High-frequency ultrasonography for the detection of subclinical arthritis in chronic plaque psoriasis patients - A cross-sectional study.

Background Psoriatic arthritis (PsA) is seen in almost 30-40% cases of psoriasis. Psoriasis precedes the onset of PsA in 85% of cases. Delay in the diagnosis of PsA may lead to poor functional outcomes and morbidity. Screening psoriasis patients with high-frequency ultrasound helps to diagnose arthritis at an early stage leading to prompt intervention and possible reduction in the morbidity associated with the disease. Objectives To determine the role of high frequency ultrasonography (USG) in the detection of subclinical PsA. Methods A cross-sectional study was conducted in a dermatology and radiology department of Armed Forces Medical College, Pune between July 2021 and December 2022. Patients of chronic plaque psoriasis with no clinical evidence of arthritis were assessed using high-frequency USG. Various parameters such as bony erosions, synovial thickening, tendon thickening, tendon hypo-echogenicity, calcifications and power doppler signals were assessed. Results A total of 117 patients were included in the study. The distal interphalangeal joint (DIP) and Achilles tendon were the most commonly affected sites. Synovial thickening in DIP was observed in 67 (57%) patients and Achilles tendon thickening was observed in 39 (33%) patients. Limitations of the study The cross-sectional nature of the study is the major limitation. A longitudinal study will be required to understand the clinical relevance of ultrasonographic changes in these patients. Another limitation of the study is the lack of age and gender-matched controls. Future research should include such controls to ensure more accurate results. Conclusion Subclinical arthritis is common in patients with chronic plaque psoriasis. High-frequency ultrasound is a useful tool for detecting subclinical synovitis and enthesitis in asymptomatic patients. The DIP joint and Achilles tendon ultrasound can be used for screening for early detection of PsA.

Role of FoxO1 in Acne and Effect of Isotretinoin on FoxO1 Expression.

Background: Nodulocystic acne is a severe type of acne that is known to improve after treatment with isotretinoin. Melnik has hypothesized a unifying concept on the mechanism of acne pathogenesis involving altered expression of Forkhead box O transcription factor (FoxO1) and role of isotretinoin in improving acne via modulating this pathway. Aim: To evaluate the pathway proposed by Melnik in acne pathogenesis by analysing the difference in the expression of FoxO1, peroxisome proliferator-activated receptor (PPARγ), and androgen receptor (AR) between acne patients and non-acne controls and the effect of treatment with isotretinoin on change in expression of these genes in acne patients. Results: The gene expression of FoxO1 was non significantly higher in acne patients as compared to controls. After treatment with isotretinoin, a significant decrease in FoxO1 expression in acne patients at mRNA (P = 0.05) level was observed. There was a significant decrease in grade 3 positivity of FoxO1 at protein level (P = 0.0009). A decrease in androgen receptor positivity (P = 0.055) at protein level was also observed. Conclusion: Reduction in FoxO1 expression appears to be an important mechanism of action of isotretinoin in acne.

Collinsella aerofaciens linked with increased ethanol production and liver inflammation contribute to the pathophysiology of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is an emerging global health problem and a potential risk factor for metabolic diseases. The bidirectional interactions between liver and gut made dysbiotic gut microbiome one of the key risk factors for NAFLD. In this study, we reported an increased abundance of Collinsella aerofaciens in the gut of obese and NASH patients living in India. We isolated C. aerofaciens from the fecal samples of biopsy-proven NASH patients and observed that their genome is enriched with carbohydrate metabolism, fatty acid biosynthesis, and pro-inflammatory functions and have the potency to increase ethanol level in blood. An animal study indicated that mice supplemented with C. aerofaciens had increased levels of circulatory ethanol, high levels of hepatic hydroxyproline, triglyceride, and inflammation in the liver. The present findings indicate that perturbation in the gut microbiome composition is a key risk factor for NAFLD.

Circulatory bone morphogenetic protein (BMP) 8B is a non-invasive predictive biomarker for the diagnosis of non-alcoholic steatohepatitis (NASH).

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a complex disease which is characterized by the deposition of fats in the hepatocytes. Further, it progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. The increasing prevalence of NAFLD urges to find the non-invasive predictive biomarkers. In this study, we sought to determine increased BMP8B levels as predictors for the progression of NAFLD. METHODS: In the present cross-sectional study, circulatory BMP8B levels were measured in healthy controls (n = 56), NAFL patients (n = 72) and NASH patients (n = 77) by using an ELISA kit. Human hepatic BMP8B mRNA expression was measured in the liver tissue of control and NASH patients. In addition, BMP8B expression was confirmed by immunohistochemistry analysis. Furthermore, hepatic BMP8B mRNA expression was measured in wild type (WT) mice, WT mice fed with choline deficient high fat diet (WT+CDHF), iNOS (inducible nitric oxide synthase) knockout (iNOS-/-) mice, iNOS-/- fed with CDHF diet (iNOS-/-+CDHF). RESULTS: Increased circulatory BMP8B levels and BMP8B mRNA expression in hepatic tissue were significantly higher in NASH patients as compared with the control subjects. BMP8B expression was increased parallel to the fibrosis score in the hepatic tissues of NASH patients. It was observed that increased BMP8B levels have shown a significant positive correlation between aspartate aminotransferase (r = 0.31, p = 0.005), alanine aminotransferase (r = 0.23, p = 0.045), APRI (r = 0.30, p = 0.009), and Fib-4 score (r = 0.25, p = 0.036) in NASH patients. BMP8B has maintained a significant association with NASH and shown high sensitivity (92.91%) and specificity (92.73%) in NASH patients. Furthermore, increased BMP8B mRNA expression levels were observed in iNOS-/-+CDHF mice. CONCLUSION: Our study findings confirmed that BMP8B increases with the severity of the disease and BMP8B shows potential as a non-invasive predictive biomarker to identify NAFLD progression. However, future studies should investigate circulatory BMP8B levels in a large number of patients and also its impact on liver during NAFLD progression.

Effect of herbal extracts and Saroglitazar on high-fat diet-induced obesity, insulin resistance, dyslipidemia, and hepatic lipidome in C57BL/6J mice.

We evaluated the effects of select herbal extracts (Tinospora cordifolia [TC], Tinospora cordifolia with Piper longum [TC + PL], Withania somnifera [WS], Glycyrrhiza glabra [GG], AYUSH-64 [AY-64], and Saroglitazar [S]) on various parameters in a diet-induced obesity mouse model. After 12 weeks of oral administration of the herbal extracts in high-fat diet (HFD)-fed C57BL/6J mice, we analyzed plasma biochemical parameters, insulin resistance (IR), liver histology, and the expression of inflammatory and fibrosis markers, along with hepatic lipidome. We also used a 3D hepatic spheroid model to assess their impact on profibrotic gene expression. Among the extracts, TC + PL showed a significant reduction in IR, liver weight, TNF-α, IL4, IL10 expression, and hepatic lipid levels (saturated triglycerides, ceramides, lysophosphocholines, acylcarnitines, diglycerides, and phosphatidylinositol levels). Saroglitazar reversed changes in body weight, IR, plasma triglycerides, glucose, insulin, and various hepatic lipid species (fatty acids, phospholipids, glycerophospholipids, sphingolipids, and triglycerides). With the exception of GG, Saroglitazar, and other extracts protected against palmitic acid-induced fibrosis marker gene expression in the 3D spheroids. TC + PL and Saroglitazar also effectively prevented HFD-induced insulin resistance, inflammation, and specific harmful lipid species in the liver.

Untargeted metabolomics and phenotype data indicate the therapeutic and prophylactic potential of Lysimachia candida Lindl. towards high-fat high-fructose-induced metabolic syndrome in rats.

The present study evaluated the therapeutic potential of the medicinal plant Lysimachia candida Lindl. against metabolic syndrome in male SD rats fed with a high-fat high-fructose (HFHF) diet. Methanolic extract of Lysimachia candida Lindl. (250 mg kg-1 body weight p.o.) was administrated to the HFHF-fed rats daily for 20 weeks. Blood samples were collected, and blood glucose levels and relevant biochemical parameters were analysed and used for the assessment of metabolic disease phenotypes. In this study, Lysimachia candida decreased HFHF diet-induced phenotypes of metabolic syndrome, i.e., obesity, blood glucose level, hepatic triglycerides, free fatty acids, and insulin resistance. Liquid chromatography-mass spectrometry-based metabolomics was done to study the dynamics of metabolic changes in the serum during disease progression in the presence and absence of the treatment. Furthermore, multivariate data analysis approaches have been employed to identify metabolites responsible for disease progression. Lysimachia candida Lindl. plant extract restored the metabolites that are involved in the biosynthesis and degradation of amino acids, fatty acid metabolism and vitamin metabolism. Interestingly, the results depicted that the treatment with the plant extract restored the levels of acetylated amino acids and their derivatives, which are involved in the regulation of beta cell function, glucose homeostasis, insulin secretion, and metabolic syndrome phenotypes. Furthermore, we observed restoration in the levels of indole derivatives and N-acetylgalactosamine with the treatment, which indicates a cross-talk between the gut microbiome and the metabolic syndrome. Therefore, the present study revealed the potential mechanism of Lysimachia candida Lindl. extract to prevent metabolic syndrome in rats.

Characterization of lipid signatures in the plasma and insulin-sensitive tissues of the C57BL/6J mice fed on obesogenic diets.

Diet-induced obesity mouse models are widely utilized to investigate the underlying mechanisms of dyslipidemia, glucose intolerance, insulin resistance, hepatic steatosis, and type 2 diabetes mellitus (T2DM), as well as for screening potential drug compounds. However, there is limited knowledge regarding specific signature lipids that accurately reflect dietary disorders. In this study, we aimed to identify key lipid signatures using LC/MS-based untargeted lipidomics in the plasma, liver, adipose tissue (AT), and skeletal muscle tissues (SKM) of male C57BL/6J mice that were fed chow, LFD, or obesogenic diets (HFD, HFHF, and HFCD) for a duration of 20 weeks. Furthermore, we conducted a comprehensive lipid analysis to assess similarities and differences with human lipid profiles. The mice fed obesogenic diets exhibited weight gain, glucose intolerance, elevated BMI, glucose and insulin levels, and a fatty liver, resembling characteristics of T2DM and obesity in humans. In total, we identified approximately 368 lipids in plasma, 433 in the liver, 493 in AT, and 624 in SKM. Glycerolipids displayed distinct patterns across the tissues, differing from human findings. However, changes in sphingolipids, phospholipids, and the expression of inflammatory and fibrotic genes showed similarities to reported human findings. Significantly modulated pathways in the obesogenic diet-fed groups included ceramide de novo synthesis, sphingolipid remodeling, and the carboxylesterase pathway, while lipoprotein-mediated pathways were minimally affected. This study provides a tissue-specific comparison of lipid composition, highlighting the usefulness of DIO models in preclinical research. However, caution is warranted when extrapolating findings from these models to dyslipidemia-associated pathologies and their complications in humans.

Effects of metformin on clinical, hormonal and relevant gene expression parameters in patients with acne: an observational study.

BACKGROUND: Acne vulgaris is associated with insulin resistance and elevated insulin-like growth factor-1 (IGF-1). Metformin is commonly used for treatment of acne in patients with polycystic ovarian syndrome (PCOS). However, the benefits of metformin in patients with acne in general are not well established. AIM: To study the effectiveness of metformin treatment in patients with acne but who do not have PCOS and to understand the mechanisms of action of metformin in acne not related to PCOS. METHOD: In this observational study, 30 patients with clinically confirmed acne vulgaris were treated with metformin (1000 mg daily) for 3 months without any other topical or systemic active intervention for their acne. The effect of metformin at the clinical, hormonal and genetic level was assessed. RESULTS: Metformin monotherapy significantly (P < 0.001) decreased the global acne grading score for acne followed by a marginal increase in insulin; with a significant (P = 0.03) increase in insulin-like growth factor-1 (IGF-1). A significant (P < 0.001) decrease in free androgen index resulting from a significant (P < 0.001) increase in sex hormone-binding globulin (SHBG) with decrease in testosterone was observed. Homeostasis model assessment insulin resistance (HOMA-IR) was not significantly changed. Forkhead box protein O1 (FOXO1) expression was significantly (P = 0.006) downregulated with metformin treatment at the mRNA level without any significant changes at protein level. Expression of lipogenic genes, namely HMGCR, SQLE and ACSL5 (P = 0.001, P = 0.03, P = 0.03, respectively) were also downregulated. CONCLUSION: Metformin monotherapy led to significant clinical improvement in acne, possibly by reducing testosterone, inhibiting FOXO1 and reducing lipid synthesis by decreasing the expression of lipogenic genes.

Effectiveness of topical pilocarpine in refractory oral lesions of pemphigus vulgaris: Results from an open-label, prospective, pilot study.

BACKGROUND: The literature suggests a beneficial role of cholinomimetic agents in the treatment of pemphigus. In the present open-label, prospective pilot study, we assessed the effectiveness of topical pilocarpine 2% eye-drops in the treatment of recalcitrant oral lesions of pemphigus. METHODS: Twenty patients with recalcitrant oral lesions of pemphigus were recruited and instructed to apply pilocarpine 2% eye-drops twice daily on the resistant oral lesions for 180 days. The systemic immunosuppression at the time of inclusion in the present study was continued at the same dose throughout the study duration. The photographs of the lesions were obtained at baseline and an interval of 30 days. The area representing the erosion was measured on clinical photographs using the imageJ software (National Institute of Health). Visual analogue scale and oral health impact profile-14 questionnaire were used to assess the degree of subjective improvement. Anti-desmoglein 1 and 3, and anti-acetylcholine M3 receptor antibodies were measured both in serum and saliva; at baseline and at the completion of the study. RESULTS: Twenty patients were recruited in this pilot study. Mean total duration of illness was 3.4±1.3 years. The mean area of the erosions decreased significantly from 142.01±130.05 mm2 to 44.38±67.78 mm2 at study completion at 180 days (p 0.002, paired t-test). Repeated measures ANOVA demonstrated a significant trend in the reduction of the mean area of the erosions from baseline to day 180 (p 0.002). Mean VAS decreased significantly from 7.2±1.0 at baseline to 5.1±1.9 at day 180 (paired t-test, p 0.001). Mean OHIP-14 decreased significantly from 10.1±2.7 at baseline to 8.4±2.9 at day 180. No significant difference was observed between pre- and post-treatment levels of anti-desmoglein 1, anti-desmoglein 3, and anti-acetylcholine M3 receptor antibodies, in both serum and saliva. LIMITATIONS: The depth component in the erosions could not be measured. An orabase formulation could be used in future studies to facilitate retention of the medication at the site of application. CONCLUSION: Topical pilocarpine holds potential for the treatment of recalcitrant oral lesions of pemphigus vulgaris. It probably brings about re-epithelialization without imparting any immunomodulatory activity. This article is protected by copyright. All rights reserved.

Saroglitazar and Hepano treatment offers protection against high fat high fructose diet induced obesity, insulin resistance and steatosis by modulating various class of hepatic and circulating lipids.

Higher global prevalence of non-alcoholic fatty liver disease (NAFLD) is associated with obesity, steatosis, and insulin resistance (IR), and often progresses to steatohepatitis (NASH). Even after more than twenty years of research, there is still no FDA approved therapy for the treatment of fatty liver disease/NASH though, Saroglitazar - a dual PPAR α/γ agonist has been recently approved as a therapeutic option for the fatty liver disease in India. Hepatoprotective Ayurvedic formulations are widely used and are considered safe. In the present study, C57BL/6 male mice on HFHF diet for four weeks were treated with vehicle, Saroglitazar (3 mg/kg/po), and Hepano - a formulation of five herbs (200 mg/kg/po), at the human equivalent therapeutic doses for additional eight weeks. These animals were evaluated after 12 weeks for obesity, body mass index (BMI), systemic insulin resistance, hyperglycaemia, dyslipidaemia, and hepatic lipid accumulation. Differential liquid chromatography-mass spectrometry (LC-MS/MS) based lipidomics analysis demonstrated significant changes in the different class of lipids [phospholipids, sphingolipids, diglycerides and triglycerides (TG)] in HFHF fed group. The protective effects of both Saroglitazar and Hepano were evident against IR, obesity and in the modulation of different class of lipids in the circulation and hepatic tissue. Saroglitazar reduced TG as well as modulated phospholipids levels, while Hepano modulated only phospholipids, ceramides, oxidised lipids, and had no effect on hepatic or circulating TG levels in HFHF fed mice. In addition, in vitro studies using HepG2, THP1 and LX2 cells demonstrated safety of both the test substances where Hepano possess better anti-inflammatory as well as anti-fibrotic potential. Overall, Saroglitazar seems to be more efficacious than Hepano in the regimen used against HFHF induced IR, obesity, and dyslipidaemia.

Evaluation of therapeutic effect of Premna herbacea in diabetic rat and isoverbascoside against insulin resistance in L6 muscle cells through bioenergetics and stimulation of JNK and AKT/mTOR signaling cascade.

BACKGROUND: Premna herbacea Roxb., a perennial herb is well documented for its therapeutic uses among the traditional health care-givers of Assam, India. Scientific validation on the traditional use of the medicinal plant using modern technology may promote further research in health care. PURPOSE: This study evaluates the therapeutic potential of methanolic extract of P. herbacea (MEPH) against type 2 diabetes mellitus (T2DM) and its phytochemical(s) in ameliorating insulin resistance (IR), thereby endorsing the plant bioactives as effective anti-hyperglycemic agents. METHODS: The anti-diabetic potential of the plant extract was explored both in L6 muscle cells and high fructose high fat diet (HF-HFD) fed male Sprague Dawley (SD) rats. Bioactivity guided fractionation and isolation procedure yielded Verbascoside and Isoverbascoside (ISOVER) as bioactive and major phytochemicals in P. herbacea. The bioenergetics profile of bioactive ISOVER and its anti-hyperglycemic potential was validated in vitro by XFe24 analyzer, glucose uptake assay and intracellular ROS generation by flourometer, FACS and confocal microscopy. The potential of ISOVER was also checked by screening various protein markers via immunoblotting. RESULTS: MEPH enhanced glucose uptake in FFA-induced insulin resistant (IR) L6 muscle cells and decreased elevated blood glucose levels in HF-HFD fed rats. Isoverbascoside (ISOVER) was identified as most bioactive phytochemical for the first time from the plant in the Premna genus. ISOVER activated the protein kinase B/AMP-activated protein kinase signaling cascades and enhanced glucose uptake in IR-L6 muscle cells. ISOVER decreased the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) and increased that of mammalian target of rapamycin (mTOR), thereby attenuating IR. However, molecular docking revealed that ISOVER increases insulin sensitivity by targeting the JNK1 kinase as a competitive inhibitor rather than mTOR. These findings were further supported by the bioenergetics profile of ISOVER. CONCLUSION: This study for the first time depicts the functional properties of ISOVER, derived from Premna herbacea, in ameliorating IR. The phytochemical significantly altered IR with enhanced glucose uptake and inhibition of ROS through JNK-AKT/mTOR signaling which may pave the way for further research in T2DM therapeutics.