👤 Prashanth Shetty

Hypertension is recognized as a modifiable risk factor for cardiovascular diseases, alongside dyslipidemia. Studies have revealed that between 15 and 31% of individuals have both hypertension and dyslipidemia. However, emerging evidence suggests that natural therapies and yoga can help manage mild increases in blood pressure. This study aimed to evaluate the impact of yogic and naturopathy treatments on lipid profiles in hypertensive patients, thereby contributing to the existing literature. A randomized controlled experiment was conducted, involving 262 hypertensive patients randomly assigned to either the study group (SG) or control group (CG). The SG, consisting of 131 individuals, received yoga and naturopathic treatments for 10 days, while the CG (n = 131) did not. The lipid profile was measured at the beginning and end of the 10 days, and they were followed up and reassessed after 9 months. The study involved a total of 262 individuals, with 111 in the SG and 125 in the CG. After the 10-day intervention period, the SG showed significant reductions in total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, very low-density lipoprotein, apolipoprotein-A (Apo-A), apolipoprotein-B (Apo-B), and lipoprotein-A (Lp-A) (p < 0.001) compared to the CG. Also, the change was observed after 9 months in Apo-A, Apo-B, and Lp-A significantly (p < 0.001). These findings underscore the potential of naturopathic and yogic interventions in improving lipid profiles in hypertensive patients, thereby contributing to the current literature. In conjunction with conventional management, these specific interventions could be considered as a safer form of complementary therapy in the treatment of dyslipidemia among hypertensive patients. Thus, these findings hold promise for the integration of naturopathic and yogic therapies in the standard care of hypertensive patients. Show less

Alzheimer's disease is a progressive, irreversible, neurodegenerative disease, i.e., characterized by the presence of amyloid plaques, hyperphosphorylated tau protein (hyper p-tau), neural damage, etc. β-amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibition is a promising avenue for slowing AD progression. In a rate-limiting step, BACE-1 cleaves the amyloid precursor protein (APP) into soluble amyloid precursor protein β (sAPPβ) and a membrane-bound C-terminal fragment called C99. γ-secretase processes C99, resulting in neurotoxic amyloid β (Aβ). Selective and potent BACE-1 inhibitors offer promising therapeutic avenues for Alzheimer's disease. While BACE-1 inhibitors have shown significant assurance as potential treatments for Alzheimer's disease, many early compounds struggled to advance clinically due to poor brain penetration, limited selectivity, and unwanted side effects. Over the last two decades, substantial progress has been made in the development of BACE-1 inhibitors, leading to the emergence of diverse structural frameworks such as aminohydontoins, dihydropyridines, pyrimidines, and iminohydantoins, and fused heterocycles. This review provides an in-depth analysis of the synthetic strategies employed. It emphasizes the structure-activity relationship (SAR) trends that have guided their optimization and the crystal structure of the enzyme used in the inhibition study. Show less

The effect of nutrition on inflammation and breast cancer (BC) prognosis is still inconclusive. Mechanism of data suggests that different types of fatty acids (FAs) play an essential role in carcinogenesis, and binding of alpha 1 antitrypsin (A1AT) may modulate carcinogenesis. The increased expression in the bound form of A1AT and release of Angiopoietin-like protein 4 (Angptl4) targets the gene of peroxisome proliferator-activated receptor-gamma (PPAR-γ). Our aim of the study was to compare the effect of FA-free (A1AT-0) and FAs bound forms of A1AT on levels of IL-1β, PPAR-gamma, and Angplt4 in breast cancer and control women. 10 women with breast cancer and ten control women within the age group 25-60 years with normal (Pi) M allele A1AT were recruited. Mononuclear cells were isolated and treated with different A1AT and FAs on the various combinations (linoleic acid, alpha-linolenic acid) for time-dependent study (2,4,18 and 24 h) and analyzed for the interleukin -1 beta(IL-1b), PPAR-gamma, and Angiopoietin-like protein 4 (Angptl4) expression by using ELISA method and gas chromatography for analyzing FAs. One-way ANOVA combined with multiple comparisons is used to compare the means. 100% of the study subjects were homozygous for the normal allele of A1AT. Time-dependent effects of A1AT and A1AT conjugated fatty acids on IL-I b, PPAR-g and Angptl4 showed statistically significant P = 0.07, P = 0.001, and P = 0.02 respectively, compared to those of the former study subjects. But within the groups, PPAR-g levels in case group (F(15,40)1.606, P = 0.003) and Angptl4 in the control group (F(15,32)0.64, P = 0.043) differed significantly. To the best of our knowledge, it's the first kind of study, and we speculate that the A1AT complex with different types of FAs results in a new form of A1AT having a solid capability to regulate the inflammation-induced synthesis, processing, and release of an active form of IL-1β. Our experimental data shows that the anti-inflammatory property of A1AT combined FAs likely to be mediated PPAR γand Angptl4 activation, thereby inhibiting the IL-1b. These findings may be worth assessing BC's biological effects and therapeutic effectiveness. Show less

Obesity is associated with dyslipidemia, ectopic lipid deposition, and insulin resistance. In mice, the global or adipose-specific loss of function of the protein angiopoietin-like 4 (ANGPTL4) leads to decreased plasma triglyceride levels, enhanced adipose triglyceride uptake, and protection from high-fat diet (HFD)-induced glucose intolerance. ANGPTL4 is also expressed highly in the liver, but the role of liver-derived ANGPTL4 is unclear. The goal of this study was to determine the contribution of hepatocyte ANGPTL4 to triglyceride and glucose homeostasis in mice during a high-fat diet challenge. We generated hepatocyte-specific ANGPTL4 deficient ( Show less

Elevated plasma triglyceride levels are associated with metabolic disease. Angiopoietin-like protein 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). Our aim was to investigate the role of adipocyte-specific deficiency of ANGPTL4 in mice during high fat diet feeding. Adipocyte-specific ANGPTL4 deficient mice were fed a high fat diet (60% kCal from fat) for either 12 weeks or 6 months. We performed plasma metabolic measurements, triglyceride clearance and uptake assays, LPL activity assays, and assessed glucose homeostasis. Mice lacking adipocyte ANGPTL4 recapitulated the triglyceride phenotypes of whole-body ANGPTL4 deficiency, including increased adipose LPL activity, lower plasma triglyceride levels, and increased uptake of triglycerides into adipose tissue. When fed a high fat diet (HFD), these mice continued to display enhanced adipose LPL activity and initially had improved glucose and insulin sensitivity. However, after 6 months on HFD, the improvements in glucose homeostasis were largely lost. Moreover, despite higher adipose LPL activity levels, mice lacking adipocyte ANGPTL4 no longer had increased triglyceride uptake into adipose compared to littermate controls after chronic high-fat feeding. These observations suggest that after chronic high-fat feeding LPL is no longer rate-limiting for triglyceride delivery to adipocytes. We conclude that while adipocyte-derived ANGPTL4 is an important regulator of plasma triglyceride levels and triglyceride partitioning under normal diet conditions, its role is diminished after chronic high-fat feeding. Show less

To ensure fetal lipid supply, maternal blood triglyceride (TG) concentrations are robustly elevated during pregnancy. Interestingly, a lower increase in maternal blood TG concentrations has been observed in some obese mothers. We have shown that high-fat (HF) feeding during pregnancy significantly reduces maternal blood TG levels. Therefore, we performed this study to investigate if and how obesity alters maternal blood TG levels. Maternal obesity was established by prepregnant HF (ppHF) feeding, which avoided the dietary effect during pregnancy. We found not only that maternal blood TG concentrations in ppHF dams were remarkably lower than in control dams but also that the TG peak occurred earlier during gestation. Hepatic TG production and intestinal TG absorption were unchanged in ppHF dams, but systemic lipoprotein lipase (LPL) activity was increased, suggesting that increased blood TG clearance contributes to the decreased blood TG concentrations in ppHF dams. Although significantly higher levels of UCP1 protein were observed in interscapular brown adipose tissue (iBAT) of ppHF dams, Show less

The hydrolysis of triglycerides in triglyceride-rich lipoproteins by LPL is critical for the delivery of triglyceride-derived fatty acids to tissues, including heart, skeletal muscle, and adipose tissues. Physiologically active LPL is normally bound to the endothelial cell protein glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), which transports LPL across endothelial cells, anchors LPL to the vascular wall, and stabilizes LPL activity. Disruption of LPL-GPIHBP1 binding significantly alters triglyceride metabolism and lipid partitioning. In this study, we modified the NanoLuc® Binary Technology split-luciferase system to develop a novel assay that monitors the binding of LPL to GPIHBP1 on endothelial cells in real time. We validated the specificity and sensitivity of the assay using endothelial lipase and a mutant version of LPL and found that this assay reliably and specifically detected the interaction between LPL and GPIHBP1. We then interrogated various endogenous and exogenous inhibitors of LPL-mediated lipolysis for their ability to disrupt the binding of LPL to GPIHBP1. We found that angiopoietin-like (ANGPTL)4 and ANGPTL3-ANGPTL8 complexes disrupted the interactions of LPL and GPIHBP1, whereas the exogenous LPL blockers we tested (tyloxapol, poloxamer-407, and tetrahydrolipstatin) did not. We also found that chylomicrons could dissociate LPL from GPIHBP1 and found evidence that this dissociation was mediated in part by the fatty acids produced by lipolysis. These results demonstrate the ability of this assay to monitor LPL-GPIHBP1 binding and to probe how various agents influence this important complex. Show less

Mice lacking glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) are unable to traffic LPL to the vascular lumen. Thus, triglyceride (TG) clearance is severely blunted, and mice are extremely hypertriglyceridemic. Paradoxically, mice lacking both GPIHBP1 and the LPL regulator, angiopoietin-like 4 (ANGPTL4), are far less hypertriglyceridemic. We sought to determine the mechanism by which Show less

Cardiotoxicity is the most serious side effect of anthracyclines (doxorubicin, daunorubicin or epirubicin). The incidence of anthracycline induced late cardiac toxicity (AIC) that is overt clinically is 3-5% in the Indian population. Polymorphism in intron 32 (deletion of 25bp) of MYBPC3 has been shown to be present exclusively in Asians and more so in South India (3-8%). The frequency of the polymorphism is significantly higher (13%) in patients with cardiomyopathy in India. Fifteen patients were identified to have cardiac dysfunction following treatment for malignant lymphoma with doxorubicin containing regimens. Peripheral blood DNA from control, amplified by polymerase chain reaction yielded a 467bp fragment while in the presence of the 25bp deletion only a 442bp fragment was detected. To confirm the presence or absence of the polymorphism, amplified DNA was restricted using Bgl1 in all samples. Bgl1 restricted amplified DNA only if the 25bp deletion was absent. A 467 base pair band was observed in all the 15 samples, which suggested the absence of polymorphism in MYBPC3. In a sample of DNA from a patient with a deletion in exon 33 (confirmed by sequencing) a 442bp fragment was detected. Amplified DNA from this patient was not restricted with Bgl1. Wild type MYBPC3 when amplified gave a distinct restriction banding pattern consisting of two bands of 401bp and 66bp. Amplified DNA from all peripheral blood samples restricted with Bgl1 suggesting the absence of the polymorphism. In this preliminary report, MYBPC3 does not seem to play a role in anthracycline induced cardiotoxicity. Show less

Angiopoietin-like 4 (ANGPTL4) is a fasting-induced inhibitor of lipoprotein lipase (LPL) and a regulator of plasma triglyceride metabolism. Here, we examined the kinetics of Gene expression, LPL activity, and triglyceride uptake were examined in fasted and fed wild-type and Show less

Type 1 hyperlipoproteinemia (T1HLP) is a rare, autosomal recessive disorder characterized by extreme elevations in serum triglyceride (TG) levels. Despite considerable progress in identifying several causal genes for T1HLP, such as LPL, APOC2, APOA5, LMF1, and GPIHBP1, the molecular basis of some extremely rare patients presenting with T1HLP remains obscure. We report a 58-year-old Hispanic female who initially presented with serum TG of 4740 mg/dL at age 23 years when she was 3 weeks postpartum and was taking an oral contraceptive for 2 weeks. Over a period of 35 years, she has had recurrent episodes of extreme hypertriglyceridemia (fasting serum TG exceeding 2000 mg/dL), which responded to a reduction of dietary fat, fibrates, and fish oil therapy. Sanger sequencing of the known T1HLP genes in this patient did not reveal any disease-causing mutations. Whole-exome sequencing revealed compound heterozygous rare variants (p.Val103Met and p.Arg540Gln) in the glucokinase regulator (GCKR) gene. GCKR encodes glucokinase regulatory protein, which is an inhibitor of glucokinase, an enzyme that drives glucose uptake in the liver. Loss of function GCKR variants, by enhancing glucose uptake in hepatocytes, may induce de novo lipogenesis and TG biosynthesis, resulting in extreme hypertriglyceridemia. We conclude that compound heterozygous rare variants in GCKR cause an extremely rare unique T1HLP, most likely by inducing excessive hepatic lipogenesis. Show less