Current Molecular Medicine - Volume 23, Issue 8, 2023

Vitiligo is the utmost common depigmenting condition consequential from melanocyte loss from the basal layer of the epidermis. Vitiligo disease mostly affects dark-skinned races and makes them more sensitive to UV radiation. It is also linked with some autoimmune diseases and various psychosocial difficulties. Melanocyte loss leads to depigmentation in vitiligo, is a major concern over decades, and even affects an individual’s day-to-day life severely. All the theories, including autoimmune, autocytotoxic, and neural, collectively decipher either prime impact on the melanogenesis inhibition or deficient adhesion inspired melanocytes disappearance. Previously it has been described that melanocyte loss in vitiligo patients is caused by defective adhesion. Melanocyte death by apoptosis mainly occurs due to melanocyte detachment or migration from the basal layer and further followed by transepidermal migration. Various cell surface molecules, i.e., cell adhesion molecules (CAMs) in affiliation with neighbouring cells and extracellular matrix (ECM), encompass a typical cell adhesion process. All these ECM molecules along with transcription factors, help in the survival and maintenance of pigmentary cells/melanocytes. Therefore, in this issue, we have tried to compile the literature available on melanocyte detachment/apoptosis in ECM due to the alteration in adhesion molecules and matrix metalloproteinases (MMPs) driven by known/unknown transcription factors.

Background: COVID-19 is a severe acute respiratory syndrome that has become a prominent source of morbidity and mortality around the world. With millions infected globally by the COVID-19 epidemic, long-term care for COVID-19 survivors has become a global concern. As a result, research into the long-term pulmonary and extrapulmonary consequences and complications of COVID is absolutely necessary. Objectives: In an attempt to better understand and mitigate post recovery mortality, early detection of the post recovery complication might prevent the severity of the complication and can be recovered. As per cases reported, post covid extrapulmonary complications were more than pulmonary complications. However, the post covid pulmonary complications were found to be more lethal and nonrecoverable in most of the cases than extrapulmonary complications. Methods: The present review is an attempt to reveal the role and importance of biomarkers associated with critical post covid pulmonary complications. COVID-19 is associated with post-covid pulmonary fibrosis, pulmonary endothelial dysfunction, pulmonary aspergillosis, pulmonary mucormycosis, biomarkers and WHO, as keywords were used to retrieve updated information. PubMed, and Google Scholar were used as search engines for this. Results: There must be a better knowledge of the post-COVID-19 pulmonary problems in terms of systemic pathophysiological results to create multidisciplinary clinics to address both long-term symptoms and potential long-term consequences. This can be achieved by revealing the molecular pathogenesis that can be validated by certain biomarkers and various diagnostic techniques. Accordingly, the clinical program can be designed to treat and effectively manage the post covid pulmonary complications in early-stage to prevent mortality. Conclusion: In order to deal with the specific logistical problems given by pandemic circumstances, effective interdisciplinary collaboration models draw on experiences learned during the early phases of the pandemic.

Background: Fungal infections have become a worldwide problem due to their involvement in numerous diseases. The risk factors for fungal infections are multiple surgeries, transplant therapies, frequent administration of antibiotics, cancer treatments, and prosthetic devices. The problem of resistance in fungi against drug therapies is widespread, becoming a severe health-related problem. Objective: The study's objective was to identify molecular targets that may open new paths for fungal treatment. Methods: Several research and review articles were studied to gather information regarding the novel mechanism of antifungal drugs. However, identifying novel targets is challenging due to the similarities between host and fungal cells. Although, the plasma membrane and cell wall of fungus offer various drug targets that may target to fight against microbial infections. Unfortunately, biofilm formation and over-expression of protein are a few mechanisms through which fungi develop resistance. Results: Despite these problems, several approaches have been working to prevent and treat fungal infections. Modifying the chemical structure of antifungal drugs may also improve their activity and pharmacokinetics. In this review article, we have discussed the molecular targets and novel techniques to be used for the development of antifungal drugs. In addition, different strategies to overcome resistance in fungi have also been described. Conclusion: This article may be helpful for the researchers working on the discovery and development of new antifungal works for resistance to fungal diseases.

Thyroid cancer is one of the most frequent cancers globally, and its incidence has risen recently. The clinical behavior of thyroid cancer includes a wide range, from benign to invasive malignant tumors. Thus, precious diagnostic activities before therapeutic work are required. Circular RNAs (circRNAs) along with microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are known as non-coding RNAs (ncRNAs). Large amounts of investigations have indicated that circRNAs can participate in multiple cellular processes, especially in tumorigenesis. Furthermore, circRNAs are stable in blood or plasma, as well as they are specific in different tissues. Therefore, they could serve as a potential diagnostic biomarker for cancer cells. Limited studies investigated the role of circRNAs in some processes involved in thyroid cancer. In this review, we summarized the current evidence on the potential clinical involvement of circRNAs in thyroid cancer.

The clustered regularly interspaced short palindromic repeats system, called CRISPR, as one of the major technological advances, allows geneticists and researchers to perform genome editing. This remarkable technology is quickly eclipsing zinc-finger nucleases (ZFNs) and other editing tools, and its ease of use and accuracy have thus far revolutionized genome editing, from fundamental science projects to medical research and treatment options. This system consists of two key components: a CRISPR-associated (Cas) nuclease, which binds and cuts deoxyribonucleic acid (DNA) and a guide ribonucleic acid (gRNA) sequence, directing the Cas nuclease to its target site. In the research arena, CRISPR has been up to now exploited in various ways alongside gene editing, such as epigenome modifications, genome-wide screening, targeted cancer therapies, and so on. This article reviews the current perceptions of the CRISPR/Cas systems with special attention to studies reflecting on the relationship between the CRISPR/Cas systems and their role in cancer therapy.

Background: According to the reports, the most vital characteristic of obesity is an aberrant accumulation of triglycerides (TG) in the adipocyte. On the other hand, circulating concentrations of apolipoprotein A1 (apoA1) have been demonstrated to be strongly correlated with the prevalence and the pathological development of obesity. Nevertheless, the underlying mechanisms whereby apoA1 modulates the pathogenesis of obesity is still not fully elucidated. Methods: Adipose-derived mesenchymal stem cells (AMSCs, isolated from the hospitalized patients were combined with 15 μg/ml recombined human apoA1 protein. The effects of apoA1 on modulating the intracellular levels of TG and the expression contents of adipogenic related cytokines were also analyzed. Furthermore, whether apoA1 modulated the adipogenesis progression via sortilin was also explored in the current research. Results: During the adipogenesis progression, apoA1 could significantly lower the quantity of intracellular lipid droplets (LDs). Meanwhile, apoA1 could decrease the intracellular levels of TG and down-regulate the expression contents of several vital adipogenic related cytokines, such as CCAAT enhancer-binding proteins α/β (C/EBPα/β), fatty acid synthetase (FAS), and fatty acid-binding protein 4 (FABP4). Moreover, the inhibitory effect of apoA1 was further verified to be induced through upregulating the SORT1 gene expression which subsequently increased sortilin protein. Consistent with these findings, silencing the SORT1 gene expression could induce the loss-of-function (LOF) of apoA1 in modulating the adipogenesis progression of AMSCs. Conclusion: In conclusion, apoA1 could suppress the adipogenesis progression of human AMSCs through, at least partly, up-regulating the SORT1 gene expression which subsequently increases the sortilin protein content. Thereby, the present research sheds light on a novel pathogenic mechanism by which apoA1 regulates adipogenesis progression and proposes that apoA1 embraces the function to treat obesity in clinical practice.

Background: Atlas human proteomics database showed MCU as highly expressed in various tumor tissues, especially in ovarian cancer. Rare studies on the role of MCU and its regulation in ovarian cancer have been reported. Objective: The objective of this study was to determine role of MCU in ovarian cancer cell SKOV3 proliferation, migration, and transformation, and explore the possible mechanism. Methods: MCU siRNA on lentiviral particles were stably transfected into SKOV3 cells. CCK-8 assay was performed to analyze cell proliferation. Soft-agar colony formation assay was employed to evaluate tumorigenesis. Western blot and immunohistochemistry analyses were performed to evaluate the expression of MCU, MICU1 and phosphorylate of Akt in the ovarian cancer cell and tissue specimens. Scratch assay was combined with trans-well plates assay to detect the migration ability of cancer cells. The ROS production and Ca²⁺ expression were also determined. Results: MCU expression was significantly higher in ovarian cancer tissues than normal tissues. MCU silencing decreased SKOV3 cell proliferation, migration, and transformation. ROS production was decreased after MCU silencing, depending on disturbed Ca²⁺ homeostasis. MICU1 expression has been found to be decreased and phosphorylation of Akt increased when MCU was silenced. Conclusion: Down-regulation of MCU inhibited SKOV3 cell proliferation, migration, and transformation via disturbing Ca²⁺ homeostasis and decreasing ROS production. MICU1 and phosphorylation of Akt are associated with MCU-mediated ovarian cancer malignancy.

Colorectal carcinoma (CRC), the foremost basis of malignancy-related death worldwide, evolves due to the stepwise amassing of a succession of genetic and epigenetic modifications. Epigenetic indicators are significant molecular hallmarks of malignancy. They play a big role in disease pathogenesis and are involved in almost all important cancer-related pathways. They can also be used as clinically useful cancer biomarkers for diagnosis, prognosis, and predicting how well treatment will work. Similarly, as gene changes in the malignant growth genome, a subset of driver genes attempts to play a useful part in CRC. Advances in our understanding of abnormal methylation in CRC have led to the development of epigenetic changes as diagnostic and prognostic biomarkers, and role of non-coding RNAs as epigenetic controllers. Beforehand, mass transcriptomics analysis is used to group CRC based on its distinctive molecular and clinicopathological features for prediction and patient analysis. The development of single-cell transcriptomics flipped the script by making it possible to evaluate the expression levels of particular neoplastic cells within a single tumor. Cell motility, growth, development, proliferation, DNA replication, recombination, their relationships with transcriptomics, and the CRC transcriptome analysis, have shown improvements. Progress in the appraisal of epigenetic alterations in CRC and their clinical applications has indicated that these changes will be ordinarily utilized as molecular markers to coordinate the anticipation and treatment of CRC. Recent improvements in our understanding of CRC and progress in genomics have led to the discovery of a number of epigenetic changes that are strongly linked to both the start and spread of cancer.

Background: Systematic lupus erythematosus (SLE) is an autoimmunemediated disease. So far, there is no relevant report on ferroptosis in SLE research, and the role of T helper 1 (Th1) and T helper 2 (Th2) cells in SLE is still unclear. Methods: This study employed SLE mice models with and without ferroptosis inhibitors (Liproxstatin128;‘1) and normal control mice. Treated mice were analyzed with hematoxylin and eosin (H) staining, immunohistochemical detection of glutathione peroxidase 4 (GPX4), malondialdehyde (MDA) detection, ELISA(enzyme-linked immunosorbent assay) detection of Th1 and Th2 cytokines and flow cytometry detection of Th1 and Th2 ratio. Results: The results showed that compared with the normal group, the SLE group exhibited significantly higher expression of anti-double-stranded deoxyribonucleic acid (anti-dsDNA), MDA and Th1 cytokines, significantly lower expression of GPX4 and Th2 cytokines and increased Th1/Th2 ratio. Similarly, compared with the SLE group, the SLE + liproxstatin-1 group showed significantly low expression of anti-dsDNA, MDA and Th1 cytokines, significantly high expression of GPX4 and Th2 cytokines and reduced Th1/Th2 ratio. Conclusion: These results demonstrate that ferroptosis may be involved in promoting SLE development. Therefore, inhibiting ferroptosis may be a potential treatment for SLE. Similarly, the Th1/Th2 ratio may have a role in promoting SLE development.

Objective: The periapical tissues, including periodontal ligament cells (PDLCs) play an important role in repairing the surrounding tissue of the teeth. A decrease in the regenerative potentiality of resident stem cells (PDLCs) has been suggested to be attributed to the decline of pulp regeneration. Therefore, examining the functional changes in periodontal tissue and cells that occur during the aging process is necessary. Methods: The changes in the cementum extract (CE) and PDLCs isolated from young and aged dog teeth were evaluated. PDLCs growth rate, senescence markers, p16 and p21, and proinflammatory cytokines, IL-6, IL-1β, and TNF-α, were analyzed by RT-PCR. Bax, an apoptosis marker, Bcl-2, a marker for cell survival, and IL-6 were examined by Western blot analyses to detect their variance expression in the CE. Results: Our results demonstrated that aged PDLCs exhibit a low growth rate and an increased expression of p16; however, no change has been demonstrated in the expression of p21. The chronic inflammatory molecules, IL-6 and TNF-α, were significantly upregulated compared to young PDLCs. Western blot analyses showed decreased expression of Bcl-2 in the CE of the aged tooth (p < 0.001). Conclusion: Taken together, aging influences the functional changes of PDLCs and CE and increases senescence, chronic inflammation, and apoptosis markers. As a result, donor age is a key factor influencing the utilization of PDLCs for tooth regeneration.

Background: Patients with type 2 diabetes mellitus have a high cardiovascular risk due, in part, to abnormalities of high-density lipoprotein mediated cholesterol efflux. The ATP-binding cassette A1 and G1 play a pivotal role in the regulation of cholesterol efflux. However, the regulation of these transporters in type 2 diabetes mellitus remains obscure. Objectives: This study aimed to investigate the expression of ATP-binding cassette A1 and G1 and their regulation by Liver X receptors in monocyte-derived macrophages in type 2 diabetes mellitus, and to determine whether the alteration of these transporters might affect cholesterol efflux from macrophages. Methods: Blood was collected from type 2 diabetic patients and healthy controls. Peripheral monocytes were differentiated into macrophages. Quantitative real-time PCR, western blots, and cholesterol efflux assays were performed. The Liver X receptor and Liver X receptor element complex in the ATP-binding cassette G1 gene promoter were detected by electrophoretic mobility supershift assay. Results: Macrophage ATP-binding cassette G1 expression and high density lipoproteininduced cholesterol efflux were significantly reduced in type 2 diabetic patients. However, the mRNA expression of ATP-binding cassette G1 in type 2 diabetic patients was not inhibited by Liver X receptor siRNA and the Liver X receptor- Liver X receptor element complexes remain unchanged similarly. Conclusion: The study suggested that the expression of ATP-binding cassette G1 and high density lipoprotein-induced cholesterol efflux in macrophages were reduced in type 2 diabetes mellitus. Impairment of cholesterol efflux and ATP-binding cassette G1 gene expression in type 2 diabetes mellitus might be regulated by a Liver X receptorindependent pathway.

Background: Irritable bowel syndrome (IBS) is a known brain-gut disorder. Currently, the molecular and cellular mechanisms of IBS remain unclear. Atractylenolide-I (ATL-I) is a majorly bioactive component extracted from Rhizoma Atractylodes Macrocephalae. Methods: Studies have revealed that ATL-I functioned as an anti-tumor drug in various cancers. However, the effects and molecular mechanisms of ATL-I on the pathological processes of colonic mucosal epithelial cells (CMECs) during IBS remain unclear. This study reports ATL-I effectively alleviated the oxidative stress-induced colonic mucosal epithelial cell dysfunction. In colonic mucosal tissues from IBS patients, we detected upregulated miR-34a-5p and suppressed glucose metabolism enzyme expressions. Under H2O2 treatment which mimics in vitro oxidative stress, miR-34a-5p was induced and glucose metabolism was inhibited in the colon mucosal epithelial cell line, NCM460. Meanwhile, ATL-I treatment effectively overcame the oxidative stress-induced miR-34a- 5p expression and glucose metabolism in NCM460 cells. Result: By bioinformatics analysis, Western blot and luciferase assay, we illustrated that miR-34a-5p directly targeted the 3’UTR region of glucose metabolism key enzyme, lactate dehydrogenase-A (LDHA) in colonic mucosal epithelial cells. Rescue experiments validated that miR-34a-5p inhibited glucose metabolism by targeting LDHA. Finally, we demonstrated that ATL-I treatment reversed the miR-34a-5p-inhibited glucose metabolism and -exacerbated colonic mucosal epithelial cell dysfunction under oxidative stress by modulating the miR-34a-5p-LDHA pathway. Conclusion: Summarily, our study reports the roles and mechanisms of ATL-I in the oxidative stress-induced colonic mucosal epithelial cell dysfunction during IBS through regulating the miR-34a-5p-LDHA-glucose metabolism axis.

Objects: Shortly after cancer is diagnosed, a phenomenon develops in cancer cells called multidrug resistance (MDR), in which cell sensitivity against anti-cancer drugs is significantly reduced. The present investigation aimed to assess the effects of nitazoxanide (NTZ), a safe drug, on LS174T/OXP-resistant cells. Methods: In the current in vitroresearch, the effects of NTZ and oxaliplatin (OXP) on the viability of LS174T and LS174T/OXP cell lines were evaluated through MTT assay. Then, the changes in expression levels of MDR1, MRP1, BCRP, and LRP genes and proteins were measured by RT-qPCR and western blotting methods, respectively. Lastly, the apoptosis status was assessed by annexin V–FITC/PI staining flow cytometry assay. Results: The IC50 values for cells resistant or sensitive to OXP were revealed (11567 nM vs. 1745 nM; p<0.05 for 24 h incubation, and 5161 nM vs. 882.2 nM; p<0.05 for 48 h incubation). Moreover, NTZ plus OXP led to a leftward shift in the cytotoxicity curve (2004 nM; p= 0.007). This co-treatment significantly decreased the expression of all genes and proteins (p<0.05). Finally, the combination of NTZ and OXP induced a significant increase in apoptosis (p<0.001). Conclusion: The data showed that NTZ treatment could increase the sensitivity of LS174T/OXP cell line to the OXP cytotoxic effects. Thus, NTZ may be efficient in reducing drug resistance in clinics by means of the negative regulation of ATP-binding cassette (ABC) transporters. However, further studies are necessary to explain the exact mechanisms of NTZ.