Dysregulation of miR-193a serves as a potential contributor to MS pathogenesis via affecting RhoA and Rock1.

BACKGROUND: Multiple sclerosis (MS) is one of the most common neurological diseases that cause chronic inflammation of the central nervous system and demyelination of the myelin sheath. At present, microRNAs (miRNAs) are considered not only a diagnostic and prognostic indicator of diseases but also a new goal in gene therapy. This study aims to find a simple, non-invasive, valuable biomarker for early detection and potential treatment of MS. METHODS: In the present study, 30 patients with MS were included. The qRT-PCR method was performed to evaluate the expression level of miR-193a, RhoA, and ROCK1. Besides, western blotting was performed to determine the expression level of RhoA and ROCK1 at protein levels. Moreover, we aimed to clarify the possible correlation between miR-193a-5p and its-regulated target genes so that miR-193a-5p mimic was transfected into MS-derived cultured PBMSs, and the expression level of RhoA and ROCK1 were then evaluated by qRT-PCR and Western blotting. In the final step, the correlation between miR-193a-5p and clinicopathological features of patients was investigated. RESULTS: Results showed that miR-193a was decreased while RhoA and ROCK1 were up-regulated in PBMCs obtained from patients with MS compared to the control group. It was also revealed that miR-193a transfection reduced RhoA and ROCK1 expression at mRNA and protein levels. The results from the Chi-square analysis showed that down-regulation of miR-193a was associated with increased CRP level, CSF IgG positivity, and MSSS (Multiple Sclerosis Severity Score), suggesting miR-193a is a potential diagnostic and prognostic indicator. CONCLUSION: We implied that miR-193a could modulate RhoA and ROCK 1 expression in MS patients, in which its down-regulation leads to increased expression of RhoA and ROCK1 and poor prognosis of patients with MS. Therefore, miR-193a and its associated targets could serve potential prognostic, diagnostic, and therapeutic efficacy in MS patients.

MicroRNA-155 acts as a potential prognostic and diagnostic factor in patients with ankylosing spondylitis by modulating SOCS3.

BACKGROUND: Ankylosing spondylitis (AS) is a progressive inflammatory disease. Our primary objective was to explore the role of miR-155 and its targeted factors in AS pathogenesis. METHODS AND RESULTS: PBMCs were isolated from 30 AS patients and 30 healthy individuals using the Ficoll-hypaque isolation approach. The expression of miR-155 and its associated targets, including Suppressor Of Cytokine Signaling 3 (SOCS3), STAT3, and IL-21, were determined using qT-qPCR. Then, PBMCs were cultured, and the effect of miR-155, SOCS3 siRNA (to suppress its expression), pEFSOCS3 (enforced expression), and their combination were investigated by qRT-PCR and western blotting. We also treated the cultured PBMCs with Brefeldin A, a potent inhibitor of cytokine secretion, to determine its effect on IL-21 expression and secretion. In addition, the association between miR-155 and patients' clinicopathological features was examined. The results showed that miR-155, IL-21, and STAT3 were increased in patients with AS, while SOCS3 had decreasing expression trend. It was also determined that miR-155 alleviates SOCS3 expression and increases IL-21 and STAT3 expression; it had a prominent effect when combined with SOCS3 siRNA. Besides, we showed that simultaneous transfection of miR-155 and pEFSOCS3 had no significant effect on IL-21 and STAT3 expression, revealing that miR-155 could alleviate the enforced expression of SOCS3. It was also proven that Brefledine A led to IL-21 up-regulation or accumulation while relieving its secretion. Also, a significant correlation between miR-155 and pathological features of AS patients was found. CONCLUSION: miR-155 acts as a potential prognostic and diagnostic biomarker. Its up-regulation leads to the down-regulation of SOCS3 and increased expression of IL-21 and STAT3 as characteristic of TH-17 lymphocytes, leading to worsening inflammatory conditions in patients with AS.

A comprehensive review about the utilization of immune checkpoint inhibitors and combination therapy in hepatocellular carcinoma: an updated review.

A pharmacological class known as immune checkpoint inhibitors (ICIs) has been developed as a potential treatment option for various malignancies, including HCC. In HCC, ICIs have demonstrated clinically significant advantages as monotherapy or combination therapy. ICIs that target programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1), as well as cytotoxic T lymphocyte antigen 4 (CTLA-4), have made significant advances in cancer treatment. In hepatocellular carcinoma (HCC), several ICIs are being tested in clinical trials, and the area is quickly developing. As immunotherapy-related adverse events (irAEs) linked with ICI therapy expands and gain worldwide access, up-to-date management guidelines become crucial to the safety profile of ICIs. This review aims to describe the evidence for ICIs in treating HCC, emphasizing the use of combination ICIs.

A comprehensive survey into the role of microRNAs in ovarian cancer chemoresistance; an updated overview.

Ovarian cancer (OC), a frequent malignant tumor that affects women, is one of the leading causes of cancer-related death in this group of individuals. For the treatment of ovarian cancer, systemic chemotherapy with platinum-based drugs or taxanes is the first-line option. However, drug resistance developed over time during chemotherapy medications worsens the situation. Since uncertainty exists for the mechanism of chemotherapy resistance in ovarian cancer, there is a need to investigate and overcome this problem. miRNAs are engaged in various signaling pathways that contribute to the chemotherapeutic resistance of ovarian cancer. In the current study, we have tried to shed light on the mechanisms by which microRNAs contribute to the drug resistance of ovarian cancer and the use of some microRNAs to combat this chemoresistance, leading to the worse outcome of ovarian cancer patients treated with systemic chemotherapeutics.

A comprehensive review about immune responses and exhaustion during coronavirus disease (COVID-19).

Coronavirus disease (COVID-19) is a viral infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The infection was reported in Wuhan, China, in late December 2019 and has become a major global concern due to severe respiratory infections and high transmission rates. Evidence suggests that the strong interaction between SARS-CoV-2 and patients' immune systems leads to various clinical symptoms of COVID-19. Although the adaptive immune responses are essential for eliminating SARS-CoV-2, the innate immune system may, in some cases, cause the infection to progress. The cytotoxic CD8+ T cells in adaptive immune responses demonstrated functional exhaustion through upregulation of exhaustion markers. In this regard, humoral immune responses play an essential role in combat SARS-CoV-2 because SARS-CoV-2 restricts antigen presentation through downregulation of MHC class I and II molecules that lead to the inhibition of T cell-mediated immune response responses. This review summarizes the exact pathogenesis of SARS-CoV-2 and the alteration of the immune response during SARS-CoV-2 infection. In addition, we've explained the exhaustion of the immune system during SARS-CoV-2 and the potential immunomodulation approach to overcome this phenomenon. Video Abstract.

Peripheral neuropathy as a very rare symptom in a patient with Niemann-Pick type C with negative enzymatic evaluation: a case report.

BACKGROUND: Niemann-Pick is a rare metabolic disease distinguished by lysosomal storage defects. This disease is characterized by sphingomyelinase acid deficiency, causing its accumulation in various organs such as the kidneys, spleen, liver, brain, and nerves. Niemann-Pick disease is categorized into four groups: A, B, C, and D. Peripheral neuropathy is an extremely rare complication in patients with Niemann-Pick type C, which certainly leads to neurologic deterioration. CASE PRESENTATION: We report a case of Niemann-Pick type C disease in a 3-year-old Iranian Azeri female patient who was hospitalized twice. The first time was at 1 month of age with symptoms of splenomegaly, jaundice, and elevated liver enzymes, and the second time was at around age 2 for loss of mental and physical abilities. The patient presented with failure to thrive. According to paraclinical examinations, mildly delayed myelination along with a nonspecific periventricular hypersignal intensity was seen. Interestingly, the patient's Niemann-Pick type C enzymatic function was evaluated twice and was negative on both occasions, while she was positive for NPC1 and NPC2 gene examinations. CONCLUSIONS: In this study, despite the enzymatic study being negative, Niemann-Pick type C disease was finally confirmed, revealing the importance of mutations in Niemann-Pick type C pathogenesis. Besides, peripheral neuropathy was diagnosed in this patient as a very rare symptom of Niemann-Pick type C.

Potential anti-inflammatory effect of anti-HMGB1 in animal models of ICH by downregulating the TLR4 signaling pathway and regulating the inflammatory cytokines along with increasing HO1 and NRF2.

Intracerebral hemorrhage (ICH) is a severe clinical problem without effective treatment; the leading cause is neuroinflammation. High-mobility group box one protein (HMGB1) is an abundant protein in the cell nucleus of most mammalian cells, which exerts its function by binding to chromatin. The present study focused on the therapeutic effect of anti-HMGB1 on ICH via the downregulation of inflammatory pathways. The ICH mice models were created by collagenase IV injection in the striatum of mice. Then, mice were received different medications and divided into three groups: anti-HMGB1, anti-Toll-like receptor 4 (TLR4), and non-treated ICH groups. Cerebrospinal fluid (CSF) was obtained, and ELISA was carried out to determine the levels of inflammatory agents. Microglial cells were isolated from the cerebral hemispheres, and then Real-Time PCR and western blot were performed. The results showed that the anti-inflammatory effects of anti-HMGB1 were tremendous than anti-TLR4. Overall, the results showed that anti-HMGB1 had a more reducer effect on pro-inflammatory cytokines release (****P < 0.0001) and expression (****P < 0.0001) than anti-TLR4 when compared with the control group. It was also determined that anti-HMGB1 increased heme-oxygenase-1 (HO1) and nuclear factor erythroid-derived factor 2-related factor 2 (NRF2) (****P < 0.0001) expression in comparison with the control group while it was not significant for anti-TLR4 (CLI-095). The present study suggested that anti-HMGB1 serves as a potential anti-inflammatory molecule via reducing TLR4-related signaling pathways, pro-inflammatory cytokines production, and increasing the production of the anti-inflammatory cytokine along with heme-oxygenase-1 HO1 and NRF2 increment.

The lethal internal face of the coronaviruses: Kidney tropism of the SARS, MERS, and COVID19 viruses.

The kidney is one of the main targets attacked by viruses in patients with a coronavirus infection. Until now, SARS-CoV-2 has been identified as the seventh member of the coronavirus family capable of infecting humans. In the past two decades, humankind has experienced outbreaks triggered by two other extremely infective members of the coronavirus family; the MERS-CoV and the SARS-CoV. According to several investigations, SARS-CoV causes proteinuria and renal impairment or failure. The SARS-CoV was identified in the distal convoluted tubules of the kidney of infected patients. Also, renal dysfunction was observed in numerous cases of MERS-CoV infection. And recently, during the 2019-nCoV pandemic, it was found that the novel coronavirus not only induces acute respiratory distress syndrome (ARDS) but also can induce damages in various organs including the liver, heart, and kidney. The kidney tissue and its cells are targeted massively by the coronaviruses due to the abundant presence of ACE2 and Dpp4 receptors on kidney cells. These receptors are characterized as the main route of coronavirus entry to the victim cells. Renal failure due to massive viral invasion can lead to undesirable complications and enhanced mortality rate, thus more attention should be paid to the pathology of coronaviruses in the kidney. Here, we have provided the most recent knowledge on the coronaviruses (SARS, MERS, and COVID19) pathology and the mechanisms of their impact on the kidney tissue and functions.