Current Molecular Pharmacology - Volume 13, Issue 4, 2020

Liver cancer is a leading cause of cancer-related death worldwide, in which hepatocellular carcinoma (HCC) accounts for the majority. Despite the progression in treatment, the prognosis remains extremely poor for HCC patients. The mechanisms of hepatocarcinogenesis are complex, of which fibrosis is acknowledged as the pre-cancerous stage of HCC. Approximately, 80-90% of HCC develops in the fibrotic or cirrhotic livers. Hepatic stellate cells (HSCs), the main effector cells of liver fibrosis, could secret various biological contents to maintain the liver inflammation. By decades, HSCs are increasingly correlated with HCC in the tumor microenvironment. In this review, we summarized the underlying mechanisms that HSCs participated in the genesis and progression of HCC. HSCs secrete various bioactive contents and regulate tumor-related pathways, subsequently contribute to metastasis, angiogenesis, immunosuppression, chemoresistance and cancer stemness. The study indicates that HSC plays vital roles in HCC progression, suggesting it as a promising therapeutic target for HCC treatment.

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

The bacterial infection is one of the major health issues throughout the world. To protect humans from the infection and infectious agents, it is important to understand the mechanism of interaction of pathogens along with their susceptible hosts. This will help us to develop a novel strategy for designing effective new drugs or vaccines. As iron is an essential metal ion required for all the living systems for their growth, as well, it is needed by pathogenic bacterial cells for their growth and development inside host tissues. To get iron from the host tissues, microbes developed an iron-chelating system called siderophore and also corresponding receptors. Siderophores are low molecular weight organic complex produced by different strains of bacteria for the procurement of iron from the environment or host body under the iron deficient-conditions. Mostly in the environment at physiological pH, the iron is present in the ferric ionic form (Fe3+), which is water- insoluble and thus inaccessible for them. Such a condition promotes the generation of siderophores. These siderophores have been used in different areas such as agriculture, treatment of diseases, culture the unculturable strains of bacteria, promotion of plant growth, controlling phytopathogens, detoxification of heavy metal contamination, etc. In the medical field, siderophores can be used as “Trojan Horse Strategy”, which forms a complex with antibiotics and also delivers these antibiotics to the desired locations, especially in antibiotic-resistant bacteria. The promising application of siderophore-based use of antibiotics for the management of bacterial resistance can be strategies to be used.

Background: Vitamin D insufficiency and deficiency can be associated with adverse effects on pregnancy outcomes, which may include recurrent pregnancy loss through the mechanisms that are yet unknown. The aim of this study was to evaluate the effect of 1,25VitD3 on regulatory T cells (Tregs) and T helper17 (Th17) cell populations In vitro in unexplained recurrent pregnancy loss (URPL) patients and healthy women. Methods: Samples from 20 non-pregnant women with a history of URPL were compared to 20 normal non-pregnant women. Peripheral blood mononuclear cells (PBMC) were divided into 3 wells for each subject: in the presence of 1, 25 VitD3 (50 nM, for 16 hours), PHA (positive control) (10μM), and without any treatment (as a baseline or negative control). The percentage of regulatory T cells and Th17 cells was measured by flow cytometry at baseline and then after cell culture experiments. Results: Our study indicated that the percentage of Tregs in patients with URPL was significantly lower than the control group (2.42 ± 0.27 vs. 3.41 ± 0.29, P= 0.01). The percentage of Th17 cells was significantly greater in URPL patients compared to the control group (2.91 ± 0.33 vs. 1.18± 0.15, P=0.001). 1, 25VitD3 treatment significantly increased the percentage of Tregs from the baseline in the URPL group compared to that in the control group (1.23 ± 0.03 vs. 1.00 ± 0.03, P= 0.01). Conclusion: Vitamin D deficiency may be a contributor to recurrent pregnancy loss and suggests supplementation of women with Vit D pre-pregnancy may be protective against URPL.

Background: Hepatic fibrosis is the major issue in chronic liver diseases such as chronic hepatitis C virus (HCV). The newly approved direct acting antiviral (DAA) agents such as Sofosbuvir (SOF) and daclatasvir (DAC) have been found to be associated with decreased fibrotic markers in HCV patients. Aim: This study tried to explore whether the reported antifibrotic effect of these drugs is antiviral dependent or drug induced. Method: Hepatic fibrosis was induced by (0.5ml/kg) CCl4 IP twice a week for six weeks. SOF (20 mg/kg/d) and DAC (30 mg/kg/d) were added in the last four weeks of treatments. Liver functions, fibrotic markers such as Hyaluronic acid and metalloproteinase-9 were detected using immunoassay. The expression of TNF-α/NF-ΚB signaling pathway as well as Bcl-2 were done using immunoassay. Results: SOF and DAC exerted a potent antifibrotic effect evidenced by their activity against hyaluronic acid HA and metalloproteinase MMP-9 significantly (P≤0.001). This effect was further proved histopathologically where liver tissues from rats treated by drugs showed marked inhibition of collagen precipitation as well as inhibition of HSCs activation. This antifibrotic action was associated with decreased expression of TNF-α /NF-ΚB signaling pathway and induction of Bcl-2. Conclusion: SOF/ DAC antifibrotic effect is independent of its antiviral activity. The molecular events associated with this effect were the downregulation of TNF-α / NF-ΚB signaling pathway and induction of Bcl-2.

Background: Osteoarthritis is a disorder of joints featuring inflammation and degeneration of articular cartilage. Recently, miRs have been found to be associated in the regulation of chondrocytes and their apoptosis. miR-18a-3p has been found to be associated in the pathogenesis of rheumatoid arthritis, however, its role in articular cartilage tissues remains unclear. Methods: C57BL/6 strain of mice and human cartilage tissue were used for the study. Histological analysis was done on isolated cartilage samples followed by TUNEL assay and immunohistochemical analysis. The chondrocytes were isolated from mouse and human cartilage tissues, RNA was isolated and subjected for qRT-PCR analysis. The chondrocytes were transfected with miR-18a-3p agomir, antagomir and siHOXA-1. Luciferase assay was done in 293T cells. Flow cytometry analysis was done and western blot analysis for studying the expression of proteins. Results: The expression of miR-18a-3p was upregulated in chondrocytes after exposing them to interlukin- 1β (IL-1β) in vitro. The transfection of miR-18a-3p antagomir halted the IL-1β mediated apoptosis. The luciferase assay suggested that miR-18a-3p targets the 3’UTR region of HOXA1 gene thus blocking its expression. The treatment of HOXA1 siRNA demonstrated the rescuing effect of miR- 18a-3p antagomir on the apoptosis of chondrocytes. Treatment of miR-18a-3p antagomir attenuated the surface of cartilage in osteoarthritis mice and the agomir worsened it. TUNEL assay suggested decreased apoptosis and over-expression of HOAX1 in osteoarthritis mice post miR-18a-3p knockdown. Conclusion: The findings confirmed the involvement of miR-18a-3p/HOXA1 pathway as a potential mechanism in the regulation of Osteoarthritis.

Background: The activation of Nrf2/HO-1 pathway has been shown to protect against cisplatin- induced nephrotoxicity by reducing oxidative stress. Berberine (Ber), an isoquinoline alkaloid, has demonstrated antioxidant, anti-inflammatory and anti-apoptotic activities in various experimental models. Aim: To check the effect of Ber on cisplatin-induced nephrotoxicity and to explore the involved mechanism. Methods: Adult male Wistar rats were divided into 6 groups: Normal, cisplatin-control, treatment groups and per se group. Normal saline and Ber (20, 40 and 80 mg/kg; p.o.) was administered to rats for 10 days. A single intraperitoneal injection of cisplatin (8 mg/kg) was injected on 7th day to induced nephrotoxicity. On 10th day, rats were sacrificed, the kidney was removed and stored for the estimation of various parameters. Results: As compared to cisplatin-control group, Ber pretreatment improved renal function system and preserved renal architecture. It also diminished oxidative stress by upregulating the expression of Nrf2/HO-1 proteins. In addition, Ber attenuated the cisplatin mediated inflammation and apoptosis. Furthermore, it also reduced the phosphorylation of p38/JNK and PARP/Beclin-1 expression in the kidney. Conclusion: Ber attenuated renal injury by activating Nrf2/HO-1 and inhibiting JNK/p38MAPKs/ PARP/Beclin-1 expression which prevented oxidative stress, inflammation, apoptosis and autophagy in renal tissue.