Relevant Aspects of Combined Protocols for Prevention of N(M)AFLD and Other Non-Communicable Diseases.

Obesity is a global health issue characterized by the excessive fat accumulation, leading to an increased risk of chronic noncommunicable diseases (NCDs), including metabolic dysfunction-associated fatty liver disease (MAFLD), which can progress from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, there are no approved pharmacological protocols for prevention/treatment of MAFLD, and due the complexity lying beneath these mechanisms, monotherapies are unlikely to be efficacious. This review article analyzes the possibility that NCDs can be prevented or attenuated by the combination of bioactive substances, as they could promote higher response rates, maximum reaction results, additive or synergistic effects due to compounds having similar or different mechanisms of action and/or refraining possible side effects, related to the use of lower doses and exposures times than monotherapies. Accordingly, prevention of mouse MAFLD is observed with the combination of the omega-3 docosahexaenoic acid with the antioxidant hydroxytyrosol, whereas attenuation of mild cognitive impairment is attained by folic acid plus cobalamin in elderly patients. The existence of several drawbacks underlying published monotherapies or combined trials, opens space for adequate and stricter experimental and clinical tryouts to achieve meaningful outcomes with human applicability.

Comparative Effectiveness of Treatments for Bacterial Vaginosis: A Network Meta-Analysis.

Bacterial vaginosis (BV) is a common vaginal dysbiosis in women of reproductive age. However, the cure rate for BV varies considerably and many women experience a relapse after the initial treatment. The present meta-analysis aimed to evaluate the clinical cure rates (CCRs) in randomized controlled trials (RCTs) through different therapies and administration routes. This meta-analysis included a final set of 25 eligible studies with a total of 57 RCTs and compared the effectiveness of BV treatments among non-pregnant and pregnant women. The initial range of CCRs varied greatly from 46.75% to 96.20% and the final pooled CCR was 75.5% (CI: 69.4-80.8) using the random model. The heterogeneity indices were Q = 418.91, I2 = 94.27%, and τ = 0.7498 (p < 0.0001). No publication bias was observed according to Funnel plot symmetry and Egger's linear regression test (p = 0.1097). To evaluate different variables, sub-group analysis, meta-regressions, and network meta-analysis were also realized. The highest P-scores in CCR were obtained by: (1) a combined therapy with local probiotic treatment and application of antibiotics by both administration route (oral clindamycin and local 5-nitroimidazole; P-score = 0.92); (2) a combined therapy with oral administration of 5-nitroimidazole and probiotic treatment (P-score = 0.82); (3) and a combined therapy with local administration of 5-nitroimidazole and oral probiotic treatment (P-score = 0.68). A clear-cut decision of the best BV treatment was not possible due to the heterogeneity of outcomes reported in the trials, indicating the necessity for a better characterization of RCTs. Finally, combined therapies suggested the reduction of the optimal concentration of antibiotics, and double phase treatments of antibiotics indicated an increment of CCRs in BV.

[10]-Gingerol improves doxorubicin anticancer activity and decreases its side effects in triple negative breast cancer models.

PURPOSE: Although doxorubicin is widely used to treat cancer, severe side effects limit its clinical use. Combination of standard chemotherapy with natural products can increase the efficacy and attenuate the side effects of current therapies. Here we studied the anticancer effects of a combined regimen comprising doxorubicin and [10]-gingerol against triple-negative breast cancer, which does not respond to hormonal or targeted therapies. METHODS: Cytotoxicity was evaluated by MTT assay, cell cycle progression and apoptosis were analyzed by flow cytometry and signaling pathways were analyzed by Western blotting in human and murine triple negative breast cancer cell systems. The anticancer/antimetastatic and toxic effects of the combined regimen was evaluated using syngeneic and xenograft orthotopic models. RESULTS: The combination of doxorubicin and [10]-gingerol significantly increased the number of apoptotic cells, compared to each compound alone. In 4T1Br4 cells, the combined regimen was the only condition able to increase the levels of active caspase 3 and γH2AX and to decrease the level of Cdk-6 cyclin. In vivo, doxorubicin (3 mg/Kg, D3) and [10]-gingerol (10 mg/Kg, G10) resulted in a significant reduction in the volume of primary tumors and a decrease in the number of circulating tumor cells (CTCs). Interestingly, only the combined regimen led to decreased tumor burdens to distant organs (i.e., metastasis) and reduced chemotherapy-induced weight loss and hepatotoxicity in tumor-bearing animals. Likewise, in a xenograft model, only the combined regimen was effective in significantly reducing the primary tumor volume and the prevalence of CTCs. CONCLUSIONS: Our data indicate that [10]-gingerol has potential to be used as a neoadjuvant or in combined therapy with doxorubicin, to improve its anticancer activity.

Neuroprotective Role of Hypothermia in Hypoxic-ischemic Brain Injury: Combined Therapies using Estrogen.

Hypoxic-ischemic brain injury is a complex network of factors, which is mainly characterized by a decrease in levels of oxygen concentration and blood flow, which lead to an inefficient supply of nutrients to the brain. Hypoxic-ischemic brain injury can be found in perinatal asphyxia and ischemic-stroke, which represent one of the main causes of mortality and morbidity in children and adults worldwide. Therefore, knowledge of underlying mechanisms triggering these insults may help establish neuroprotective treatments. Selective Estrogen Receptor Modulators and Selective Tissue Estrogenic Activity Regulators exert several neuroprotective effects, including a decrease of reactive oxygen species, maintenance of cell viability, mitochondrial survival, among others. However, these strategies represent a traditional approach of targeting a single factor of pathology without satisfactory results. Hence, combined therapies, such as the administration of therapeutic hypothermia with a complementary neuroprotective agent, constitute a promising alternative. In this sense, the present review summarizes the underlying mechanisms of hypoxic-ischemic brain injury and compiles several neuroprotective strategies, including Selective Estrogen Receptor Modulators and Selective Tissue Estrogenic Activity Regulators, which represent putative agents for combined therapies with therapeutic hypothermia.

Bacterial Therapy of Cancer: Promises, Limitations, and Insights for Future Directions.

Spontaneous tumors regression has been associated with microbial infection for 100s of years and inspired the use of bacteria for anticancer therapy. Dr. William B. Coley (1862-1936), a bone- sarcoma surgeon, was a pioneer in treating his patients with both live bacterial-based and mixture of heat-killed bacteria known as "Coley's toxins." Unfortunately, Coley was forced to stop his work which interrupted this field for about half a century. Currently, several species of bacteria are being developed against cancer. The bacterial species, their genetic background and their infectious behavior within the tumor microenvironment are thought to be relevant factors in determining their anti-tumor effectiveness in vivo. In this perspective article we will update the most promising results achieved using bacterial therapy (alone or combined with other strategies) in clinically-relevant animal models of cancer and critically discuss the impact of the bacterial variants, route of administration and mechanisms of bacteria-cancer-cell interaction. We will also discuss strategies to apply this information using modern mouse models, molecular biology, genetics and imaging for future bacterial therapy of cancer patients.

Synergism of arsenic trioxide and MG132 in Raji cells attained by targeting BNIP3, autophagy, and mitochondria with low doses of valproic acid and vincristine.

We previously demonstrated that arsenic trioxide (ATO) and proteasome inhibitor MG132 synergistically induced cell death in promonocytic leukaemia cell line U937 but were antagonistic in Burkitt's lymphoma cell line Raji. Here we explore the role of autophagy, expression of BNIP3, and mitochondrial mass, in determining whether ATO and MG132 interaction can be shifted from antagonism to synergism in Raji cells. Treatment with ATO+MG132 increased the percentage of cells with collapsed mitochondrial membrane potential (MMP) in U937 cells, but had no effect in Raji cells. Mitochondria were found in cytoplasmic marginal location in U937 cells but at perinuclear location in Raji cells. ATO+MG132 increased mitochondrial mass in U937 cells but decreased it in Raji cells, while autophagy was increased in both cell lines. BNIP3 was expressed in U937 cells at cytoplasmic marginal locations and was hardly detected in Raji cells. Histone deacetylase (HDAC) inhibitor valproic acid (VPA) increased expression of BNIP3 in Raji cells at perinuclear locations. However antagonism between ATO and MG132 was increased in the presence of low doses of VPA. Addition of vincristine (VCR) blocked autophagy, while VPA+VCR treatment of Raji cells at sub-cytotoxic doses caused BNIP3 and mitochondria to redistribute to cytoplasmic peripheral location and increased mitochondrial mass. ATO+MG132 in the presence of subcytotoxic doses of VPA+VCR caused collapse of MMP in Raji cells, while interaction between ATO and MG132 shifted from antagonism to synergism. We conclude that synergism between ATO and MG132 was attained in Raji cells by disruption of the perinuclear mitochondrial cluster, blockage of selective autophagy of mitochondria (mitophagy) by VCR, increased mitochondrial mass, and upregulation of BNIP3 by VPA.