Effect of coadministration of omega-3 fatty acids with glimepiride on glycemic control, lipid profile, irisin, and sirtuin-1 in type 2 diabetes mellitus patients: a randomized controlled trial.

BACKGROUND AND OBJECTIVE: Type 2 diabetes mellitus (T2DM) is caused by insulin resistance or tissue insensitivity to insulin, as well as relative insulin insufficiency. Diabetes that is uncontrolled for an extended period of time is linked to substantial comorbidities and organ damage. The purpose of the current study is to assess the effect of coadministration of omega-3 fatty acids with glimepiride on blood glucose, lipid profile, serum irisin, and sirtuin-1 levels in T2DM patients. METHODS: This clinical trial involved 70 type 2 diabetic patients randomly assigned to glimepiride 3 mg with either omega-3 capsules contained fish oil 1000 mg, 13% of eicosapentaenoic acid (EPA) and 9% docosahexaenoic acid (DHA) (omega-3 group, n = 35) or placebo capsules contained corn oil and linoleic acid (control group, n = 35) daily for three months. Blood samples were obtained at the start of the study and 12 weeks later for biochemical examination of HbA1c%, FBG, fasting insulin, and lipid profile. In addition, the atherogenic index of plasma (AIP) was calculated. Human enzyme-linked immunosorbent assay (ELISA) kits were utilized for assessing serum irisin and sirtuin-1 levels before and after the intervention. RESULTS: Compared to the control group, omega-3 fatty acids decreased serum fasting blood glucose (FBG, p < 0.001), glycated hemoglobin percent (HbA1C%, p < 0.001), total cholesterol (TC, p < 0.001), triglycerides (TGs, p = 0.006), low density lipoprotein (LDL, p = 0.089), and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR, p = 0.021) after three months of intervention. However, a significant increase was reported in serum irisin and high density lipoprotein (HDL) between both groups after intervention (p = 0.026 and p = 0.007, respectively). The atherogenic index of plasma (AIP) increased in the control group but decreased in the omega-3 group, with significant differences between the two groups (p < 0.001). CONCLUSION: The present study found that supplementing with omega-3 fatty acids might dramatically enhance blood irisin levels, as well as improve glycemic control and lipid profile in type 2 diabetes mellitus patients using glimepiride. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov under identifier NCT03917940 . (The registration date: April 17, 2019).

Leflunomide abrogates neuroinflammatory changes in a rat model of Alzheimer's disease: the role of TNF-α/NF-κB/IL-1ß axis inhibition.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is associated with disrupted cognition and behavior. Neuroinflammatory pathogenesis is the main component that contributes to AD initiation and progression through microglial activation and neuronal damage. Thus, targeting inflammatory pathways may help manage AD. In this study, for the first time, the potential prophylactic and therapeutic effects of leflunomide were investigated either alone or in combination with rivastigmine in aluminum chloride (AlCl3)-induced AD-like rats using behavioral, biochemical, and histological approaches. Thirty-six adult male albino rats were divided into two protocols: the treatment protocol, subdivided into five groups (n = 6)-(1) control group, (2) AlCl3 (50, 70, 100 mg/kg/I.P) group, (3) reference group (rivastigmine 2 mg/kg/P.O.), (4) experimental group (leflunomide 10 mg/kg/P.O.), and (5) combination group (rivastigmine + leflunomide); and the prophylactic protocol (leflunomide 10 mg/kg/P.O.), which started 2 weeks before AlCl3 induction. The results showed that AlCl3 disrupted learning and memory parameters in rats and increased amyloid-ß plaque deposition and neurofibrillary tangle aggregation. Moreover, AlCl3 administration markedly elevated acetylcholinesterase activity, nuclear factor-kappa ß, tumor necrosis factor-α, and interleukin-1 beta, and marked degenerative changes in the pyramidal neurons. However, administration of leflunomide alone or with rivastigmine in AlCl3-induced AD rats restored most of the behavioral, biochemical, and histological parameters triggered by AlCl3 in rats. Our findings suggest that leflunomide can potentially restore most of the neuronal damage in the hippocampal tissues of AlCl3-induced AD rats. However, these preclinical findings still need to be confirmed in clinical trials.

Investigation of the protective and therapeutic effects of Lactobacillus casei and Saccharomyces cerevisiae in a breast cancer mouse model.

Introduction: The development of novel strategies for cancer therapy is crucial to improve standard treatment protocols. Aim: This study aimed to determine the protective and therapeutic effects of heat-killed preparations of Lactobacillus casei and Saccharomyces cerevisiae in a breast cancer mouse model. Methods: Forty-two female BALB/c mice (7-8 weeks old) were divided into six groups (seven mice per group). Four groups were injected with 107 Ehrlich ascites tumor (EAT) cells suspended in phosphate-buffered saline (PBS) subcutaneously into the left side of the mammary fat pad. Tumor growth was monitored weekly until all animals developed a palpable tumor. The tumor-bearing mice in the experimental groups received heat-killed L. casei or S. cerevisiae three times per week for 35 days. The mice in the control group received PBS. The remaining two groups received heated L. casei or S. cerevisiae and then were injected with EAT cells. After 35 days, all mice were sacrificed to determine the immune response. Results: Animals that received heated S. cerevisiae exhibited the lowest rate of tumor growth compared with the other groups. TGF-ß and IL-4 secretion was increased in all mice, whereas the secretion of INF-γ and IL-10 was decreased in breast tissues. Moreover, at the histopathological level, the volume of viable tumor in the control group was higher than in the treated groups. Conclusion: Supplementary treatment with S. cerevisiae resulted in the best outcome in the breast cancer model compared with other treated and vaccinated groups.

Epigenetic restoration and activation of ERß: an inspiring approach for treatment of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. TNBC lacks targeted therapy receptors, rendering endocrine and HER2-targeted therapies ineffective. TNBC is typically treated with cytotoxic chemotherapy followed by surgery. Targeting epigenetic modifications could potentially be a new effective TNBC target therapy. The aim of this study is to examine the effects of epigenetic drugs, decitabine as DNA methyltransferase inhibitor (DNMTI) and vorinostat as histone deacetylase inhibitor (HDACI), and the ERß agonist DPN on ERα and ERß re-expressions in the MDA-MB-231 cells as a model of TNBC. METHODS: Using MTT assay, the IC50 of decitabine, vorinostat, and DPN on MDA-MB-231 cells were determined. The effects of all drugs alone or in combinations on MDA-MB-231 cells were evaluated. qRT-PCR was used to determine ERα & ERß gene expression. Caspase-3 activity and the protein expression levels of VEGF, Cyclin D1, and IGF-1 were assessed. RESULTS: Both ERα and ERß mRNA were re-expressed in different high levels in all treated groups, especially in the triple therapy group compared with control. Significantly, the triple drugs therapy showed the lowest levels of VEGF, Cyclin D1, and IGF-1 and the highest level of Caspase-3 activity, indicating a possible antitumor effect of ERß activation through decreasing proliferation and angiogenesis and increasing apoptosis in MDA-MB-231 cells. CONCLUSIONS: The antiproliferative effect of ERß could be retained when co-expressed with Erα using a powerful epigenetic combination of Decitabine and vorinostat with DPN.

Effect of amlodipine versus bisoprolol in hypertensive patients on maintenance hemodialysis: A randomized controlled trial.

BACKGROUND: Left ventricular hypertrophy and asymmetric dimethylarginine (ADMA) are surrogate markers of cardiovascular disease (CVD) in the dialysis population. This study aimed to evaluate the effect of a calcium channel blocker-based antihypertensive regimen compared to a beta-blocker-based antihypertensive regimen on left ventricular mass index (LVMI) and ADMA levels in hypertensive patients on hemodialysis (HD). METHODS: This was a parallel-design, open-label, single-center randomized controlled trial on 46 hypertensive patients on maintenance HD, with no history of CVD. Patients were randomly assigned to receive amlodipine 10 mg/d (n = 23) or bisoprolol 10 mg/d (n = 23). Office-based blood pressure (BP) was targeted to ≤ 140/ 90 mm Hg. The outcome was the change in LVMI and ADMA from baseline to 6 months. RESULTS: Baseline demographic and clinical characteristics did not vary between groups. After 6 months of treatment, amlodipine-based therapy induced a greater reduction in LVMI from baseline than bisoprolol-based treatment (35 ±â€Š34.2 vs 9.8 ±â€Š35.9 gm/m2; P = .017). A similar reduction in the mean BP occurred with treatment in both groups. ADMA concentration decreased significantly from baseline in the amlodipine group (0.75 ±â€Š0.73 to 0.65 ±â€Š0.67 nmol/mL; P = .001), but increased nonsignificantly in the bisoprolol group (0.64 ±â€Š0.61 to 0.78 ±â€Š0.64 nmol/mL; P = .052). CONCLUSION: This study showed that compared to a bisoprolol-based regimen, an amlodipine-based antihypertensive regimen resulted in a significantly greater reduction in LVMI and ADMA levels from baseline in hypertensive patients on HD despite similar BP reduction in both groups. These findings support the re-evaluation of amlodipine as a potential first-line antihypertensive treatment in patients on HD without previous CVD. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04085562, registered September 2019.

Catalpol synergistically potentiates the anti-tumour effects of regorafenib against hepatocellular carcinoma via dual inhibition of PI3K/Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer characterized by dysregulation of several crucial cellular signaling pathways such as PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 pathways. Novel therapies targeting these pathways have been discovered such as regorafenib which is small molecular multi-kinase inhibitor mainly targets VEGF/VEGFR2. Catalpol is an iridoid glycoside richly found in rehmannia glutinosa which is a fundamental herb used extensively in traditional Chinese medicine. It is evidenced that catalpol has many pharmacological effects on nervous and cardiovascular systems, in addition to exhibiting hypoglycemic, anti-inflammatory, anti-proliferative and anti-tumour activities. However, its effect on HCC isn't clear enough. So, this study aimed to investigate the anti-tumour effects of catalpol either alone or in combination with regorafenib on HCC. METHODS AND RESULTS: In vitro experiments were performed using HepG2 and HUH-7 hepatocellular carcinoma cell lines. MTT assays evaluated anti-proliferative effects of catalpol and/or regorafenib. Combination index was calculated via compusyn software to detect synergism. Tumour biomarkers were measured using ELISA technique. Results showed that catalpol has anti-tumour effects against HCC via targeting PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 pathways. In addition, results revealed that our novel combination of catalpol and regorafenib showed potent synergistic anti-tumour effect via suppressing both of PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways and their downstreams. CONCLUSION: Catalpol and/or regorafenib markedly suppressed PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways and consequently showed potent anti-tumour effects against HCC. Results encourage further pre-clinical and clinical studies of this novel combination as a promising targeted therapy for HCC management.

Systemic bee venom exerts anti-arthritic and anti-inflammatory properties in a rat model of arthritis.

Bee venom (BV) is widely used as a traditional China medicine to treat various conditions, including rheumatoid arthritis (RA). The aim of the present study was to evaluate the effects of systemic BV (60 mg/kg) as an anti-arthritic natural product, compare it with Methotrexate and determine the possible underlying mechanisms of BV action using complete Freund's adjuvant-induced arthritic rats. The development of signs of RA signs (knee joint circumference and arthritis scoring index) was evaluated. Erythrocyte sedimentation rate, serum tumor necrosis factor-α (TNF-α) and serum interleukin-1ß (IL-1ß) levels were measured at the end of the study. Histopathological examination followed by immunostaining of NF-κB (P65) was performed on the affected knee joints. Additionally, in vitro cyclooxygenase (COX) inhibition activity, carrageenan paw edema test and acetic acid writhing tests were performed to evaluate the anti-inflammatory and analgesic effects of the assessed dose and compared with diclofenac. An acute toxicity test was performed to establish the safety of BV at high doses. The results of the present study highlighted the potential of systemic BV on preventing the development of signs of RA. BV also significantly reduced serum levels of TNF-α, IL-1ß and NF-κB in the affected joints. In addition to its potent analgesic activity, BV exhibited favorable inhibitory activity of the COX pathway in both in vivo and in vitro models. Therefore, high dose administration of systemic BV displayed safe and promising anti-arthritic, anti-inflammatory and analgesic properties through regulation of different mechanisms associated with the pathogenesis of RA.

Chemopreventive and antitumor effects of benzyl isothiocynate on HCC models: A possible role of HGF /pAkt/ STAT3 axis and VEGF.

BACKGROUND: Benzyl isothiocyanate (BITC) is a member of the isothiocyanate compounds that found in cruciferous vegetables. BITC has a potential anticancer effect in different types of tumors. Few studies referred to the antineoplastic effect of BITC against HCC. The mechanism of BITC concerning retardation of HCC progression is incompletely understood. AIM OF THE WORK: This study evaluated the role of HGF, pAkt and STAT3 in BITC induced HCC growth retardation. METHOD: HCC was induced in mice using diethylnitrosamine (DEN) 75 mg/kg once a week for 4 weeks. BITC 10 and 20 mg/kg was given to mice orally each day for 10 weeks. The HCC cell lines HepG2 and Huh-7 were also used to evaluate the effect of BITC on tumor cells behavior. Immunoassay was used to detect expressions of caspase-3 activity, VEGF, MMP-2, TNF-α, HGF and pAkt. STAT3 expression was detected in liver tissues using immunohistochemical staining. RESULTS: BITC has a potential role in suppressing hepatic precancerous lesion progression in mice. The drug increased caspase-3 activity in tumor cells and inhibited the angiogenic marker VEGF. It also decreased the metastatic marker MMP-2. This anticancer effect of BITC was observed in DEN treated mice as well as in hepatoma cell lines. The reported antineoplastic activity was correlated with downregulation of HGF and its downstream molecules pAkt and STAT3. CONCLUSION: The effect of BITC on HGF /pAkt/ STAT3 axis has a potential role in both chemopreventive and chemotherapeutic effects of BITC.