Herbal-based therapeutics for diabetic patients with SARS-Cov-2 infection.

Human SARS Coronavirus-2 (SARS-CoV-2) has infected more than 170 million people worldwide, being responsible for about 3.5 million deaths so far. Despite ongoing investigations, there is still more to understand the mechanism of COVID-19 infection completely. However, it has been evidenced that SARS-CoV-2 can cause Coronavirus disease (COVID-19) notably in diabetic people. Approximately 35% of the patients who died of this disease had diabetes. A growing number of studies have evidenced that hyperglycemia is a significant risk factor for severe SARS-CoV-2 infection and plays a key role in COVID-19 mortality and diabetes comorbidity. The uncontrolled hyperglycemia can produce low-grade inflammation and impaired immunity-mediated cytokine storm that fail multiple organs and sudden death in diabetic patients with SARS-CoV-2 infection. More importantly, SARS-CoV-2 infection and interaction with ACE2 receptors also contribute to pancreatic and metabolic impairment. Thus, using of diabetes medications has been suggested to be beneficial in the better management of diabetic COVID-19 patients. Herbal treatments, as safe and affordable therapeutic agents, have recently attracted a lot of attention in this field. Accordingly, in this review, we intend to have a deep look into the molecular mechanisms of diabetic complications in SARS-CoV-2 infection and explore the therapeutic potentials of herbal medications and natural products in the management of diabetic COVID-19 patients based on recent studies and the existing clinical evidence.

Non-coding RNAs as Key Regulators of the Notch Signaling Pathway in Glioblastoma: Diagnostic, Prognostic, and Therapeutic Targets.

Glioblastoma multiforme (GBM) is a highly invasive brain malignancy originating from astrocytes, accounting for approximately 30% of central nervous system malignancies. Despite advancements in therapeutic strategies including surgery, chemotherapy, and radiopharmaceutical drugs, the prognosis for GBM patients remains dismal. The aggressive nature of GBM necessitates the identification of molecular targets and the exploration of effective treatments to inhibit its proliferation. The Notch signaling pathway, which plays a critical role in cellular homeostasis, becomes deregulated in GBM, leading to increased expression of pathway target genes such as MYC, Hes1, and Hey1, thereby promoting cellular proliferation and differentiation. Recent research has highlighted the regulatory role of non-coding RNAs (ncRNAs) in modulating Notch signaling by targeting critical mRNA expression at the post-transcriptional or transcriptional levels. Specifically, various types of ncRNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been shown to control multiple target genes and significantly contribute to the carcinogenesis of GBM. Furthermore, these ncRNAs hold promise as prognostic and predictive markers for GBM. This review aims to summarize the latest studies investigating the regulatory effects of ncRNAs on the Notch signaling pathway in GBM.

MiR-138-5p improves the chemosensitivity of MDA-MB-231 breast cancer cell line to paclitaxel.

BACKGROUND: Chemotherapy is a predominant strategy for breast cancer (BC) treatment and paclitaxel (PTX) has been known as a conventional chemotherapeutic drug. However, insensitivity of BC cells to PTX limits the anti-tumor effects of this agent. MicroRNAs are closely related to BC which are suggested as therapeutic factors in the combination therapy of BC. We examined the possible efficacy of miR-138-5p restoration in combination with PTX to impove BC treatment. METHODS: The human breast cancer cell line MDA-MB-231 was transfected with miR-138-5p mimics and treated with PTX, in a combined or separate manner. The MTT assay was accomplished to determine inhibitory doses of PTX. Annexin V/PI assay and DAPI staining were applied to evaluate apoptosis. Flow cytometry was applied to determine cells arrested in different phases of the cell-cycle. Expression levels of molecular factors involved in cell migration, proliferation, apoptosis, and cell cycle were determined via western blotting and qRT-PCR. RESULTS: MiR-138-5p combined with PTX suppressed cell migration via modulating MMP2, E-cadherin, and vimentin and sustained colony formation and proliferation by downregulation of the PI3K/AKT pathway. qRT-PCR showed that miR-138-5p increases BC chemosensitivity to PTX by regulating the apoptosis factors, including Bcl-2, Bax, Caspase 3, and Caspase 9. Moreover, miR-138-5p restoration and paclitaxel therapy combined arrest the cells in the sub-G1 and G1 phases of cell cycle by regulating p21, CCND1, and CDK4. CONCLUSIONS: Restored miR-138-5p intensified the chemosensitivity of MDA-MB-231 cell line to PTX, and the combination of miR-138-5p with PTX might represent a novel approach in BC treatment.

Bile acid-based advanced drug delivery systems, bilosomes and micelles as novel carriers for therapeutics.

Diabetes mellitus affects almost half a billion patients worldwide and results from either destruction of ß-cells responsible for insulin secretion or increased tissue resistance to insulin stimulation and the reduction of glycemic control. Novel drug delivery systems can improve treatment efficacy in diabetic patients. The low aqueous solubility of most oral antidiabetic drugs decreases drug bioavailability; therefore, there is a demand for the use of novel methods to overcome this issue. The application of bile acids mixed micelles and bilosomes can provide an enhancement in drug efficacy. Bile acids are amphiphilic steroidal molecules that contain a saturated tetracyclic hydrocarbon cyclopentanoperhydrophenanthrene ring, and consist of three 6-membered rings and a 5-membered ring, a short aliphatic side chain, and a tough steroid nucleus. This review offers a comprehensive and informative data focusing on the great potential of bile acid, their salts, and their derivatives for the development of new antidiabetic drug delivery system.

Increased circulating platelet and endothelial-derived microparticles in patients with cardiac syndrome X.

BACKGROUND: Cardiac syndrome X (CSX) has been associated with endothelial dysfunction and inflammation. We conducted a case-control study to evaluate the association between plateletý and endothelial-derived microparticles (PMPs and EMPs), as specific quantitative plasma markers of endothelial dysfunction, and the presence of CSX. METHODS: The present study was conducted on 40 CSX patients and 19 healthy individuals. C-reactive protein (CRP), and hematological and biochemical parameters were evaluated. The MP concentration in platelet-poor plasma (PPP) was quantitatively determined through flow cytometry using specific anti-human CD31, CD41a, CD62E, and CD144 antibodies. RESULTS: The mean platelet volume (MPV) and positive CRP rate (≥ 3.8 mg/l) were higher in patients compared to controls (P = 0.020 and P = 0.010, respectively). The CD62E+, CD144+, and CD31+41- EMPs, as well as CD41+ and CD31+CD41+ PMPs showed significant increase in CSX patients compared to controls (P < 0.050). There were direct correlations between the mean percentage of detected EMPs and PMPs as well as between their expression intensity; however, a reverse correlation was seen between the percentage of MPs and CD144 and CD41. Moreover, the MP level was reversely associated with prothrombin time (PT) and partial thromboplastin time (PTT) values. Only CD31+CD41+ PMP was correlated with CRP. CONCLUSION: It seems that EMPs and PMPs increase in CSX, which may contribute to various processes involved in the development of this syndrome.

MicroRNA-124-3p suppresses PD-L1 expression and inhibits tumorigenesis of colorectal cancer cells via modulating STAT3 signaling.

Programmed death ligand 1 (PD-L1) plays a significant role in colorectal tumorigenesis through induction of regulatory T cells (Tregs) and suppression of antitumor immunity. Furthermore, microRNAs (miRNAs) as the posttranscriptional regulators of gene expression show considerable promise as a therapeutic target for colorectal cancer (CRC) treatment. Considering this, in vitro effects of miRNA-124 (miR-124-3p) on CRC cell tumorigenesis and Tregs differentiation via targeting PD-L1 were investigated in the current study. Functional analysis showed that miR-124 is significantly downregulated in CRC tissues as compared with marginal normal samples (p < .0001), and its downregulation was negatively correlated with PD-L1 expression. Moreover, a specific region in PD-L1 3'-untranslated region was predicted as the miR-124 target and validated using the luciferase assay. Further investigation showed that transfection of HT29 and SW480 cells with miR-124 mimics significantly reduced PD-L1 mRNA, protein, and cell surface expression, and inhibited Tregs in coculture models via modulating interleukin [IL]-10, IL-2, tumor necrosis factor α, transforming growth factor beta, and interferon gamma expression levels. Besides, miR-124 overexpression decreased CRC cell proliferation and arrested cell cycle at the G1 phase through downregulation of c-Myc and induced apoptosis in CRC cells via upregulation of both intrinsic and extrinsic pathways. Also, miR-124 exogenous overexpression could reduce colony and spheroid formation ability of CRC cells via downregulating CD44 mRNA expression. miR-124 also diminished MMP-9 expression and subsequently suppressed cell migration and invasion. We also illustrated that STAT3 signaling was repressed by miR-124 in CRC cells. Taken together, our findings imply that considering the involvement of miR-124 in the regulation of PD-L1 through colorectal tumorigenesis and its remarkable antitumor effects, this miRNA could be regarded as the promising target for the development of therapeutic approaches for colorectal cancer.

PD-L1 silencing inhibits triple-negative breast cancer development and upregulates T-cell-induced pro-inflammatory cytokines.

Triple-negative breast cancer (TNBC) is an invasive tumor with a high incidence of distant metastasis and poor prognosis. In TNBC cells, high PD-L1 expression can induce an immunosuppressive tumor microenvironment, repressing the anti-tumoral immune responses. Although FDA-approved agents targeting the PD-1/PD-L1 axis are potent to eliminate tumoral cells, their immune-related adverse events have become worrisome. As the regulator of gene expression, siRNAs can directly target PD-L1 in breast cancer cells. The gene modification of tumoral PD-L1 can reduce our reliance on the current method of targeting the PD-L1/PD-1 axis. We initiated the study with bioinformatics analysis; the results indicated that TNBC and the MDA-MB-231 cells significantly overexpressed PD-L1 compared to other breast cancer subtypes and cell lines. Our results demonstrated that PD-L1 silencing substantially reduced PD-L1 expression at mRNA and protein levels in MDA-MB-231 cells. Moreover, our results demonstrated that PD-L1 knockdown reduced cancer cell proliferation and induced apoptosis via intrinsic and extrinsic apoptosis pathways. We observed that PD-L1 silencing effectively inhibited the migration of TNBC cells. Further investigation also displayed that silencing of PD-L1 in breast cancer cells induced T-cell cytotoxic function by upregulating the gene expression of pro-inflammatory cytokines, i.e., IL-2, IFN-γ, and TNF-α, and downregulating the gene expression of anti-inflammatory cytokines, i.e., IL-10, and TGF-ß, in a co-culture system.

Molecular mechanisms of breast cancer chemoresistance by immune checkpoints.

Progression of resistance to chemotherapy in breast cancer (BC) has been recognized as a main factor in decreasing the survival of patients with this malignancy. Recent investigations have described the involvement of immune checkpoint molecules in the progress of drug resistance in breast carcinoma patients. In the present study, the molecular participation of immune checkpoint factors in chemoresistance of BC both in-vitro and in-vivo is reviewed. Numerous immune checkpoints such as PD-1/PD-L1, CTLA-4, B7-H3, B7-H4, B7-1, and B7-2 have been specified as positive regulators of resistance to various drug types in BC. In several molecular pathways of drug resistance in BC, immune checkpoints affect the chemoresistance of this cancer in a drug- and cell-type-dependent manner. In addition, immune checkpoints promote chemoresistance in response to particular drugs in specific BC cell lines. Furthermore, several the immune checkpoint molecules have not been evaluated in the field of the chemoresistance in breast malignancy either in-vitro or in-vivo. Overall, investigations have indicated that targeting immune checkpoint molecules may be considered as a novel method to improve existing anti-BC treatments.

Interaction between DNA damage response and autophagy in colorectal cancer.

The subjection of DNA to numerous lethal damages is threatening for the stability and integrity of the whole body genome. DNA damage response (DDR) is a critical phosphorylation-based signaling pathway developed for the maintaining of the genome against these threatens. Recent studies showed that various targets of DDR are involved in the activation of autophagy, as one of the important effectors of this signaling. The interplay between DDR and autophagy may have a critical role in the pathogenesis of various malignancies such as colorectal cancer, which can be a basement for the designing novel therapeutic strategies for combating this cancer type. On the other hand, autophagy is also demonstrated to be contributed to the regulation of DDR components. Therefore, in this review article, we will discuss the crosstalk between DDR and autophagy and their exact function in the pathogenesis of various human cancer types, with special attention on colorectal cancer.