Oreocnide integrifolia (Gaud.)Miq. exhibits hypoglycemic and hypolipidemic potentials on streptozotocin diabetic rats

Oreocnide integrifolia (Gaud.)Miq (Urticaceae) leaves are used to alleviate diabetic symptoms in folk medicine in northeast India. In the present study, dose and duration dependent hypoglycemic potentials were evaluated in streptozotocin induced diabetic rats. Administration of aqueous leaf extract (100, 250, 500 and 750 mg/kg body weight orally once daily) to diabetic rats reduced glycemic levels by 56 % by 4 weeks of treatment and was comparable to standard reference drug Metformin. The experimental data also revealed significant improvement in lowering lipid profile, Urea, Creatinine, Hb, HbA1c and insulin levels. The present study clearly demonstrates hypoglycemic and hypolipidemic potential of Oreocnide integrifolia leaf extract

Amelioration of carbon tetrachloride induced hepatotoxicity in rats by standardized Feronia limonia. Linn leaf extracts

The hepatoprotective potential of standardized Feronia limonia (Family, Rutaceae) methanolic extract (FL-7) and chloroform soluble fraction (FL-9) were assessed against carbon tetrachloride (CCl4) induced oxidative stress and hepatotoxicity in rats. Rats treated with CCl4 recorded significant elevation in plasma markers of hepatic injury, alteration in hepatic antioxidant status and histopathological damages. However, rats pretreated with FL-7 (200 or 400 mg/kg, p.o.) and FL-9 (100 or 200 mg/kg, p.o.) for 7 days and later administered CCl4 (0.5 ml/kg, i.p.) recorded lowered indices of the above mentioned parameters and minimal histological damage in a dose dependent manner. These results were comparable to that of CCl4+silymarin treated rats. The results obtained with FL-7 and FL-9 are attributable to their free radical scavenging potential due to high contents of polyphenols and flavonols recorded herein. Overall, this study establishes the efficacy of FL-7 and FL-9 as hepatoprotective agents against CCl4 induced hepatotoxicity in rats

Natural Products for the Treatment of Obesity, Metabolic Syndrome, and Type 2 Diabetes 2014

Editorial. In the modern and contemporary world, the incidence of obesity, metabolic syndrome, and type II diabetes is rising continuously due to modernization in life style and dietary habits. Herbal medicines have been shown to be beneficial against coexistence of these ailments. In 2013, we published a special issue on “Natural products for the treatment of obesity, metabolic syndrome, and type 2 diabetes” in EvidenceBased Complementary and Alternative Medicine (eCAM). After receiving an overwhelming number of submissions and successful compilation of research/review articles in the first season, the decision to publish annual special issue on this subject has been made by eCAM. Herein we present the 2014 issue in this series. This special issue consists of 5 original research papers and 4 review articles

Natural Products for the Treatment of Obesity, Metabolic Syndrome, and Type 2 Diabetes 2016

Editorial: The prevalence of obesity, metabolic syndrome, and type 2 diabetes is continuously on rise due to modernization of life style and changing dietary habits. Use of herbal medicines for the treatment of metabolic diseases is a viable option and list of potential candidates is ever expanding. This 2016 edition of this special issue regarding natural products for the treatment of obesity, metabolic syndrome, and type 2 diabetes contains 8 articles accepted from a total of 21 submissions consisting of 6 research articles and 2 clinical studies

Efavirenz, a CYP46a1 activator Ameliorates Pathological Neovascularization in A Mouse Model of Oxygen-Induced Retinopathy

Introduction: In a prior study, we documented the predominant reliance of the developing retina on the alternate bile acid (BA) synthesis pathway. However, in the context of oxygen-induced retinopathy (OIR) in mouse models, retinal BA synthesis undergoes significant dysregulation, marked by a pronounced reduction in the activity of the key rate-limiting enzyme, Cytochrome P450 enzymes (CYP or P450) 46A1. Objective: The objective of this current investigation is to assess the impact of efavirenz (EFV)-mediated activation of CYP46A1 on retinal neovascularization in OIR mice, a model representative of retinopathy of prematurity (ROP). Methods: Seven-day-old (P7) C57BL/6J mice were subjected to the OIR procedure following the methodology outlined by Smith et al. OIR-induced mice received EFV treatment at doses of either 10 or 20 mg/kg body weight from P7 to P17, while age-matched room air mice were included as controls. Retinal neovascularization and avascular area were evaluated in mouse retinal flat mounts stained with isolectin-B4. Results: Our findings revealed that while a dosage of 10 mg/kg EFV did not confer significant protection against OIR pathology, treatment with 20 mg/kg EFV led to a notable reduction in both avascular area and pathological neovascularization within OIR mouse retinas. Importantly, we observed no substantial evidence of retinal or systemic toxicity associated with EFV treatment in neonatal mice. Conclusion: In summary, our preliminary investigations suggest that pharmacological activation of CYP46A1 using efavirenz holds promise in ameliorating critical pathological features linked to neovascularization in OIR mice, thereby potentially positioning efavirenz as a therapeutic candidate for ROP

Interleukin-1β orchestrates underlying inflammatory responses in microglia via Kruppel-like factor 4

Microglia are the resident macrophages of the CNS, which secrete several pro‐ and anti‐inflammatory cyto‐chemokines including interleukin‐1β (IL‐1β), in response to pathogenic stimuli. Once secreted, IL‐1β binds to IL‐1 receptor present on microglia and initiates the production of inflammatory cytokines in microglia. However, the detailed information regarding the molecular mechanisms of IL‐1β triggered inflammatory pathways in microglia is lacking. Our studies focused on the role of Krüppel‐like factor 4 (Klf4) in mediating the regulation of pro‐inflammatory gene expression upon IL‐1β stimulation in microglia. Our studies show that stimulation of microglia with IL‐1β robustly induces Klf4 via PI3K/Akt pathway which positively regulates the production of endogenous IL‐1β as well as other pro‐inflammatory markers, cyclooxygenase‐2, monocyte chemoattractant protein‐1 and interleukin‐6 (IL‐6). In addition, we report that Klf4 negatively regulates the expression of inducible nitric oxide synthase, thereby playing a key role in regulating the immunomodulatory activities of microglia. IL‐1β is a potent pro‐inflammatory cytokine which regulates inflammation in brain via activation of microglia. In this regard, we unravelled mechanisms for IL‐1β mediated regulation of downstream Cox‐2, iNOS (inducible nitric oxide synthase) as well as other cyto‐chemokines in microglia and have established a role for Klf4 in mediating microglial activation. We further report that Klf4 mediates the production of endogenous IL‐1β in response to exogenous IL‐1β stimulation. We hereby propose a novel transcription factor underlying IL‐1β mediated modulation of inflammation in the CNS

CD8+ T–NK cell crosstalk establishes preemptive immunosurveillance to eliminate antigen–escape tumors

Background and objectiveTumor antigen–escape variants undermine immunotherapy by subverting lymphocyte effector functions and reshaping tumor–immune dynamics. It is essential to delineate functional interplay within immune networks during tumor progression. We investigated whether homeostatic crosstalk between CD8+T cells and natural killer (NK) cells preempts tumor antigen–escape. MethodsAdoptive CD8+T cell transfers were administered before (D–7, homeostatic pre-priming) or after (D+1) tumor establishment in Rag1−/− and Rag1−/−γc−/− mice. Antigen presentation, immune activation, proliferation, cytotoxicity, and memory were quantified by flow cytometry, live bioluminescence and confocal imaging. Monoculture, co-culture, and a 3D silica nanofiber carpet mimicking basement-membrane-like topography modeled intercellular interactions. Signaling arrays and motion metrics (Speed-Distance Index, deceleration) were conducted. Human ligand–receptor pairs engaged in CD8+T–NK crosstalk were probed in silico.Results and discussionPre-tumor D–7 CD8+T cell transfer completely suppressed antigen–escape tumors with NK cells as major effectors showing elevated CD25, CD69, CD107a, and GzmB, marking activated and effector phenotype, and promoting central-memory CD62L⁺CD44⁺CD8⁺TCM precursors. By contrast, post-tumor D+1–transferred CD8+T cells allowed emergence of tumor variants resistant to antigen-specific cytolysis as assessed on day 25, despite those T cells retaining higher intrinsic cytotoxic capacity than the D–7 T cell cohort. Mechanistically, CD8+T and NK cells formed stable contacts through pseudopodial intercellular nanotubes enabling bidirectional membrane exchange and signaling via STAT, Akt, and mTOR pathways, augmenting NK effector function and promoting CD8+TCM differentiation. In silico analysis identified human ligand–receptor pairs engaged in CD8+T–NK adhesion, stimulatory and regulatory axes, including CD200–CD200R, PD-L1–PD-1, and CD18/CD11a–DNAM-1 (CD226). Together, data support a three-phase model of preemptive immunosurveillance initiated by early CD8⁺T–NK crosstalk.ConclusionHomeostatic conditioning and effector cooperativity between CD8+T and NK cells protect against tumor immune escape. The findings uncover a mechanistic axis of preemptive immunosurveillance that lays the foundation for next-generation preventive immunotherapies to control antigen–escape tumors

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival