived monocytes, highlighting the absolute need to further investigate their repopulation pattern in adult CNS. Shedding light on the molecular cues and drivers orchestrating BAM generation is essential for delineating their cellular identity. BAMs are receiving more attention since they are gradually incorporated into neurodegenerative and neuroinflammatory disease evaluations. The present review provides insights towards the current understanding regarding the ontogeny of BAMs and their involvement in CNS diseases, paving their way into targeted therapeutic strategies and precision medicine. Full article

(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)

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24 pages, 9452 KiB

Open AccessArticle

De Novo Design of Anti-COVID Drugs Using Machine Learning-Based Equivariant Diffusion Model Targeting the Spike Protein

by Vidya Niranjan, Akshay Uttarkar, Ananya Ramakrishnan, Anagha Muralidharan, Abhay Shashidhara, Anushri Acharya, Avila Tarani and Jitendra Kumar

Curr. Issues Mol. Biol. 2023, 45(5), 4261-4284; https://doi.org/10.3390/cimb45050271 - 12 May 2023

Cited by 3 | Viewed by 2253

Abstract

The drug discovery and research for an anti-COVID-19 drug has been ongoing despite repurposed drugs in the market. Over time, these drugs were discontinued due to side effects. The search for effective drugs is still under process. The role of Machine Learning (ML) [...] Read more.

The drug discovery and research for an anti-COVID-19 drug has been ongoing despite repurposed drugs in the market. Over time, these drugs were discontinued due to side effects. The search for effective drugs is still under process. The role of Machine Learning (ML) is critical in the search for novel drug compounds. In the current work, using the equivariant diffusion model, we built novel compounds targeting the spike protein of SARS-CoV-2. Using the ML models, 196 de novo compounds were generated which had no hits on any major chemical databases. These novel compounds fulfilled all the criteria of ADMET properties to be lead-like and drug-like compounds. Of the 196 compounds, 15 were docked with high confidence in the target. These compounds were further subjected to molecular docking, the best compound having an IUPAC name of (4aS,4bR,8aS,8bS)-4a,8a-dimethylbiphenylene-1,4,5,8(4aH,4bH,8aH,8bH)-tetraone and a binding score of −6.930 kcal/mol. The principal compound is labeled as CoECG-M1. Density Function Theory (DFT) and Quantum optimization was carried out along with the study of ADMET properties. This suggests that the compound has potential drug-like properties. The docked complex was further subjected to MD simulations, GBSA, and metadynamics simulations to gain insights into the stability of binding. The model can be in the future modified to improve the positive docking rate. Full article

(This article belongs to the Special Issue Drug Development and Repositioning Methodology on COVID-19)

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15 pages, 350 KiB

Open AccessReview

Preclinical Models and Promising Pharmacotherapeutic Strategies in Liver Fibrosis: An Update

by Tea Omanovic Kolaric, Lucija Kuna, Marina Covic, Hrvoje Roguljic, Anita Matic, Renata Sikora, Marija Hefer, Ana Petrovic, Vjera Mihaljevic, Robert Smolic, Ines Bilic-Curcic, Aleksandar Vcev and Martina Smolic

Curr. Issues Mol. Biol. 2023, 45(5), 4246-4260; https://doi.org/10.3390/cimb45050270 - 11 May 2023

Viewed by 1458

Abstract

Liver fibrosis represents one of the greatest challenges in medicine. The fact that it develops with the progression of numerous diseases with high prevalence (NAFLD, viral hepatitis, etc.) makes liver fibrosis an even greater global health problem. Accordingly, it has received much attention [...] Read more.

Liver fibrosis represents one of the greatest challenges in medicine. The fact that it develops with the progression of numerous diseases with high prevalence (NAFLD, viral hepatitis, etc.) makes liver fibrosis an even greater global health problem. Accordingly, it has received much attention from numerous researchers who have developed various in vitro and in vivo models to better understand the mechanisms underlying fibrosis development. All these efforts led to the discovery of numerous agents with antifibrotic properties, with hepatic stellate cells and the extracellular matrix at the center of these pharmacotherapeutic strategies. This review focuses on the current data on numerous in vivo and in vitro models of liver fibrosis and on various pharmacotherapeutic targets in the treatment of liver fibrosis. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases, 2nd Volume)

18 pages, 4777 KiB

Open AccessArticle

The Epigenetic Reader Protein SP140 Regulates Dendritic Cell Activation, Maturation and Tolerogenic Potential

by Mohammed Ghiboub, Matthew Bell, Dovile Sinkeviciute, Rab K. Prinjha, Menno P. J. de Winther, Nicola R. Harker, David F. Tough and Wouter J. de Jonge

Curr. Issues Mol. Biol. 2023, 45(5), 4228-4245; https://doi.org/10.3390/cimb45050269 - 11 May 2023

Viewed by 2335

Abstract

SP140 is an epigenetic reader protein expressed predominantly in immune cells. GWAS studies have shown an association between SP140 single nucleotide polymorphisms (SNPs) and diverse autoimmune and inflammatory diseases, suggesting a possible pathogenic role for SP140 in immune-mediated diseases. We previously demonstrated that [...] Read more.

SP140 is an epigenetic reader protein expressed predominantly in immune cells. GWAS studies have shown an association between SP140 single nucleotide polymorphisms (SNPs) and diverse autoimmune and inflammatory diseases, suggesting a possible pathogenic role for SP140 in immune-mediated diseases. We previously demonstrated that treatment of human macrophages with the novel selective inhibitor of the SP140 protein (GSK761) reduced the expression of endotoxin-induced cytokines, implicating a role of SP140 in the function of inflammatory macrophages. In this study, we investigated the effects of GSK761 on in vitro human dendritic cell (DC) differentiation and maturation, assessing the expression of cytokines and co-stimulatory molecules and their capacity to stimulate T-cell activation and induce phenotypic changes. In DCs, lipopolysaccharide (LPS) stimulation induced an increase in SP140 expression and its recruitment to transcription start sites (TSS) of pro-inflammatory cytokine genes. Moreover, LPS-induced cytokines such as TNF, IL-6, and IL-1β were reduced in GSK761- or SP140 siRNA- treated DCs. Although GSK761 did not significantly affect the expression of surface markers that define the differentiation of CD14⁺ monocytes into immature DCs (iDCs), subsequent maturation of iDCs to mature DCs was significantly inhibited. GSK761 strongly reduced expression of the maturation marker CD83, the co-stimulatory molecules CD80 and CD86, and the lipid-antigen presentation molecule CD1b. Finally, when the ability of DCs to stimulate recall T-cell responses by vaccine-specific T cells was assessed, T cells stimulated by GSK761-treated DCs showed reduced TBX21 and RORA expression and increased FOXP3 expression, indicating a preferential generation of regulatory T cells. Overall, this study suggests that SP140 inhibition enhances the tolerogenic properties of DCs, supporting the rationale of targeting SP140 in autoimmune and inflammatory diseases where DC-mediated inflammatory responses contribute to disease pathogenesis. Full article

(This article belongs to the Special Issue Advances in Understanding Molecular Basis of Inflammatory Diseases)

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14 pages, 1774 KiB

Open AccessArticle

Low-Molecular-Weight Chondroitin Sulfates Alleviate Simulated Microgravity-Induced Oxidative Stress and Bone Loss in Mice

by Rong Lan, Ye Li, Xinying Zhao, Rong Shen, Ruili Wang, Ruixin Mao and Shuangsheng Guo

Curr. Issues Mol. Biol. 2023, 45(5), 4214-4227; https://doi.org/10.3390/cimb45050268 - 10 May 2023

Viewed by 1364

Abstract

(1) Background: Many studies have shown that microgravity experienced by astronauts or long-term bedridden patients results in increased oxidative stress and bone loss. Low-molecular-weight chondroitin sulfates (LMWCSs) prepared from intact chondroitin sulfate (CS) have been demonstrated to possess good antioxidant and osteogenic activities [...] Read more.

(1) Background: Many studies have shown that microgravity experienced by astronauts or long-term bedridden patients results in increased oxidative stress and bone loss. Low-molecular-weight chondroitin sulfates (LMWCSs) prepared from intact chondroitin sulfate (CS) have been demonstrated to possess good antioxidant and osteogenic activities in vitro. This study aimed to assess the antioxidant activity of the LMWCSs in vivo and evaluate their potential in preventing microgravity-induced bone loss. (2) Methods: we used hind limb suspension (HLS) mice to simulate microgravity in vivo. We investigated the effects of LMWCSs against oxidative stress damage and bone loss in HLS mice and compared the findings with those of CS and a non-treatment group. (3) Results: LMWCSs reduced the HLS-induced oxidative stress level, prevented HLS-induced alterations in bone microstructure and mechanical strength, and reversed changes in bone metabolism indicators in HLS mice. Additionally, LMWCSs downregulated the mRNA expression levels of antioxidant enzyme- and osteogenic-related genes in HLS mice. The results showed that overall effect of LMWCSs was better than that of CS. (4) Conclusions: LMWCSs protect against the bone loss caused by simulated microgravity, which may be related to their ability to reduce oxidative stress. LMWCSs can be envisaged as potential antioxidants and bone loss protective agents in microgravity. Full article

(This article belongs to the Section Molecular Medicine)

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14 pages, 3345 KiB

Open AccessArticle

Cloning, Expression, and Functional Characterization of FUT1, a Key Gene for Histo-Blood Group Antigens Synthesis in Crassostrea gigas

by Binbin Gui, Lin Yao, Meng Qu, Weiran Zhang, Mingyu Li, Yanhua Jiang and Lianzhu Wang

Curr. Issues Mol. Biol. 2023, 45(5), 4200-4213; https://doi.org/10.3390/cimb45050267 - 09 May 2023

Viewed by 1327

Abstract

Histo-blood group antigens (HBGAs) comprise a family of cell-surface carbohydrates that are considered norovirus-specific binding receptors or ligands. HBGA-like molecules have also been detected in oysters as common norovirus carriers, although the pathway involved in the synthesis of these molecules in oysters has [...] Read more.

Histo-blood group antigens (HBGAs) comprise a family of cell-surface carbohydrates that are considered norovirus-specific binding receptors or ligands. HBGA-like molecules have also been detected in oysters as common norovirus carriers, although the pathway involved in the synthesis of these molecules in oysters has yet to be elucidated. We isolated and identified a key gene involved in the synthesis of HBGA-like molecules, FUT1, from Crassostrea gigas, named CgFUT1. Real-time quantitative polymerase chain reaction analysis showed that CgFUT1 mRNA was expressed in the mantle, gill, muscle, labellum, and hepatopancreatic tissues of C. gigas, with the hepatopancreas exhibiting the highest expression level. A recombinant CgFUT1 protein with a molecular mass of 38.0 kDa was expressed in Escherichia coli using a prokaryotic expression vector. A eukaryotic expression plasmid was constructed and transfected into Chinese hamster ovary (CHO) cells. The expression of CgFUT1 and membrane localization of type H-2 HBGA-like molecules in CHO cells were detected using Western blotting and cellular immunofluorescence, respectively. This study indicated that CgFUT1, expressed in C. gigas tissues, can synthesize type H-2 HBGA-like molecules. This finding provides a new perspective for analyzing the source and synthetic pathway of HBGA-like molecules in oysters. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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19 pages, 5356 KiB

Open AccessArticle

Antiphotoaging Effect of AGEs Blocker™ in UVB-Irradiated Cells and Skh:HR-1 Hairless Mice

by JaeIn Jung, Yean-Jung Choi, JinHee Yoo, Su-Young Choi and EunJi Kim

Curr. Issues Mol. Biol. 2023, 45(5), 4181-4199; https://doi.org/10.3390/cimb45050266 - 09 May 2023

Viewed by 2039

Abstract

Chronic exposure to ultraviolet (UV) radiation is a major cause of photoaging. It involves extrinsic aging, wrinkle formation, and skin dehydration, and leads to excessive production of active oxygen that adversely affects the skin. Here, we investigated the antiphotoaging effect of AGEs Blocker [...] Read more.

Chronic exposure to ultraviolet (UV) radiation is a major cause of photoaging. It involves extrinsic aging, wrinkle formation, and skin dehydration, and leads to excessive production of active oxygen that adversely affects the skin. Here, we investigated the antiphotoaging effect of AGEs Blocker^TM (AB), which comprises Korean mint aerial part and fig and goji berry fruits. Compared to its individual components, AB was more potent at increasing the expression of collagen and hyaluronic acid and decreasing MMP-1 expression in UVB-irradiated Hs68 fibroblasts and HaCaT keratinocytes. In Skh:HR-1 hairless mice exposed to 60 mJ/cm² UVB for 12 weeks, oral administration of 20 or 200 mg/kg/day AB restored skin moisture by improving UVB-induced erythema, skin moisture, and transepidermal water loss, and alleviated photoaging by improving UVB-induced elasticity and wrinkles. Moreover, AB upregulated the mRNA levels of hyaluronic acid synthase and collagen-related Col1a1, Col3a1, and Col4a1 genes, increasing hyaluronic acid and collagen expression, respectively. AB inhibited UVB-induced MAPK and AP-1 (c-fos) activation, resulting in significantly downregulated expression of MMP-1 and -9, which are responsible for collagen degradation. AB also stimulated the expression and activity of antioxidative enzymes and reduced lipid peroxidation. Thus, AB is a potential preventive and therapeutic agent for photoaging. Full article

(This article belongs to the Section Molecular Medicine)

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13 pages, 3044 KiB

Open AccessArticle

Integrin Subunit Alpha M, ITGAM Nonsynonymous SNP Is Associated with Knee Osteoarthritis among Thais: A Case-Control Study

by Kamphon Intharanut, Plaiwan Suttanon and Oytip Nathalang

Curr. Issues Mol. Biol. 2023, 45(5), 4168-4180; https://doi.org/10.3390/cimb45050265 - 09 May 2023

Cited by 1 | Viewed by 1092

Abstract

Knee osteoarthritis (OA), which is one of the most common degenerative joint diseases, presents a multifactorial etiology, involving multiple causative factors including genetic and environmental determinants. Four human neutrophil antigen (HNA) systems can be determined using each HNA allele by single-nucleotide polymorphisms (SNPs). [...] Read more.

Knee osteoarthritis (OA), which is one of the most common degenerative joint diseases, presents a multifactorial etiology, involving multiple causative factors including genetic and environmental determinants. Four human neutrophil antigen (HNA) systems can be determined using each HNA allele by single-nucleotide polymorphisms (SNPs). However, there are no data on HNA polymorphisms and knee OA in Thailand, so we investigated the association of HNA SNPs and knee OA in the Thai population. In a case-control study, detection of HNA-1, -3, -4, and -5 alleles by polymerase chain reaction with sequence-specific priming (PCR-SSP) was performed in participants with and without symptomatic knee OA. Logistic regression models were used to estimate the odds ratio (OR) and 95% confidence interval (CI) between cases and controls. Among 200 participants, 117 (58.5%) had knee OA; 83 (41.5%) did not and were included as controls in this study. An integrin subunit alpha M (ITGAM) nonsynonymous SNP, rs1143679, was markedly associated with symptomatic knee OA. The ITGAM*01*01 genotype was identified as an important increased risk factor for knee OA (adjusted OR = 5.645, 95% CI = 1.799–17.711, p = 0.003). These findings may contribute to our understanding of the application prospects for therapeutic approaches to knee OA. Full article

(This article belongs to the Special Issue Advances in Understanding Molecular Basis of Inflammatory Diseases)

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17 pages, 4060 KiB

Open AccessArticle

Genome-Wide Identification of Candidate Genes Associated with Heat Stress in Mulberry (Morus alba L.)

by Xin Jin, Michael Ackah, Adolf Acheampong, Qiaonan Zhang, Lei Wang, Qiang Lin, Changyu Qiu and Weiguo Zhao

Curr. Issues Mol. Biol. 2023, 45(5), 4151-4167; https://doi.org/10.3390/cimb45050264 - 08 May 2023

Cited by 2 | Viewed by 1375

Abstract

Mulberry (Morus alba L.) is an economically important plant for the silk industry and has the possibility of contributing immensely to Chinese pharmacopeia because of its health benefits. Domesticated silkworms feed only on mulberry leaves, meaning that the worms’ survival depends on [...] Read more.

Mulberry (Morus alba L.) is an economically important plant for the silk industry and has the possibility of contributing immensely to Chinese pharmacopeia because of its health benefits. Domesticated silkworms feed only on mulberry leaves, meaning that the worms’ survival depends on the mulberry tree. Mulberry production is threatened by climate change and global warming. However, the regulatory mechanisms of mulberry responses to heat are poorly understood. We performed transcriptome analysis of high-temperature-stressed (42 °C) M. alba seedlings using RNA-Seq technologies. A total of 703 differentially expressed genes (DEGs) were discovered from 18,989 unigenes. Among these, 356 were up-regulated, and 347 were down-regulated. KEGG analysis revealed that most DEGs were enriched in valine, leucine and isoleucine degradation, and in starch and sucrose metabolism, alpha-linolenic acid metabolism, carotenoid biosynthesis and galactose metabolism, among others. In addition, TFs such as the NAC, HSF, IAA1, MYB, AP2, GATA, WRKY, HLH and TCP families were actively involved in response to high temperatures. Moreover, we used RT-qPCR to confirm the expression changes of eight genes under heat stress observed in the RNA-Seq analysis. This study provides M. alba transcriptome profiles under heat stress and provides theoretical bases to researchers for better understanding mulberry heat response mechanisms and breeding heat-tolerant mulberry plants. Full article

(This article belongs to the Special Issue Functional Genomics and Comparative Genomics Analysis in Plants)

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16 pages, 1176 KiB

Open AccessArticle

Deregulation of Autophagy and Apoptosis in Patients with Myelodysplastic Syndromes: Implications for Disease Development and Progression

by Georgia Tsekoura, Andreas Agathangelidis, Christina-Nefeli Kontandreopoulou, Angeliki Taliouraki, Georgia Mporonikola, Maria Stavropoulou, Panagiotis T. Diamantopoulos, Nora-Athina Viniou, Vassiliki Aleporou, Issidora Papassideri and Panagoula Kollia

Curr. Issues Mol. Biol. 2023, 45(5), 4135-4150; https://doi.org/10.3390/cimb45050263 - 08 May 2023

Viewed by 1293

Abstract

(1) Background: Myelodysplastic neoplasms (MDSs) consist of a group of blood malignancies with a complex biological background. In this context, we investigated the role of autophagy and apoptosis in the pathogenesis and progression of MDSs. (2) Methods: To address this issue, we performed [...] Read more.

(1) Background: Myelodysplastic neoplasms (MDSs) consist of a group of blood malignancies with a complex biological background. In this context, we investigated the role of autophagy and apoptosis in the pathogenesis and progression of MDSs. (2) Methods: To address this issue, we performed a systematic expression analysis on a total of 84 genes in patients with different types of MDSs (low/high risk of malignancy) versus healthy individuals. Furthermore, real-time quantitative PCR (qRT-PCR) was used to validate significantly upregulated or downregulated genes in a separate cohort of MDS patients and healthy controls. (3) Results: MDS patients were characterized by lower expression levels for a large series of genes involved in both processes compared to healthy individuals. Of importance, deregulation was more pronounced in patients with higher-risk MDS. Results from the qRT-PCR experiments displayed a high level of concordance with the PCR array, strengthening the relevance of our findings. (4) Conclusions: Our results indicate a clear effect of autophagy and apoptosis on MDS development, which becomes more pronounced as the disease progresses. The results from the present study are expected to assist in our understanding of the biological background of MDSs as well as in the identification of novel therapeutic targets. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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11 pages, 1880 KiB

Open AccessArticle

Cycle Threshold (Ct) Values of SARS-CoV-2 Detected with the GeneXpert^® System and a Mutation Associated with Different Target Gene Failure

by Keita Yamashita, Terumi Taniguchi, Noriyasu Niizeki, Yuki Nagao, Akira Suzuki, Akihiro Toguchi, Shiori Takebayashi, Jinko Ishikawa, Osanori Nagura, Kazuki Furuhashi, Moriya Iwaizumi and Masato Maekawa

Curr. Issues Mol. Biol. 2023, 45(5), 4124-4134; https://doi.org/10.3390/cimb45050262 - 07 May 2023

Cited by 1 | Viewed by 2129

Abstract

SARS-CoV-2 nucleic acid detection tests enable rapid virus detection; however, it is challenging to identify genotypes to comprehend the local epidemiology and infection routes in real-time qRT-PCR. At the end of June 2022, our hospital experienced an in-hospital cluster of COVID-19. When examined [...] Read more.

SARS-CoV-2 nucleic acid detection tests enable rapid virus detection; however, it is challenging to identify genotypes to comprehend the local epidemiology and infection routes in real-time qRT-PCR. At the end of June 2022, our hospital experienced an in-hospital cluster of COVID-19. When examined using the GeneXpert^® System, the cycle threshold (Ct) value of the N2 region of the nucleocapsid gene of SARS-CoV-2 was approximately 10 cycles higher than that of the envelope gene. Sanger sequencing revealed a G29179T mutation in the primer and probe binding sites. A review of past test results revealed differences in Ct values in 21 of 345 SARS-CoV-2-positive patients, of which 17 cases were cluster-related and 4 were not. Including these 21 cases, 36 cases in total were selected for whole-genome sequencing (WGS). The viral genomes in the cluster-related cases were identified as BA.2.10, and those in the non-cluster cases were closely related and classified as being downstream of BA.2.10 and other lineages. Although WGS can provide comprehensive information, its use is limited in various laboratory settings. A measurement platform reporting and comparing Ct values of different target genes can improve test accuracy, enhance our understanding of infection spread, and be applied to the quality control of reagents. Full article

(This article belongs to the Special Issue Tailored Molecular and Pathophysiological Approach to COVID-19: Ambition and Need)

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24 pages, 5553 KiB

Open AccessArticle

Overexpression of OLIG2 and MYT1L Transcription Factors Enhance the Differentiation Potential of Human Mesenchymal Stem Cells into Oligodendrocytes

by Ifrah Fahim, Aisha Ishaque, Faiza Ramzan, Shamsul Azlin Bin Ahmad Shamsuddin, Anwar Ali, Asmat Salim and Irfan Khan

Curr. Issues Mol. Biol. 2023, 45(5), 4100-4123; https://doi.org/10.3390/cimb45050261 - 07 May 2023

Viewed by 1710

Abstract

Background: Demyelinating diseases represent a broad spectrum of disorders and are characterized by the loss of specialized glial cells (oligodendrocytes), which eventually leads to neuronal degeneration. Stem cell-based regenerative approaches provide therapeutic options to regenerate demyelination-induced neurodegeneration. Objectives: The current study aims to [...] Read more.

Background: Demyelinating diseases represent a broad spectrum of disorders and are characterized by the loss of specialized glial cells (oligodendrocytes), which eventually leads to neuronal degeneration. Stem cell-based regenerative approaches provide therapeutic options to regenerate demyelination-induced neurodegeneration. Objectives: The current study aims to explore the role of oligodendrocyte-specific transcription factors (OLIG2 and MYT1L) under suitable media composition to facilitate human umbilical-cord-derived mesenchymal stem cells (hUC-MSCs) differentiation toward oligodendrocyte for their potential use to treat demyelinating disorders. Methodology: hUC-MSCs were isolated, cultured, and characterized based on their morphological and phenotypic characteristics. hUC-MSCs were transfected with OLIG2 and MYT1L transcription factors individually and in synergistic (OLIG2 + MYT1L) groups using a lipofectamine-based transfection method and incubated under two different media compositions (normal and oligo induction media). Transfected hUC-MSCs were assessed for lineage specification and differentiation using qPCR. Differentiation was also analyzed via immunocytochemistry by determining the expression of oligodendrocyte-specific proteins. Results: All the transfected groups showed significant upregulation of GFAP and OLIG2 with downregulation of NES, demonstrating the MSC commitment toward the glial lineage. Transfected groups also presented significant overexpression of oligodendrocyte-specific markers (SOX10, NKX2.2, GALC, CNP, CSPG4, MBP, and PLP1). Immunocytochemical analysis showed intense expression of OLIG2, MYT1L, and NG2 proteins in both normal and oligo induction media after 3 and 7 days. Conclusions: The study concludes that OLIG2 and MYT1L have the potential to differentiate hUC-MSCs into oligodendrocyte-like cells, which is greatly facilitated by the oligo induction medium. The study may serve as a promising cell-based therapeutic strategy against demyelination-induced neuronal degeneration. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Demyelinating Disorders of the Central Nervous System)

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20 pages, 3292 KiB

Open AccessReview

The Effect of Probiotic Supplementation on the Gut–Brain Axis in Psychiatric Patients

by Hussein Sabit, Areej Kassab, Donia Alaa, Shaza Mohamed, Shaimaa Abdel-Ghany, Mohamed Mansy, Osama A. Said, Mona A. Khalifa, Halah Hafiz and Asmaa M. Abushady

Curr. Issues Mol. Biol. 2023, 45(5), 4080-4099; https://doi.org/10.3390/cimb45050260 - 06 May 2023

Cited by 5 | Viewed by 3067

Abstract

The pathophysiology of several psychiatric diseases may entail disturbances in the hypothalamic–pituitary–adrenal (HPA) axis and metabolic pathways. Variations in how these effects present themselves may be connected to individual variances in clinical symptoms and treatment responses, such as the observation that a significant [...] Read more.

The pathophysiology of several psychiatric diseases may entail disturbances in the hypothalamic–pituitary–adrenal (HPA) axis and metabolic pathways. Variations in how these effects present themselves may be connected to individual variances in clinical symptoms and treatment responses, such as the observation that a significant fraction of participants do not respond to current antipsychotic drugs. A bidirectional signaling pathway between the central nervous system and the gastrointestinal tract is known as the microbiota–gut–brain axis. The large and small intestines contain more than 100 trillion microbial cells, contributing to the intestinal ecosystem’s incredible complexity. Interactions between the microbiota and intestinal epithelium can alter brain physiology and affect mood and behavior. There has recently been a focus on how these relationships impact mental health. According to evidence, intestinal microbiota may play a role in neurological and mental illnesses. Intestinal metabolites of microbial origin, such as short-chain fatty acids, tryptophan metabolites, and bacterial components that might stimulate the host’s immune system, are mentioned in this review. We aim to shed some on the growing role of gut microbiota in inducing/manipulating several psychiatric disorders, which may pave the way for novel microbiota-based therapies. Full article

(This article belongs to the Special Issue The Development of Metabolites from the Gut Microbiome via In Silico Strategy)

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17 pages, 2309 KiB

Open AccessArticle

The Effect of Ethanol Extract from Mesua ferrea Linn Flower on Alzheimer’s Disease and Its Underlying Mechanism

by Kusawadee Plekratoke, Chantana Boonyarat, Orawan Monthakantirat, Natsajee Nualkaew, Jinda Wangboonskul, Suresh Awale, Yaowared Chulikhit, Supawadee Daodee, Charinya Khamphukdee, Suchada Chaiwiwatrakul and Pornthip Waiwut

Curr. Issues Mol. Biol. 2023, 45(5), 4063-4079; https://doi.org/10.3390/cimb45050259 - 06 May 2023

Cited by 1 | Viewed by 1859

Abstract

The effects of Mesua ferrea Linn flower (MFE) extract on the pathogenic cascade of Alzheimer’s disease (AD) were determined by an in vitro and cell culture model in the search for a potential candidate for the treatment of AD. The 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) [...] Read more.

The effects of Mesua ferrea Linn flower (MFE) extract on the pathogenic cascade of Alzheimer’s disease (AD) were determined by an in vitro and cell culture model in the search for a potential candidate for the treatment of AD. The 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay exhibited that the MFE extract had antioxidant activities. According to the Ellman and the thioflavin T method’s result, the extracts could inhibit acetylcholinesterase and β-amyloid (Aβ) aggregation. Studies on neuroprotection in cell culture found that the MFE extract could reduce the death of human neuroblastoma cells (SH-SY5Y) caused by H₂O₂ and Aβ. Western blot analysis exhibited that the MFE extract alleviated H₂O₂-induced neuronal cell damage by downregulating the pro-apoptotic proteins, including cleaved caspase-3, Bax, and by enhancing the expression of anti-apoptotic markers including MCl₁, BCl_xl, and survivin. Moreover, MFE extract inhibited the expression of APP, presenilin 1, and BACE, and increased the expression of neprilysin. In addition, the MFE extract could enhance scopolamine-induced memory deficit in mice. Overall, results showed that the MFE extract had several modes of action related to the AD pathogenesis cascade, including antioxidants, anti-acetylcholinesterase, anti-Aβ aggregation, and neuroprotection against oxidative stress and Aβ. Therefore, the M. ferrea L. flower might be a possibility for further development as a medication for AD. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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13 pages, 3063 KiB

Open AccessArticle

Physiological and Biochemical Properties of Cotton Seedlings in Response to Cu²⁺ Stress

by Hao Zhou, Ke-Hai Zhou, Gang Zhao, Pei-Pei Wang, Dai-Gang Yang, Xiong-Feng Ma and Jun-Shan Gao

Curr. Issues Mol. Biol. 2023, 45(5), 4050-4062; https://doi.org/10.3390/cimb45050258 - 05 May 2023

Cited by 1 | Viewed by 1393

Abstract

Copper(II) (Cu²⁺) is essential for plant growth and development. However, high concentrations are extremely toxic to plants. We investigated the tolerance mechanism of cotton under Cu²⁺ stress in a hybrid cotton variety (Zhongmian 63) and two parent lines with different [...] Read more.

Copper(II) (Cu²⁺) is essential for plant growth and development. However, high concentrations are extremely toxic to plants. We investigated the tolerance mechanism of cotton under Cu²⁺ stress in a hybrid cotton variety (Zhongmian 63) and two parent lines with different Cu²⁺ concentrations (0, 0.2, 50, and 100 μM). The stem height, root length, and leaf area of cotton seedlings had decreased growth rates in response to increasing Cu²⁺ concentrations. Increasing Cu²⁺ concentration promoted Cu²⁺ accumulation in all three cotton genotypes’ roots, stems, and leaves. However, compared with the parent lines, the roots of Zhongmian 63 were richer in Cu²⁺ and had the least amount of Cu²⁺ transported to the shoots. Moreover, excess Cu²⁺ also induced changes in cellular redox homeostasis, causing accumulation of hydrogen peroxide (H₂O₂) and malondialdehyde (MDA). Conversely, antioxidant enzyme activity increased, while photosynthetic pigment content decreased. Our findings indicated that the hybrid cotton variety fared well under Cu²⁺ stress. This creates a theoretical foundation for the further analysis of the molecular mechanism of cotton resistance to copper and suggests the potential of the large-scale planting of Zhongmian 63 in copper-contaminated soils. Full article

(This article belongs to the Special Issue Stress and Signal Transduction in Plants)

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15 pages, 4458 KiB

Open AccessArticle

Anti-Leukemic Effects of Idesia polycarpa Maxim Branch on Human B-Cell Acute Lymphoblastic Leukemia Cells

by Chan-Seong Kwon, Ji-Eun Lee, Byeol-Eun Jeon, Ye-Rin Woo, Yun-Seo Kim, Jae-Woo Kim, Chae-Jin Park, Seo-Yun Jang and Sang-Woo Kim

Curr. Issues Mol. Biol. 2023, 45(5), 4035-4049; https://doi.org/10.3390/cimb45050257 - 04 May 2023

Viewed by 1306

Abstract

Patients with pediatric B-cell acute lymphoblastic leukemia (B-ALL) have a high survival rate, yet the prognosis of adults and patients with relapsed/refractory disease is relatively poor. Therefore, it is imperative to develop new therapeutic strategies. Here, we screened 100 plant extracts from South [...] Read more.

Patients with pediatric B-cell acute lymphoblastic leukemia (B-ALL) have a high survival rate, yet the prognosis of adults and patients with relapsed/refractory disease is relatively poor. Therefore, it is imperative to develop new therapeutic strategies. Here, we screened 100 plant extracts from South Korean Flora and investigated their anti-leukemic effect using CCRF-SB cells as a B-ALL model. The top cytotoxic extract identified in this screening was the Idesia polycarpa Maxim. branch (IMB), which efficiently inhibited the survival and proliferation of CCRF-SB cells, while having minimal to no impact on normal murine bone marrow cells. Mechanistically, the IMB-induced proapoptotic effect involves the increase of caspase 3/7 activity, which was shown to be associated with the disruption of the mitochondrial membrane potential (MMP) through the reduction in antiapoptotic Bcl-2 family expression. IMB also promoted the differentiation of CCRF-SB cells via the upregulation of the expression of differentiation-related genes, PAX5 and IKZF1. Given that resistance to glucocorticoid (GC) is often found in patients with relapsed/refractory ALL, we investigated whether IMB could restore GC sensitivity. IMB synergized GC to enhance apoptotic rate by increasing GC receptor expression and downmodulating mTOR and MAPK signals in CCRF-SB B-ALL cells. These results suggest that IMB has the potential to be a novel candidate for the treatment of B-ALL. Full article

(This article belongs to the Special Issue Natural Products and Their Biological Activities)

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18 pages, 5792 KiB

Open AccessArticle

1α,25-Dihydroxyvitamin D₃ Improves Follicular Development and Steroid Hormone Biosynthesis by Regulating Vitamin D Receptor in the Layers Model

by Manman Cheng, Zhenquan Song, Yan Guo, Xuliang Luo, Xuelian Li, Xiaohui Wu and Yanzhang Gong

Curr. Issues Mol. Biol. 2023, 45(5), 4017-4034; https://doi.org/10.3390/cimb45050256 - 04 May 2023

Cited by 2 | Viewed by 1253

Abstract

1α,25-Dihydroxyvitamin D₃ (VitD₃) is the active form of vitamin D, and it regulates gene expression and protein synthesis in mammalian follicle development. However, the function of VitD₃ in the follicular development of layers remains unclear. This study investigated, through [...] Read more.

1α,25-Dihydroxyvitamin D₃ (VitD₃) is the active form of vitamin D, and it regulates gene expression and protein synthesis in mammalian follicle development. However, the function of VitD₃ in the follicular development of layers remains unclear. This study investigated, through in vivo and in vitro experiments, the effects of VitD₃ on follicle development and steroid hormone biosynthesis in young layers. In vivo, ninety 18-week-old Hy-Line Brown laying hens were randomly divided into three groups for different treatments of VitD₃ (0, 10, and 100 μg/kg). VitD₃ supplementation promoted follicle development, increasing the number of small yellow follicles (SYFs) and large yellow follicles (LYFs) and the thickness of the granulosa layer (GL) of SYFs. Transcriptome analysis revealed that VitD₃ supplementation altered gene expression in the ovarian steroidogenesis, cholesterol metabolism, and glycerolipid metabolism signaling pathways. Steroid hormone-targeted metabolomics profiling identified 20 steroid hormones altered by VitD₃ treatment, with 5 being significantly different among the groups. In vitro, it was found that VitD₃ increased cell proliferation, promoted cell-cycle progression, regulated the expression of cell-cycle-related genes, and inhibited the apoptosis of granulosa cells from pre-hierarchical follicles (phGCs) and theca cells from prehierarchical follicles (phTCs). In addition, the steroid hormone biosynthesis-related genes, estradiol (E2) and progesterone (P4) concentrations, and vitamin D receptor (VDR) expression level was significantly altered by VitD₃. Our findings identified that VitD₃ altered the gene expression related to steroid metabolism and the production of testosterone, estradiol, and progesterone in the pre-hierarchical follicles (PHFs), resulting in positive effects on poultry follicular development. Full article

(This article belongs to the Special Issue Molecular Research on Female Reproductive Diseases)

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Curr. Issues Mol. Biol., Volume 45, Issue 5 (May 2023) – 45 articles

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