Synergetic Potential of Combination Probiotic Complex with Phytopharmaceuticals in Valproic Acid Induced Autism: Prenatal Model

Background: Autism spectrum disorder (ASD) is a developing neuronal disorder with hindered social correspondence and repetitive behaviors. Hereditary and ecological factors have been related to this problem, including the introduction of valproic acid during pregnancy. Dysbiosis is the most common comorbid condition in autism, numerous probiotic strains have been known to forestall social impairments in autism. Method: Prenatal autism model was done on 12th embryonic day of pregnancy in Wistar rats with the valproic acid dose 400 mg/kg, i.p. Those offspring exhibiting autistic symptoms were selected for study and were treated with polyphenols, probiotics and their combination for the study period of postnatal day (PND) 08-50. Results: Prenatal model showed significant autistic and dysbiotic symptoms in the animals. With the probiotic and polyphenols treatment combination it was understood that bio-activation of polyphenols are crucial in the correction of neurochemical abnormality, oxidative stress, behavioral deficits and neuroprotection. Probiotic complex with acetyl-l-carnitine combination was also essential for the growth of gut bacteria, functionality of brain. Through this combination study behavioral and biochemical alterations were recovered. Conclusion: Establishing a good ecosystem in the gut with good probiotics and polyphenols-like compounds is essential, gut targeted brain functionality is a remarkable way to challenge autistic disorder, advice on this combination may be helpful in the right way of accessing the gut-brain-axis and useful in amending of autism.

Interventions to Improve Adherence to Antiretroviral Therapy (ART) in Sub-Saharan Africa: An Updated Systematic Review

Optimal adherence to antiretroviral therapy (ART) remains the bedrock of effective therapy and management of human immunodeficiency virus (HIV). This systematic review examines the effect of interventions in improving ART adherence in sub-Saharan Africa (SSA), which bears the largest global burden of HIV infection. In accordance with PRISMA guidelines, and based on our inclusion and exclusion criteria, PUBMED, MEDLINE, and Google Scholar databases were searched for published studies on ART adherence interventions from 2010 to 2019. Thirty-one eligible studies published between 2010 to 2019 were identified, the categories of interventions were structural, behavioral, biological, cognitive, and combination. Study characteristics varied across design, intervention type, intervention setting, country, and outcome measurements. Many of the studies were behavioral interventions conducted in hospitals with more studies being randomized controlled trial (RCT) interventions. Despite the study variations, twenty-four studies recorded improvements. Notwithstanding, more quality studies such as RCTs should be conducted, especially among key affected populations (KAPs) to control transmission of resistant strains of the virus. Reliable objective measures of adherence should replace the conventional subjective self-report. Furthermore, long-term interventions with longer duration should be considered when evaluating the effectiveness of interventions.

Discovery of vanoxerine dihydrochloride as a CDK2/4/6 triple-inhibitor for the treatment of human hepatocellular carcinoma

Background Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). Methods We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC. Results We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxicdrugin human HCC QGY7703 and Huh7 cells (IC50: 3.79 μM for QGY7703and 4.04 μM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1-arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40 mg/kg, i.p.) injection for 21 days produced significant anti-tumor activity (p < 0.05), which was comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerinedihydrochloride treatment group. Conclusions The present study isthe first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.

Discovery of Vanoxerine Dihydrochloride as a CDK2 / 4 / 6 Triple-Inhibitor for the Treatment of Human Hepatocellular Carcinoma

Background: Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). Methods: We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC.Results: We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxic drug in human HCC QGY7703 and Huh7 cells (IC50: 3.79μM for QGY7703and 4.04μM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1‑arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40mg/kg, i.p.) injection for 21 days produced significant anti‑tumor activity (p<0.05), which was comparable to that achieved by 5-Fu (10mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerine dihydrochloride treatment group.Conclusions: The present study is the first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.

No additive effect of combining sumatriptan and olcegepant in the GTN mouse model of migraine

Introduction Despite recent advances in migraine treatment there is a need for therapies with higher clinical efficacy and/or fewer side effects. Triptans (5-HT1B/1D/1F agonists) are essential in the present treatment regime and gepants (CGRP-receptor antagonists) are recognized as effective in acute migraine treatment. Triptans and gepants have different mechanisms of action and here we tested the hypothesis that a combination of these drugs (sumatriptan and olcegepant) would result in an additive effect. Methods Using the validated glyceryl trinitrate mouse model of migraine, we initially tested dose-response relationships of sumatriptan (0.1, 0.3, and 0.6 mg/kg IP) and olcegepant (0.25, 0.50, and 1.0 mg/kg IP) to find suitable high and low doses. Subsequently, we performed a combination study of the two drugs with a low and a high dose. All experiments were vehicle (placebo) controlled and blinded. Results Sumatriptan significantly reduced glyceryl trinitrate-induced allodynia (F(4,54) = 13.51, p < 0.0001) at all doses. Olcegepant also reduced glyceryl trinitrate-induced allodynia (F(4,53) = 16.11, p < 0.0001) with the two higher doses being significantly effective. Combining 0.50 mg/kg olcegepant with 0.1 or 0.6 mg/kg sumatriptan did not have any improved effect compared to either drug alone ( p > 0.50 on all days) in our mouse model. Conclusion Combining olcegepant and sumatriptan did not have an additive effect compared to single-drug treatment in this study. Triptan-gepant combinations will therefore most likely not improve migraine treatment. Nevertheless, further studies are necessary, and combinations should also be examined in patients with migraine.

Synergistic tumor inhibition of colon cancer cells by nitazoxanide and obeticholic acid, a farnesoid X receptor ligand

The tumor-suppressive role of Farnesoid X receptor (FXR) in colorectal tumorigenesis supports restoring FXR expression as a novel therapeutic strategy. However, the complicated signaling network and tumor heterogeneity hinder the effectiveness of FXR agonists in the clinical setting. These difficulties highlight the importance of identifying drug combinations with potency and specificity to enhance the antitumor effects of FXR agonists. In this study, we found that the β-catenin level affected the antitumor effects of the FXR agonist OCA on colon cancer cells. Mechanistic studies identified a novel FXR/β-catenin complex in colon cancer cells. Furthermore, the depletion of β-catenin expedited FXR nuclear localization and enhanced its occupancy of the SHP promoter and thereby sensitized colon cancer cells to OCA. Furthermore, we utilized a drug combination study and identified that the antiparasitic drug nitazoxanide (NTZ) abrogated β-catenin expression and acted synergistically with OCA in colon cancer cells. The combination of OCA plus NTZ exerts synergistic tumor inhibition in CRC both in vitro and in vivo by cooperatively upregulating SHP expression. In conclusion, our study offers useful evidence for the clinical use of FXR agonists combined with β-catenin inhibitors in combating CRC.