Reducing saturated fat intake lowers LDL-C but increases Lp(a) levels in African Americans: the GET-READI feeding trial

Reducing dietary saturated fatty acids (SFA) intake results in a clinically significant lowering of low-density lipoprotein cholesterol (LDL-C) across ethnicities. In contrast, dietary SFA’s role in modulating emerging cardiovascular risk factors in different ethnicities remains poorly understood. Elevated levels of lipoprotein(a) [Lp(a)], an independent cardiovascular risk factor, disproportionally affect individuals of African descent. Here, we assessed the responses in Lp(a) levels to dietary SFA reduction in 166 African Americans enrolled in GET-READI (The Gene-Environment Trial on Response in African Americans to Dietary Intervention), a randomized controlled feeding trial. Participants were fed two diets in random order for 5 weeks each: 1) an average American diet (AAD) (37% total fat: 16% SFA), and 2) a diet similar to the Dietary Approaches to Stop Hypertension (DASH) diet (25% total fat: 6% SFA). The participants’ mean age was 35 years, 70% were women, the mean BMI was 28 kg/m², and the mean LDL-C was 116 mg/dl. Compared to the AAD diet, LDL-C was reduced by the DASH-type diet (mean change: −12 mg/dl) as were total cholesterol (−16 mg/dl), HDL-C (−5 mg/dl), apoA-1 (−9 mg/dl) and apoB-100 (−5 mg/dl) (all P < 0.0001). In contrast, Lp(a) levels increased following the DASH-type diet compared with AAD (median: 58 vs. 44 mg/dl, P < 0.0001). In conclusion, in a large cohort of African Americans, reductions in SFA intake significantly increased Lp(a) levels while reducing LDL-C. Future studies are warranted to elucidate the mechanism(s) underlying the SFA reduction-induced increase in Lp(a) levels and its role in cardiovascular risk across populations.     

10,12-Conjugated linoleic acid supplementation improves HDL composition and function in mice

Obesity is associated with inflammation, insulin resistance, and type 2 diabetes, which are major risk factors for CVD. One dietary component of ruminant animal foods, 10,12-conjugated linoleic acid (10,12 CLA), has been shown to promote weight loss in humans. Previous work has shown that 10,12 CLA is atheroprotective in mice by a mechanism that may be distinct from its weight loss effects, but this exact mechanism is unclear. To investigate this, we evaluated HDL composition and function in obese LDL receptor (Ldlr^?/?) mice that were losing weight because of 10,12 CLA supplementation or caloric restriction (CR; weight-matched control group) and in an obese control group consuming a high-fat high-sucrose diet. We show that 10,12 CLA-HDL exerted a stronger anti-inflammatory effect than CR- or high-fat high-sucrose-HDL in cultured adipocytes. Furthermore, the 10,12 CLA-HDL particle (HDL-P) concentration was higher, attributed to more medium- and large-sized HDL-Ps. Passive cholesterol efflux capacity of 10,12 CLA-HDL was elevated, as was expression of HDL receptor scavenger receptor class B type 1 in the aortic arch. Murine macrophages treated with 10,12 CLA in vitro exhibited increased expression of cholesterol transporters Abca1 and Abcg1, suggesting increased cholesterol efflux potential of these cells. Finally, proteomics analysis revealed elevated Apoa1 content in 10,12 CLA-HDL-Ps, consistent with a higher particle concentration, and particles were also enriched with alpha-1-antitrypsin, an emerging anti-inflammatory and antiatherosclerotic HDL-associated protein. We conclude that 10,12 CLA may therefore exert its atheroprotective effects by increasing HDL-P concentration, HDL anti-inflammatory potential, and promoting beneficial effects on cholesterol efflux.     

Transgelin: a new gene involved in LDL endocytosis identified by a genome-wide CRISPR-Cas9 screen

A significant proportion of patients with elevated LDL and a clinical presentation of familial hypercholesterolemia do not carry known genetic mutations associated with hypercholesterolemia, such as defects in the LDL receptor. To identify new genes involved in the cellular uptake of LDL, we developed a novel whole-genome clustered regularly interspaced short palindromic repeat-Cas9 KO screen in HepG2 cells. We identified transgelin (TAGLN), an actin-binding protein, as a potentially new gene involved in LDL endocytosis. In silico validation demonstrated that genetically predicted differences in expression of TAGLN in human populations were significantly associated with elevated plasma lipids (triglycerides, total cholesterol, and LDL-C) in the Global Lipids Genetics Consortium and lipid-related phenotypes in the UK Biobank. In biochemical studies, TAGLN-KO HepG2 cells showed a reduction in cellular LDL uptake, as measured by flow cytometry. In confocal microscopy imaging, TAGLN-KO cells had disrupted actin filaments as well as an accumulation of LDL receptor on their surface because of decreased receptor internalization. Furthermore, TAGLN-KO cells exhibited a reduction in total and free cholesterol content, activation of SREBP2, and a compensatory increase in cholesterol biosynthesis. TAGLN deficiency also disrupted the uptake of VLDL and transferrin, other known cargoes for receptors that depend upon clathrin-mediated endocytosis. Our data suggest that TAGLN is a novel factor involved in the actin-dependent phase of clathrin-mediated endocytosis of LDL. The identification of novel genes involved in the endocytic uptake of LDL may improve the diagnosis of hypercholesterolemia and provide future therapeutic targets for the prevention of cardiovascular disease.     

Comparison between genetic and pharmaceutical disruption of Ldlr expression for the development of atherosclerosis

Antisense oligonucleotides (ASOs) against Ldl receptor (Ldlr-ASO) represent a promising strategy to promote hypercholesterolemic atherosclerosis in animal models without the need for complex breeding strategies. Here, we sought to characterize and contrast atherosclerosis in mice given Ldlr-ASO with those bearing genetic Ldlr deficiency. To promote atherosclerosis, male and female C57Bl6/J mice were either given weekly injections of Ldlr-ASO (5 mg/kg once per week) or genetically deficient in Ldlr (Ldlr^?/?). Mice consumed either standard rodent chow or a diet high in saturated fat and sucrose with 0.15% added cholesterol for 16 weeks. While both models of Ldlr deficiency promoted hypercholesterolemia, Ldlr^?/? mice exhibited nearly 2-fold higher cholesterol levels than Ldlr-ASO mice, reflected by increased VLDL and LDL levels. Consistent with this, the en face atherosclerotic lesion area was 3-fold and 3.6-fold greater in male and female mice with genetic Ldlr deficiency, respectively, as compared with the modest atherosclerosis observed following Ldlr-ASO treatment. Aortic sinus lesion sizes, fibrosis, smooth muscle actin, and necrotic core areas were also larger in Ldlr^?/? mice, suggesting a more advanced phenotype. Despite a more modest effect on hypercholesterolemia, Ldlr-ASO induced greater hepatic inflammatory gene expression, macrophage accumulation, and histological lobular inflammation than was observed in Ldlr^?/? mice. We conclude Ldlr-ASO is a promising tool for the generation of complex rodent models with which to study atherosclerosis but does not promote comparable levels of hypercholesterolemia or atherosclerosis as Ldlr^?/? mice and increases hepatic inflammation. Thus, genetic Ldlr deficiency may be a superior model, depending on the proposed use.     

2-Hydroxypropyl-β-cyclodextrin mitigates pathological changes in a mouse model of retinal cholesterol dyshomeostasis

CYP46A1 is a CNS-specific enzyme, which eliminates cholesterol from the brain and retina by metabolism to 24-hydroxycholesterol, thus contributing to cholesterol homeostasis in both organs. 2-Hydroxypropyl-β-cyclodextrin (HPCD), a Food and Drug Administration-approved formulation vehicle, is currently being investigated off-label for treatment of various diseases, including retinal diseases. HPCD was shown to lower retinal cholesterol content in mice but had not yet been evaluated for its therapeutic benefits. Herein, we put Cyp46a1^?/? mice on high fat cholesterol-enriched diet from 1 to 14 months of age (control group) and at 12 months of age, started to treat a group of these animals with HPCD until the age of 14 months. We found that as compared with mature and regular chow-fed Cyp46a1^?/? mice, control group had about 6-fold increase in the retinal total cholesterol content, focal cholesterol and lipid deposition in the photoreceptor-Bruch’s membrane region, and retinal macrophage activation. In addition, aged animals had cholesterol crystals at the photoreceptor-retinal pigment epithelium interface and changes in the Bruch’s membrane ultrastructure. HPCD treatment mitigated all these manifestations of retinal cholesterol dyshomeostasis and altered the abundance of six groups of proteins (genetic information transfer, vesicular transport, and cytoskeletal organization, endocytosis and lysosomal processing, unfolded protein removal, lipid homeostasis, and Wnt signaling). Thus, aged Cyp46a1^?/? mice on high fat cholesterol-enriched diet revealed pathological changes secondary to retinal cholesterol overload and supported further studies of HPCD as a potential therapeutic for age-related macular degeneration and diabetic retinopathy associated with retinal cholesterol dyshomeostasis.     

Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans

The large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, the effects of the CETPi dalcetrapib and anacetrapib on HDL particle composition were studied in rabbits and humans. The association of rabbit HDL to the LDL receptor (LDLr) in vitro was also evaluated. New Zealand White rabbits receiving atorvastatin were treated with dalcetrapib or anacetrapib. A subset of patients from the dal-PLAQUE-2 study treated with dalcetrapib or placebo were also studied. In rabbits, dalcetrapib and anacetrapib increased HDL-C by more than 58% (P < 0.01) and in turn raised large apo E-containing HDL by 66% (P < 0.001) and 59% (P < 0.01), respectively. Additionally, HDL from CETPi-treated rabbits competed with human LDL for binding to the LDLr on HepG2 cells more than control HDL (P < 0.01). In humans, dalcetrapib increased concentrations of large HDL particles (+69%, P < 0.001) and apo B-depleted plasma apo E (+24%, P < 0.001), leading to the formation of apo E-containing HDL (+47%, P < 0.001) devoid of apo A-I. Overall, in rabbits and humans, CETPi increased large apo E-containing HDL particle concentration, which can interact with hepatic LDLr. The catabolism of these particles may depend on an adequate level of LDLr to contribute to reverse cholesterol transport.     

Health Care Disparities in Outpatient Diabetes Management During the Coronavirus Disease 2019 Pandemic: Where Do We Stand Now?

ObjectiveWe examined diabetes outpatient management during the first 2 years of the Coronavirus Disease 2019 pandemic in an endocrinology practice with a focus on health care disparities in outcomes.MethodsWe conducted a retrospective cohort study examining adults with diabetes during 3 time periods: T1 (March 2019-February 2020), T2 (March 2020-February 2021), and T3 (March 2021-February 2022). Clinical outcomes included body mass index (BMI), systolic blood pressure (SBP), Hemoglobin A1c (HgbA1c), low-density lipoprotein cholesterol (LDL), and urine albumin:creatinine ratio. Appointment types (virtual vs in-person) were also collected.ResultsFrequencies of HgbA1c, BMI, and SBP measurements reduced by 36.0%, 46.3%, and 48.5% in T2, respectively, and remaining 8.7% (HgbA1c), 13.4% (BMI), and 15.2% (SBP) lower at the end of the study period (P < .001) compared to prepandemic levels. However, the average HgbA1c and LDL slightly improved. Clinic appointments per patient increased during the pandemic, fueled by telehealth utilization. Women had fewer in-person visits during T2, those older than 65 had better HgbA1c, and the most socioeconomically deprived group had the worst HgbA1c during every time period. In addition, black patients had worse HgbA1c, LDL, and SBP values throughout the study, which did not worsen over the pandemic.ConclusionWhile the frequency of health measurements had not fully recovered 2 years into the pandemic, this did not translate to worse diabetes management or a widening of pre-existing disparities. Our study emphasizes the role of equitable health care in minimizing inequalities in diabetes, particularly during times of crisis.     

Is the Neutrophil-to-Lymphocyte Ratio an Exceptional Indicator for Metabolic Syndrome Disease and Outcomes?

ObjectivesTo show that there is relation between neutrophil-to-lymphocyte ratio (NLR) and metabolic syndrome and also, its components.FindingsMetabolic syndrome is associated with elevated fasting blood glucose, increased blood pressure, central obesity, decreased high-density lipoprotein, and increased triglyceride levels. Because of its growing incidence and prevalence and the effect that it has on developing other noncommunicable diseases, the importance gets even more value. The prediction and control of this disease in its early stages and in the most inexpensive way is of crucial need. Due to the role of chronic low-grade inflammation in metabolic syndrome, cytokines and inflammatory factors (like interleukin-6 and tumor necrosis factor-α) play a critical role on this phenomenon. The NLR is an inflammatory marker that has an unchallenging availability and has a reasonable cost. The NLR is related to obesity, type 2 diabetes, hypertension, and blood cholesterol levels.ConclusionThis suggests that there may be a relationship between the NLR and metabolic syndrome. The NLR, as a low-grade inflammation marker, indicates a positive relationship with central obesity. Also, studies indicate that the incidence of diabetes, its severity, and its control are related to the NLR. Hypertension and hyperlipidemia can both be noticed with higher NLRs. This rapid review assesses the association between metabolic syndrome and the NLR.     

Circadian PER1 controls daily fat absorption with the regulation of PER1-PKA on phosphorylation of bile acid synthetase

Several epidemiological studies suggest a correlation between eating time and obesity. Night eating syndrome characterized by a time-delayed eating pattern is positively associated with obesity in humans as well as in experimental animals. Here, we show that oil intake at night significantly makes more fat than that at day in wild-type mice, and circadian Period 1 (Per1) contributes to this day–night difference. Per1-knockout mice are protected from high-fat diet–induced obesity, which is accompanied by a reduction in the size of the bile acid pool, and the oral administration of bile acids restores fat absorption and accumulation. We identify that PER1 directly binds to the major hepatic enzymes involved in bile acid synthesis such as cholesterol 7alpha-hydroxylase and sterol 12alpha-hydroxylase. A biosynthesis rhythm of bile acids is accompanied by the activity and instability of bile acid synthases with PER1/PKA-mediated phosphorylation pathways. Both fasting and high fat stress enhance Per1 expression, increasing the fat absorption and accumulation. Our findings reveal that Per1 is an energy regulator and controls daily fat absorption and accumulation. Circadian Per1 controls daily fat absorption and accumulation, suggesting Per1 is a potential candidate of a key regulator in stress response and the relevant obesity risk.     

Nordic Walking Improves Cardiometabolic Parameters,Fitness Performance,and Quality of Life in Older Adults With Type 2 Diabetes

ObjectiveTo assess the effect of Nordic walking (NW) on cardiometabolic health, physical performance, and well-being in sedentary older adults with type 2 diabetes (T2D).MethodsFifteen subjects with T2D (female, 5; male, 10; age, 65 ± 6.2 years [mean ± standard deviation]; body mass index, 27.3 ± 4.9 kg/m² [mean ± standard deviation]) were enrolled in a 6-month NW training program. The fasting glucose and glycosylated hemoglobin levels, lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), systolic blood pressure (SBP), and diastolic blood pressures were measured before and after the intervention. Participants’ quality of life (Short-Form Health Survey) and physical fitness (6-minute walking test) were also evaluated.ResultsCompared with baseline, NW significantly improved the fasting glucose level (103.5 ± 18.5 vs 168.7 ± 37.7 mg/dL, P = .01), SBP (121.8 ± 12.2 vs 133 ± 14.4 mm Hg, P = .02), physical fitness (759.88 ± 69 vs 615.5 ± 62.6 m, P < .001), and both mental health (54.5 ± 4.4 vs 45.7 ± 5.6, P < .01) and physical health (49.8 ± 4.7 vs 40.3 ± 5.9, P < .01). The levels of glycosylated hemoglobin (6.15% ± 0.8% vs 6.4% ± 1%, P = .46), total cholesterol (162.2 ± 31.2 vs 175.5 ± 28.8 mg/dL, P = .13), low-density lipoprotein cholesterol (95.2 ± 24.2 vs 106.3 ± 32.3 mg/dL, P = .43), and triglycerides (135.5 ± 60.8 vs 127.6 ± 57.4 mg/dL, P = 0.26) improved without reaching significance.ConclusionNW training improved the glycemic levels, SBP, physical fitness, and perception of quality of life in older adults with T2D. NW represents a suitable complementary strategy to improve the global health status in this population.     

Cholesterol metabolism: from lipidomics to immunology

Oxysterols, the oxidized forms of cholesterol or of its precursors, are formed in the first steps of cholesterol metabolism. Oxysterols have interested chemists, biologists, and physicians for many decades, but their exact biological relevance in vivo, other than as intermediates in bile acid biosynthesis, has long been debated. However, in the first quarter of this century, a role for side-chain oxysterols and their C-7 oxidized metabolites has been convincingly established in the immune system. 25-Hydroxycholesterol has been shown to be synthesized by macrophages in response to the activation of Toll-like receptors and to offer protection against microbial pathogens, whereas 7α,25-dihydroxycholesterol has been shown to act as a chemoattractant to lymphocytes expressing the G protein-coupled receptor Epstein-Barr virus-induced gene 2 and to be important in coordinating the action of B cells, T cells, and dendritic cells in secondary lymphoid tissue. There is a growing body of evidence that not only these two oxysterols but also many of their isomers are of importance to the proper function of the immune system. Here, we review recent findings related to the roles of oxysterols in immunology.     

Effects of taurine supplementation on productive performance,nutrient digestibility and gene expression of nutrient transporters in quails reared under heat stress

This study was conducted to examine the effects of dietary taurine supplementation on productive performance, nutrient digestibility, antioxidant status, and the gene expression of ileal nutrient transporters in laying quails reared under heat stress (HS). One hundred and eighty laying Japanese quails (Coturnix coturnix japonica) were fed a basal diet or basal diet supplemented with either 2.5 or 5 g of taurine per kg of diet, and reared at either 22 ± 2 °C for 24 h/d (thermoneutral, TN) or 34 ± 2 °C for 8 h/d (HS) for 12 weeks. The quails reared under HS consumed less feed, produced less egg, and had lower dry matter, organic matter and crude protein apparent digestibilities compared with the quails reared under the TN condition (P = 0.001). However, increasing taurine concentrations in the diet improved feed intake and egg production (P = 0.001), but also the apparent digestibilities (P ≤ 0.027) in quails reared under HS. The greater doses (5 g/kg) of taurine resulted in more responses. The quails reared under HS had greater serum and liver MDA concentrations (P = 0.0001) which decreased with dietary taurine supplementations, particularly greater doses. The gene expressions of ileal PEPT1, EAAT3, CAT1, CAT2, SGLT1, SGLT5, GLUT2, and GLUT5 decreased under HS conditions (P = 0.001). However, supplementing taurine, in a dose-dependent fashion, to the diet of quails reared under HS resulted in increases in the gene expressions of the transporters (P < 0.05) except for CAT1. The results of the present work showed that taurine supplementation, particularly with greater doses (5 g/kg), to the diet of laying quails kept under HS acts as alleviating negative effects of HS, resulting in improvements in productive performance and nutrient digestion, and also upregulation of ileal nutrient transporters.     

COUNTERPOINT: Artificial Sweeteners for Obesity—Better than Sugary Alternatives; Potentially a Solution

ObjectiveNonnutritive (NNSs) are used in place of sugars to reduce caloric and glycemic intake while providing desired sweetness, commonly replacing sugar-sweetened beverages (SSBs) with “diet” (zero-calorie) alternatives. Concern has developed due to observational data associating NNSs with obesity and adiposity-based chronic disease. This counterpoint argues that, in general, NNSs used in place of added or excess sugars in the diet are likely beneficial.MethodsA literature review was conducted on interventional trials investigating NNSs and obesity or type 2 diabetes mellitus. Key words used in the search included artificial sweeteners, nonnutritive sweeteners, saccharin, sucralose, aspartame, stevia/steviol, acesulfame potassium, meal replacements, type 2 diabetes mellitus, obesity, and weight.ResultsInterventional data and indirect interventional data consistently showed beneficial effects on weight and cardiometabolic health, including glycemia, when SSBs or other energy-dense foods were replaced by artificially sweetened beverages or artificially sweetened meal replacements.ConclusionAlthough NNSs correlate with obesity and adiposity-based chronic disease, those data are fraught with confounding and error. Plausibility has been suggested on the basis of preclinical research on neuroendocrine control of appetite, satiety, and cravings plus the gut microbiome. However, interventional data reveal that replacing caloric/glycemic energy intake via NNSs creates an energy deficit resulting in weight loss and improvement in disease—especially dysglycemic disease. Intensive dietary intervention using artificially sweetened meal replacements shows a marked clinical benefit without detriment from their NNSs. Furthermore, beverages sweetened with NNSs rather than SSBs have been noted to be a critical component for those succeeding in maintaining weight loss. Although individual responses to the effects of NNSs are always warranted just like in any clinical situation, patients should not be advised to avoid NNSs in the context of dietary intervention to improve quality and energy deficit.     

Does a MediDiet With Additional Extra Virgin Olive Oil and Pistachios Reduce the Incidence of Gestational Diabetes?

ObjectiveThe present study aimed to evaluate gestational diabetes mellitus (GDM) incidence in pregnant women following the Mediterranean diet (MedDiet) with the addition of extra virgin olive oil (EVOO) and pistachios.MethodsA total of 560 pregnant patients were enrolled in the present study. The MedDiet was introduced in both the interventional group (IG) and the control group. The women in the IG received 40 mL of EVOO every day along with 25 to 30 g of roasted pistachios. The incidence of GDM was recorded along with specific maternal and neonatal outcomes.ResultsThe nutritional scores and MedDiet adherence screener scores were not statistically different between the groups at baseline, but the difference was statistically significant and higher in the IG at 24 to 28 weeks (P = .001) and at 36 to 38 weeks (P = .001). GDM was diagnosed in 51 (20.4%) women in the control group and 34 (13.6%) women in the IG. The MedDiet significantly reduced GDM incidence (P = .02) after adjusting for confounding factors.ConclusionThe present study shows that dietary intervention in pregnant women, including a MedDiet and increased consumption of EVOO and pistachios, decreases the incidence of GDM.     

Efficacy of choline and DHA supplements or enriched environment exposure during early adult obesity in mitigating its adverse impact through aging in rats

IntroductionThe aim of this study was to assess the efficacy of choline and DHA or exposure to environmental enrichment in obese adult and aging rats on alterations in body mass index, serum lipid profile and arterial wall changes, despite stopping high fat diet consumption and interventions during adulthood.Methods21 day old male Sprague Dawley rats were assigned as Experiment-1 & 2 - PND rats were divided into 4 groups with interventions for 7 months (n = 8/group). NC– Normal control fed normal chow diet; OB- Obese group, fed high fat diet; OB + CHO + DHA- fed high fat diet and oral supplementation of choline, DHA. OB + EE- fed high fat diet along with exposure to enriched environment .Experiment-2 had similar groups and interventions as experiment 1 but for next 5 months were fed normal chow diet without any interventions. Body mass index was assessed and blood was analyzed for serum lipid profile. Common Carotid Artery (CCA) was processed for Haematoxylin and eosin, Verhoff Vangeison stains. Images of tissue sections were analyzed and quantified using image J and tissue quant software.ResultsIn experiment.1, mean body mass index (p < 0.001), serum lipid profile (p < 0.01), thickness of tunica intima (p < 0.05), tunica media (p < 0.01) and percentage of collagen fibers (p < 0.01) of CCA were significantly increased in OB compared to NC. These were significantly attenuated in OB + CHO + DHA and OB + EE compared to OB. In experiment.2, mean body mass index (p < 0.01), serum lipid profile (p < 0.05) and thickness of tunica media of CCA (p < 0.01) were significantly increased in OB compared to NC. In OB + CHO + DHA and OB + EE, significant attenuation was observed in mean body mass index and mean thickness of tunica media compared to same in OB.ConclusionAdult obesity has negative impact on body mass index, serum lipid profile and arterial wall structure that persists through aging. Supplementation of choline and DHA or exposure to enriched environment during obesity attenuates these negative impacts through aging.     

Obesity: Overview of Weight Management

IntroductionObesity is a chronic illness that requires a multifaceted personalized treatment approach.Methods & FindingsUsing current guidelines and recent studies in weight management, this article reviews the multiple components of weight management: lifestyle intervention (dietary intervention, physical activity, and behavioral interventions), pharmacotherapy, endoscopic procedures, and surgical procedures. This review briefly discusses specific diets and dietary strategies, compensatory mechanisms acting against weight loss, recent changes to Food and Drug Administration approved antiobesity medications, and technological advances in weight management delivery.ConclusionCurrent literature is lacking large studies on the safety and efficacy of combination therapies involving pharmacotherapy plus 1 or more procedures.     

The small GTPase RAB10 regulates endosomal recycling of the LDL receptor and transferrin receptor in hepatocytes

The low-density lipoprotein receptor (LDLR) mediates the hepatic uptake of circulating low-density lipoproteins (LDLs), a process that modulates the development of atherosclerotic cardiovascular disease. We recently identified RAB10, encoding a small GTPase, as a positive regulator of LDL uptake in hepatocellular carcinoma cells (HuH7) in a genome-wide CRISPR screen, though the underlying molecular mechanism for this effect was unknown. We now report that RAB10 regulates hepatocyte LDL uptake by promoting the recycling of endocytosed LDLR from RAB11-positive endosomes to the plasma membrane. We also show that RAB10 similarly promotes the recycling of the transferrin receptor, which binds the transferrin protein that mediates the transport of iron in the blood, albeit from a distinct RAB4-positive compartment. Taken together, our findings suggest a model in which RAB10 regulates LDL and transferrin uptake by promoting both slow and rapid recycling routes for their respective receptor proteins.     

Psidium guajava Linn leaf ethanolic extract: In vivo giardicidal potential with ultrastructural damage,anti-inflammatory and antioxidant effects

Introduction and aimConsidering the magnitude of giardiasis problem, the side-effects of the used anti-giardia drugs and the resistance posed against them, the current study aimed to evaluate the in-vivo giardicidal effect of Psidium guajava leaf extract (PGLE).MethodsFor fulfilling this aim, five Swiss-albino mice groups were included; GI: non-infected, GII: Giardia-infected and non-treated, GIII: Giardia-infected and metronidazole-treated, GIV: Giardia-infected and PGLE-treated, and GV: Giardia-infected and treated with both metronidazole and PGLE. Treatment efficacy was assessed via; Giardia cyst viability and trophozoite count, trophozoite electron microscopic ultrastructure, duodenal histopathological scoring, immunohistochemistry for TNF-α and duodenal scanning electron microscopy. Moreover, mice serum liver enzymes, total bilirubin, albumin, lipid profile including; total cholesterol, HDL, LDL and triglycerides were assessed. Additionally, hepatic oxidative stress markers including; malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH) and superoxide dismutase (SOD) were measured.ResultsResults showed that PGLE whether alone or combined with metronidazole has induced significant trophozoite count reduction and major architectural changes. Duodenal histological improvement, and local protective anti-inflammatory effect were confirmed. PGLE has also helped in healing of Giardia-induced gut atrophy. Thus, offered a comprehensive therapy for both the pathogen and the resultant pathological sequalae. Serum markers showed favorable hepatoprotective effect. Total cholesterol, LDL and triglycerides levels were less in PGLE-treated group than in metronidazole-treated group. Hepatic oxidative stress markers revealed the promising extract antioxidant effect. This study highlights, the promising in-vivo giardicidal PGLE activity, that was comparable to metronidazole, thus, the extract would be an ideal strongly recommended treatment for giardiasis. When combined with metronidazole, the extract potentiated its therapeutic effect. Besides, having hepatoprotective, anti-inflammatory, and antioxidant properties, the extract can combat the major side effects of metronidazole therapy.     

Associations between serum cholesterol and immunophenotypical characteristics of circulatory B cells and Tregs

Blood lipids play a major role in the manifestation of cardiovascular diseases. Recent research suggested that there are connections between cholesterol levels and immunological alterations. We investigated whether there is an association between serum cholesterol levels (total, HDL, and LDL) and immune cells (B cell and regulatory T cells [Tregs]). The analysis was based on data from 231 participants of the MEGA study in Augsburg, Germany, recruited between 2018 and 2021. Most participants were examined two different times within a period of 9 months. At every visit, fasting venous blood samples were taken. Immune cells were analyzed immediately afterward using flow cytometry. Using multivariable-adjusted linear regression models, the associations between blood cholesterol concentrations and the relative quantity of several B-cell and Treg subsets were analyzed. We found that particularly HDL cholesterol concentrations were significantly associated to some immune cell subpopulations: HDL cholesterol showed significant positive associations with the relative frequency of CD25++ Tregs (as proportion of all CD4+CD25++ T cells) and conventional Tregs (defined as the proportion of CD25+CD127− cells on all CD45RA−CD4+ T cells). Regarding B cells, HDL cholesterol values were inversely associated with the cell surface expression of IgD and with naïve B cells (CD27−IgD+ B cells). In conclusion, HDL cholesterol levels were associated with modifications in the composition of B-cell and Treg subsets demonstrating an important interconnection between lipid metabolism and immune system. Knowledge about this association might be crucial for a deeper and more comprehensive understanding of the pathophysiology of atherosclerosis.