Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).

Indole-3-propionic acid mitigates chlorpyrifos-mediated neurotoxicity by modulating cholinergic and redox-regulatory systems, inflammatory stress, apoptotic responses and DNA damage in rats.

This study probed the neuroprotective influence of indole-3-propionic acid (IPA) in rats exposed to chlorpyrifos (CPF) alone at 5 mg/kg body weight or co-administered with IPA at 12.5 and 25 mg/kg for 14 days. Behavioral data indicated that IPA significantly (p < 0.05) abated CPF-mediated anxiogenic-like behaviors with concomitant improvement in the locomotor and exploratory behaviors as substantiated by track plots and heat maps data. Also, IPA mitigated CPF-mediated diminution in cholinergic and antioxidant defense systems whereas it markedly improved thioredoxin level and thioredoxin reductase activity in cerebral and cerebellar tissues of the animals. Co-administration of IPA significantly enhanced anti-inflammatory cytokine, interleukin-10 but suppressed oxidative and inflammatory stress, caspase-9 and caspase-3 activation with concomitant reduction in 8-hydroxy-2'-deoxyguanosine (8-OHdG) level and histological damage. Collectively, IPA-mediated neuroprotection involves modulation of cholinergic and redox-regulatory systems, inflammatory stress, apoptotic responses and DNA damage in cerebrum and cerebellum of rats.

Piperine mitigates behavioral impairments and provides neuroprotection against 3-nitropropinoic acid-induced Huntington disease-like symptoms.

Background: Piperine (PIP) is a powerful anti-oxidant and anti-inflammatory alkaloid which has been widely used in the treatment of various pathological conditions. However, few studies have clearly discussed the protective effects and potential mechanism of PIP in different neurological diseases. The aim of this study was to investigate the neuroprotective effect of PIP against 3-nitropropioninc acid (3-NP) induced neurobehavioral, biochemical and histopathological alterations in animals.Methods: Adult male Wistar rats were randomly divided into three groups. Group 1, the vehicle administered control group, received normal saline (p.o.). Group 2 received 3-NP (20 mg/kg.b.wt., i.p.) for 4 consecutive days. Group 3 received PIP (10 mg/kg.b.wt., p.o.) twice daily for a period of 4 days, 30 min before and 6 h after the 3-NP injection. Upon termination of treatment schedule, behavioral experiments were performed to access the behavioral outcomes. The brain striatal tissue was used for the estimation of monoamine oxidase activity and serotonin level. In addition, astrocytes activation was observed by GFAP immunostaining.Results: Our results showed that 3-NP induced behavioral impairments are attenuated by PIP co-treatment. Next, the extent of neuronal loss and astrocytes activation was reduced in the striatal brain region in PIP treated rats. Finally, it was observed that PIP alleviated the behavioral, biochemical, immunohistochemical and histological alterations.Conclusion: The results of the current study reveal the neuroprotective competency of PIP against Huntington disease like symptoms in rats.

Modulation by antenatal therapies of cardiovascular and renal programming in male and female offspring of preeclamptic rats.

Morbidity and mortality risks are enhanced in preeclamptic (PE) mothers and their offspring. Here, we asked if sexual dimorphism exists in (i) cardiovascular and renal damage evolved in offspring of PE mothers, and (ii) offspring responsiveness to antenatal therapies. PE was induced by administering NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered orally with L-NAME, atrasentan (endothelin ETA receptor antagonist), terutroban (thromboxane A2 receptor antagonist, TXA2), or α-methyldopa (α-MD, central sympatholytic drug). Cardiovascular and renal profiles were assessed in 3-month-old offspring. Compared with offspring of non-PE rats, PE offspring exhibited elevated systolic blood pressure and proteinuria and reduced heart rate and creatinine clearance (CrCl). Apart from a greater bradycardia in male offspring, similar PE effects were noted in male and female offspring. While terutroban, atrasentan, or α-MD partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in cardiorenal inflammatory (tumor necrosis factor alpha, TNFα) and oxidative (isoprostane) markers were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-MD, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-MD in rectifying cardiac structural damage, myofiber separation, and cytoplasmic alterations, in PE offspring. The repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-MD, the conventional PE therapy.

Review: The Nutritional Management of Multiple Sclerosis With Propionate.

Over the last 15 years there has been an accumulation of data supporting the concept of a gut-brain axis whereby dysbiosis of the gut microbiota can impact neurological function. Such dysbiosis has been suggested as a possible environmental exposure triggering multiple sclerosis (MS). Dysbiosis has been consistently shown to result in a reduction in short-chain fatty acid (SCFA) producing bacteria and a reduction in stool and plasma levels of propionate has been shown for MS patients independent of disease stage and in different geographies. A wealth of evidence supports the action of propionate on T-cell activity, resulting in decreased T-helper cell 1 (Th1) and T-helper cell 17 (Th17) numbers/activity and increased regulatory T cell (Treg cell) numbers/activity and an overall anti-inflammatory profile. These different T-cell populations play various roles in the pathophysiology of MS. A recent clinical study in MS patients demonstrated that supplementation of propionate reduces the annual relapse rate and slows disease progression. This review discusses this data and the relevant mechanistic background and discusses whether taming of the overactive immune system in MS is likely to allow easier bacterial and viral infection.

GW9508 ameliorates cognitive dysfunction via the external treatment of encephalopathy in Aß1-42 induced mouse model of Alzheimer's disease.

The functions and mechanisms of GPR40 receptor to ameliorating the Alzheimer's disease (AD) by external treatment of encephalopathy remain unknown. In present study, the typical Aß1-42 induced mice model was applied to explore the functions and mechanisms of GPR40 receptor by external treatment of encephalopathy in AD. GPR40 agonist GW9508 and antagonist GW1100 were given by i.g injection to activate/inhibit the GPR40 receptor respectively in the gut of AD mouse which illustrated the function and mechanism of GPR40 receptor in ameliorating AD symptoms by external treatment of encephalopathy. A series of behavioral experiments were used to investigate the cognitive function and memory ability of mice, while molecular biology experiments such as Western blot, ELISA, flow cytometry were used to detect the corresponding changes of signaling pathways. The results revealed that intragastric administrated GW9508 could significantly ameliorate cognitive deficits of AD mouse, up-regulate the expression levels of gut-brain peptides both in blood circulation and hypothalamus thus up-regulate the expression levels of α-MSH in hypothalamus, while the negative autophagy-related proteins and inflammation-related proteins were down-regulated correspondingly. Meanwhile, GW9508 could also inhibit the pathological process of neuroinflammation in microglia. GW1100 reversed the effects of GW9508 significantly. These results suggested that GPR40 was an underlying therapeutic target for the external treatment of encephalopathy related to AD and GPR40 agonist could be explored as the emerging AD therapeutic drug.

Nano-ivabradine averts behavioral anomalies in Huntington's disease rat model via modulating Rhes/m-tor pathway.

Huntington's disease (HD) is characterized by abnormal involuntary movements together with cognitive impairment and disrupted mood changes. 3-nitropropionic acid (3-NP) is one of the chemo-toxic models used to address the striatal neurotoxicity pattern encountered in HD. This study aims to explain the neuroprotective effect of nano-formulated ivabradine (nano IVA) in enhancing behavioral changes related to 3-NP model and to identify the involvement of ras homolog enriched striatum (Rhes)/mammalian target of rapamycin (m-Tor) mediated autophagy pathway. Rats were divided into 6 groups, the first 3 groups received saline (control), ivabradine (IVA), nano IVA respectively, the fourth received a daily dose of 3-NP (20 mg/kg, s.c) for 2 weeks, the fifth received 3-NP + IVA (1 mg/kg, into the tail vein, every other day for 1 week) and the last group received 3-NP + nano IVA (1 mg/kg, i.v, every other day for 1 week). Interestingly, nano IVA reversed motor disabilities, improved memory function and overcame the psychiatric changes. It boosted expression of autophagy markers combined with down regulation of Rhes, m-Tor and b-cell lymphoma 2 protein levels. Also, it restored the normal level of neurotransmitters and myocardial function related-proteins. Histopathological examination revealed a preserved striatal structure with decreased number of darkly-degenerated neurons. In conclusion, the outcomes of this study provide a well-recognized clue for the promising neuroprotective effect of IVA and the implication of autophagy and Rhes/m-Tor pathways in the 3-NP induced HD and highlight the fact that nano formulations of IVA would be an auspicious approach in HD therapy.

A Phase 1 Study to Investigate the Effects of Cortexolone 17α-Propionate, Also Known as Clascoterone, on the QT Interval Using the Meal Effect to Demonstrate ECG Assay Sensitivity.

Cortexolone 17α-propionate, also known as clascoterone, is a potent androgen receptor inhibitor intended for the topical treatment of skin diseases associated with androgenic pathway alterations. In nonclinical studies, cortexolone 17α-propionate was found to have a weak inhibitory effect on human Ether-à-go-go-Related Gene (hERG) potassium channels, which are vital for normal electrical activity in the heart. When used in a cream formulation, little cortexolone 17α-propionate is absorbed. However, the solution formulation developed for the treatment of androgenetic alopecia leads to a measurable systemic concentration and accumulation of the antiandrogen. This phase 1 study assessed the effect of cortexolone 17α-propionate on the QTc interval using concentration-effect analysis and the effect of a meal on QTc to confirm assay sensitivity. Thirty-two volunteers were randomly assigned to receive the active drug or a matching vehicle as placebo. Participants were dosed twice daily on days 1 to 3 (225 mg applied topically as a 7.5% solution 12 hours apart) and once on day 4. Pharmacokinetic and electrocardiogram assessments were performed after supratherapeutic doses. Assay sensitivity was successfully confirmed by using the food effect on the QTc interval. The results of this concentration-QTc analysis demonstrate that cortexolone 17α-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested.

A Data-Mining Approach for the Quantitative Assessment of Physicochemical Properties of Molecular Compounds in the Skin Flux.

This paper aimed to provide an insight into the mechanism of transdermal penetration of drug molecules with respect to their physicochemical properties, such as solubility (S), the presence of enantiomer (ET) and logarithm of octanol-water partition coefficient (log P), molecular weight (MW), and melting point (MP). Propionic acid derivatives were evaluated for their flux through full-thickness skin excised from hairless mice upon being delivered from silicone-based pressure-sensitive adhesive (PSA) matrices in the presence or absence of various enhancers. The skin fluxes of model compounds were calculated based on the data obtained using the method engaged with the diffusion cell system. The statistical design of experiments (DoE) based on the factorial approach was used to find variables that have a significant impact on the outcomes. For the prediction of skin flux, a quantitative equation was derived using the data-mining approach on the relationship between skin permeation of model compounds (~125 mg/ml) and involved physicochemical variables. The most influential variables for the skin flux of propionic acid derivatives were the melting point (0.97) followed by the presence of enantiomer (0.95), molecular mass (0.93), log P values (0.86), and aqueous solubility (0.80). It was concluded that the skin flux of molecular compounds can be predicted based on the relationship between their physicochemical properties and the interaction with cofactors including additives and enhancers in the vehicles.

Beneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men.

Non-alcoholic steatohepatitis (NASH) is the most rapidly growing liver disease that is nevertheless without approved pharmacological treatment. Despite great effort in developing novel NASH therapeutics, many have failed in clinical trials. This has raised questions on the adequacy of preclinical models. Elafibranor is one of the drugs currently in late stage development which had mixed results for phase 2/interim phase 3 trials. In the current study we investigated the response of elafibranor in APOE*3Leiden.CETP mice, a translational animal model that displays histopathological characteristics of NASH in the context of obesity, insulin resistance and hyperlipidemia. To induce NASH, mice were fed a high fat and cholesterol (HFC) diet for 15 weeks (HFC reference group) or 25 weeks (HFC control group) or the HFC diet supplemented with elafibranor (15 mg/kg/d) from week 15-25 (elafibranor group). The effects on plasma parameters and NASH histopathology were assessed and hepatic transcriptome analysis was used to investigate the underlying pathways affected by elafibranor. Elafibranor treatment significantly reduced steatosis and hepatic inflammation and precluded the progression of fibrosis. The underlying disease pathways of the model were compared with those of NASH patients and illustrated substantial similarity with molecular pathways involved, with 87% recapitulation of human pathways in mice. We compared the response of elafibranor in the mice to the response in human patients and discuss potential pitfalls when translating preclinical results of novel NASH therapeutics to human patients. When taking into account that due to species differences the response to some targets, like PPAR-α, may be overrepresented in animal models, we conclude that elafibranor may be particularly useful to reduce hepatic inflammation and could be a pharmacologically useful agent for human NASH, but probably in combination with other agents.

A semi-mechanistic exposure-response model to assess the effects of verinurad, a potent URAT1 inhibitor, on serum and urine uric acid in patients with hyperuricemia-associated diseases.

Verinurad, a uric acid transporter 1 (URAT1) inhibitor, lowers serum uric acid by promoting its urinary excretion. Co-administration with a xanthine oxidase inhibitor (XOI) to simultaneously reduce uric acid production rate reduces the potential for renal tubular precipitation of uric acid, which can lead to acute kidney injury. The combination is currently in development for chronic kidney disease and heart failure. The aim of this work was to apply and extend a previously developed semi-mechanistic exposure-response model for uric acid kinetics to include between-subject variability to verinurad and its combinations with XOIs, and to provide predictions to support future treatment strategies. The model was developed using data from 12 clinical studies from a total of 434 individuals, including healthy volunteers, patients with hyperuricemia, and renally impaired subjects. The model described the data well, taking into account the impact of various patient characteristics such as renal function, baseline fractional excretion of uric acid, and race. The potencies (EC50s) of verinurad (reducing uric acid reuptake), febuxostat (reducing uric acid production), and oxypurinol (reducing uric acid production) were: 29, 128, and 13,030 ng/mL, respectively. For verinurad, symptomatic hyperuricemic (gout) subjects showed a higher EC50 compared with healthy volunteers (37 ng/mL versus 29 ng/mL); while no significant difference was found for asymptomatic hyperuricemic patients. Simulations based on the uric acid model were performed to assess dose-response of verinurad in combination with XOI, and to investigate the impact of covariates. The simulations demonstrated application of the model to support dose selection for verinurad.

Preparation and Evaluation of Colon-Targeted Prodrugs of the Microbial Metabolite 3-Indolepropionic Acid as an Anticolitic Agent.

Microbial metabolites play a critical role in mucosal homeostasis by mediating physiological communication between the host and colonic microbes, whose perturbation may lead to gut inflammation. The microbial metabolite 3-indolepropionic acid (3-IPA) is one such communication mediator with potent antioxidative and anti-inflammatory activity. To apply the metabolite for the treatment of colitis, 3-IPA was coupled with acidic amino acids to yield colon-targeted 3-IPA, 3-IPA-aspartic acid (IPA-AA) and 3-IPA-glutamic acid (IPA-GA). Both conjugates were activated to 3-IPA in the cecal contents, which occurred faster for IPA-AA. Oral gavage of IPA-AA (oral IPA-AA) delivered a millimolar concentration of IPA-AA to the cecum, liberating 3-IPA. In a 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat colitis model, oral IPA-AA ameliorated rat colitis and was less effective than sulfasalazine (SSZ), a current anti-inflammatory bowel disease drug. To enhance the anticolitic activity of 3-IPA, it was azo-linked with the GPR109 agonist 5-aminonicotinic acid (5-ANA) to yield IPA-azo-ANA, expecting a mutual anticolitic action. IPA-azo-ANA (activated to 5-ANA and 2-amino-3-IPA) exhibited colon specificity in in vitro and in vivo experiments. Oral IPA-azo-ANA mitigated colonic damage and inflammation and was more effective than SSZ. These results suggest that colon-targeted 3-IPA ameliorated rat colitis and its anticolitic activity could be enhanced by codelivery of the GPR109A agonist 5-ANA.

Examining the non-spatial pretraining effect on a water maze spatial learning task in rats treated with multiple intracerebroventricular (ICV) infusions of propionic acid: Contributions to a rodent model of ASD.

Propionic acid (PPA) is produced by enteric gut bacteria and is a dietary short chain fatty acid. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioural changes, including adverse effects on cognition, similar to those seen in autism spectrum disorders (ASD). Previous research has shown that repeated ICV infusions of PPA result in impaired spatial learning in a Morris water maze (MWM) as evidenced by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than control rats. In the current study rats were first given non-spatial pretraining (NSP) in the water maze in order to familiarize the animals with the general requirements of the non-spatial aspects of the task before spatial training was begun. Then the effects of ICV infusions of PPA on acquisition of spatial learning were examined. PPA treated rats failed to show the positive effects of the non-spatial pretraining procedure, relative to controls, as evidenced by increased search latencies, longer distances travelled, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. Thus, PPA treatment blocked the effects of the pretraining procedure, likely by impairing sensorimotor components or memory of the pretraining.

Dapagliflozin Added to Verinurad Plus Febuxostat Further Reduces Serum Uric Acid in Hyperuricemia: The QUARTZ Study.

CONTEXT: Combining a sodium-glucose cotransporter 2 inhibitor with a xanthine oxidase inhibitor (XOI) and a urate transporter 1 (URAT1) inhibitor may enhance serum uric acid (sUA) lowering. However, concerns exist regarding high urinary UA (uUA) excretion rates and subsequent crystallization in renal tubules. OBJECTIVE: To assess whether dapagliflozin added to verinurad, a selective URAT1 inhibitor, and febuxostat, an XOI, increases uUA excretion. DESIGN: Randomized, placebo-controlled, 2-way crossover study (NCT03316131). PATIENTS: Adults with asymptomatic hyperuricemia. INTERVENTIONS: Subjects (N = 36) were randomized to oral once-daily 9 mg verinurad plus 80 mg febuxostat plus 10 mg dapagliflozin for 7 days and 7 days of oral once-daily 9 mg verinurad plus 80 mg febuxostat plus placebo with an intervening 7- to 21-day washout period. MAIN OUTCOME MEASURE: Difference in peak uUA excretion between groups from baseline to day 7. Secondary outcomes included changes in sUA levels and 24-h uUA excretion. RESULTS: Both regimens lowered mean peak uUA excretion (least squares mean changes from baseline: -12.9 mg/h [95% confidence interval (CI): -21.0 to -4.7], dapagliflozin; -13.2 mg/h [95% CI -21.3 to -5.0], placebo). sUA concentrations were lower with dapagliflozin (mean treatment difference -62.3 µmol/L [95% CI -82.8 to -41.8]). Dapagliflozin did not impact verinurad pharmacokinetics, its main metabolites, or febuxostat or fasting plasma glucose levels vs verinurad plus febuxostat. There were no clinically relevant changes in safety parameters. CONCLUSIONS: Dapagliflozin further reduced sUA without influencing uUA excretion, suggesting that its combination with verinurad and febuxostat at the doses tested does not adversely affect kidney function. CLINICAL TRIAL REGISTRATION NUMBER: NCT03316131.

The Combinatorial Effect of Acetate and Propionate on High-Fat Diet Induced Diabetic Inflammation or Metaflammation and T Cell Polarization.

High-fat diet (HFD) alters the gut microbiota and its fermentation products mainly acetate, propionate, and butyrate. Butyrate is well studied as a regulator of host metabolism and inflammation while acetate and propionate still need to be studied. Therefore, we aim to decipher the role of acetate and propionate alone and in combination in HFD-induced diabetic mice. HFD was given to mice for 4 months followed by treatment of butyrate, acetate, and propionate as well as acetate + propionate in combination for 1 month. Diabetic outcome was confirmed by evaluating fasting glucose, lipid profile, oral glucose tolerance test, % HbA1c, fasting insulin, and glucagon. To check the immune response, spleen and mesenteric lymph node-specific T cell polarization and serum cytokine profile were studied. HFD-fed mice showed increased body weight and diabetic characteristics while treatment with acetate and propionate regulated their levels in a healthy manner similar to butyrate. In HFD-fed mice, Th1 and Th17 cells were increased while Treg cells were decreased along with increased pro-inflammatory cytokines and decreased IL-10 in serum. The T cell polarization and cytokine profile was reversed by the treatment of acetate and propionate alone and in combination. Acetate reduced the levels of IL-1ß and IL-6 and acetate + propionate reduced IL-6 more significantly than butyrate. Although, we did not find any synergistic effect in combination group, the results were better compared with acetate, propionate, and butyrate. In conclusion, acetate + propionate effectively reduced inflammation and improved insulin sensitivity in HFD-induced diabetic mice.

Impact of dietary propionate on fructose-induced changes in lipid metabolism, gut microbiota and short-chain fatty acids in mice.

Propionate has antimicrobial activity and is suggested to influence lipid metabolism. Here, we investigated the effect of propionate on lipid metabolism and the gut microbiome in fructose-fed mice as a model of diet-induced steatosis and gut dysbiosis. Therefore, 48 male wild-type mice were fed isoenergetic diets with either 0% fructose (F-) or 40% fructose (F+) that contained 0% propionate (P-) or 1% propionate (P+) for 7 weeks. Mice that received the F+ diets developed fatty livers, had fewer small intestinal proteobacteria and colonic actinobacteria and were characterised by changes in bacterial genera (e.g., Allobaculum, Lachnospiraceae, and Escherichia). Interestingly, mice fed the F+ diets had higher levels of propionate and butyrate in the circulation than mice fed the F- diets (p < 0.05). Treatment with propionate influenced neither hepatic or plasma lipids nor levels of circulating SCFAs. With the exception of Verrucomicrobia, other bacterial phyla were not affected by propionate.

Supplementing the Diet with Sodium Propionate Suppresses the Severity of Viral Immuno-inflammatory Lesions.

This report evaluates a dietary manipulation approach to suppress the severity of ocular infections caused by herpes simplex virus infection. The virus causes chronic damage to the cornea that results from a T-cell-orchestrated inflammatory reaction to the infection. Lesion severity can be limited if cells with regulatory activity predominate over proinflammatory T cells and nonlymphoid inflammatory cells. In this report, we show that this outcome can be achieved by including the short-chain fatty acid (SCFA) salt sodium propionate (SP) in the drinking water. Animals given the SP supplement developed significantly fewer ocular lesions than those receiving no supplement. Corneas and lymphoid organs contained fewer CD4 Th1 and Th17 T cells, neutrophils, and macrophages than those of controls, but a higher frequency of regulatory T cells (Treg) was present. The inclusion of SP in cultures to induce CD4 T cell subsets in vitro reduced the magnitude of Th1 and Th17 responses but expanded Treg induction. Dietary manipulation was an effective approach to limit the severity of viral immuno-inflammatory lesions and may be worth exploring as a means to reduce the impact of herpetic lesions in humans.IMPORTANCE Herpetic lesions are a significant problem, and they are difficult to control with therapeutics. Our studies show that the severity of herpetic lesions in a mouse model can be diminished by changing the diet to include increased levels of SCFA, which act to inhibit the involvement of inflammatory T cells. We suggest that changing the diet to include higher levels of SCFA might be a useful approach to reducing the impact of recurrent herpetic lesions in humans.

Pharmacokinetics and Safety of Chiglitazar, a Peroxisome Proliferator-Activated Receptor Pan-Agonist, in Patients < 65 and ≥ 65 Years With Type 2 Diabetes.

The effect of age on the pharmacokinetics and safety of chiglitazar was evaluated in patients < 65 and ≥ 65 years with type 2 diabetes mellitus (T2DM). A total of 20 T2DM patients (<65 vs ≥65 years 1:1) completed the study. Patients received multiple doses of 48 mg chiglitazar once daily for 7 days consecutively. After the first dosing, chiglitazar maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) in patients ≥ 65 years were similar to those observed in patients < 65 years, with the geometric mean ratio (GMR) for Cmax and AUC being 97.22% and 96.83%, respectively. No significant difference was observed in Cmax (GMR, 97.23%) in the steady state. Compared with the patients < 65 years, a slight increase (8%-13%) of AUC was observed in the patients ≥ 65 years after multiple doses. Chiglitazar was generally well tolerated following multiple doses in both age groups. In conclusion, there were no significant clinical influences on the pharmacokinetic properties and safety profiles of chiglitazar between patients with T2DM < 65 and ≥ 65 years, indicating that in the future it is not required to adjust the dosing regimen by age for T2DM patients ≥ 65 years.

Chronic central modulation of LPA/LPA receptors-signaling pathway in the mouse brain regulates cognition, emotion, and hippocampal neurogenesis.

Several studies have demonstrated that lysophosphatidic acid (LPA) acts through its LPA receptors in multiple biological and behavioral processes, including adult hippocampal neurogenesis, hippocampal-dependent memory, and emotional regulation. However, analyses of the effects have typically involved acute treatments, and there is no information available regarding the effect of the chronic pharmacological modulation of the LPA/LPA receptors-signaling pathway. Thus, we analyzed the effect of the chronic (21 days) and continuous intracerebroventricular (ICV) infusion of C18:1 LPA and the LPA1-3 receptor antagonist Ki16425 in behavior and adult hippocampal neurogenesis. Twenty-one days after continuous ICV infusions, mouse behaviors in the open field test, Y-maze test and forced swimming test were assessed. In addition, the hippocampus was examined for c-Fos expression and α-CaMKII and phospho-α-CaMKII levels. The current study demonstrates that chronic C18:1 LPA produced antidepressant effects, improved spatial working memory, and enhanced adult hippocampal neurogenesis. In contrast, chronic LPA1-3 receptor antagonism disrupted exploratory activity and spatial working memory, induced anxiety and depression-like behaviors and produced an impairment of hippocampal neurogenesis. While these effects were accompanied by an increase in neuronal activation in the DG of C18:1 LPA-treated mice, Ki16425-treated mice showed reduced neuronal activation in CA3 and CA1 hippocampal subfields. Treatment with the antagonist also induced an imbalance in the expression of basal/activated α-CaMKII protein forms. These outcomes indicate that the chronic central modulation of the LPA receptors-signaling pathway in the brain regulates cognition and emotion, likely comprising hippocampal-dependent mechanisms. The use of pharmacological modulation of this pathway in the brain may potentially be targeted for the treatment of several neuropsychiatric conditions.