The effects of allium sativum on immunity within the scope of COVID-19 infection.

The severity of coronavirus disease 2019 (COVID-19) infection is quite variable and the manifestations varies from asymptomatic disease to severe acute respiratory infection. Fever, dry cough, dyspnea, myalgia, fatigue, loss of appetite, olfactory and gustatory dysfunctions are the most prevalent general symptoms. Decreased immune system cells such as suppressed regulatory T cells, cytotoxic and helper T cells, natural killer cells, monocytes/macrophages and increased proinflammatory cytokines are the characteristic features. Compounds derived from Allium sativum (garlic) have the potential to decrease the expression of proinflammatory cytokines and to reverse the immunological abnormalities to more acceptable levels. Allium sativum is suggested as a beneficial preventive measure before being infected with SARS-CoV-2 virus. Allium sativum is a functional food well-known for its immunomodulatory, antimicrobial, antiinflammatory, antimutagenic, antitumor properties. Its antiviral efficiency was also demonstrated. Some constituents of this plant were found to be active against protozoan parasites. Within this context, it appears to reverse most immune system dysfunctions observed in patients with COVID-19 infection. The relations among immune system parameters, leptin, leptin receptor, adenosin mono phosphate-activated protein kinase, peroxisome proliferator activated receptor-gamma have also been interpreted. Leptin's role in boosting proinflammatory cytokines and in appetite decreasing suggest the possible beneficial effect of decreasing the concentration of this proinflammatory adipose tissue hormone in relieving some symptoms detected during COVID-19 infection. In conclusion, Allium sativum may be an acceptable preventive measure against COVID-19 infection to boost immune system cells and to repress the production and secretion of proinflammatory cytokines as well as an adipose tissue derived hormone leptin having the proinflammatory nature.

The effects of Vitis vinifera L. phenolic compounds on a blood-brain barrier culture model: Expression of leptin receptors and protection against cytokine-induced damage.

ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal properties of grapes (Vitis vinifera L.) are well known since ancient times. Ethnobotanical grape preparations, like the Ayurvedic Darakchasava are used as cardiotonic and for the treatment of cardiovascular diseases. Dried grape products are also applied in Iranian traditional medicine for memory problems, which are linked to the pathology of brain microvessels, a special part of the cardiovascular system. The anti-inflammatory and protective effects of these traditional preparations on the cardiovascular system are related to their bioactive phenolic compounds. AIM OF THE STUDY: The blood-brain barrier (BBB), formed by brain capillaries, is not only involved in inflammatory and other diseases of the central nervous system, but also in many systemic diseases with an inflammatory component. Dietary obesity is a systemic chronic inflammatory condition in which the peripheral and central vascular system is affected. Among the cerebrovascular changes in obesity defective leptin transport across the BBB related to central leptin resistance is observed. Our aim was to study the protective effects of grape phenolic compounds epicatechin (EC), gallic acid (GA) and resveratrol (RSV) and grape-seed proanthocyanidin-rich extract (GSPE) on a cytokine-induced vascular endothelial inflammation model. Using a culture model of the BBB we investigated cytokine-induced endothelial damage and changes in the expression of leptin receptors and leptin transfer. MATERIALS AND METHODS: For the BBB model, primary cultures of rat brain endothelial cells, glial cells and pericytes were used in co-culture. Cells were treated by tumor necrosis factor-α (TNF-α) and interleukin-1 ß (IL-1ß) (10 ng/ml each) to induce damage. Cell toxicity was evaluated by the measurement of impedance. The expression of leptin receptors was assessed by RT-qPCR and western blot. The production of reactive oxygen species (ROS) and nitric oxide (NO) were detected by fluorescent probes. RESULTS: GSPE (10 µg/ml), EC (10 µM), GA (1 µM) or RSV (10 µM) did not change the viability of brain endothelial cells. The gene expression of the short leptin receptor isoform, Ob-Ra, was up-regulated by GSPE, EC and RSV, while the mRNA levels of Lrp2 and clusterin, clu/ApoJ were not affected. The tested compounds did not change the expression of the long leptin receptor isoform, Ob-Rb. RSV protected against the cytokine-induced increase in albumin permeability of the BBB model. GSPE and EC exerted an antioxidant effect and GSPE increased NO both alone and in the presence of cytokines. The cytokine-induced nuclear translocation of transcription factor NF-κB was blocked by GSPE, GA and RSV. Cytokines increased the mRNA expression of Lrp2 which was inhibited by EC. RSV increased Ob-Ra and Clu in the presence of cytokines. Cytokines elevated leptin transfer across the BBB model, which was not modified by GSPE or RSV. CONCLUSION: Our results obtained on cell culture models confirm that natural grape compounds protect vascular endothelial cells against inflammatory damage in accordance with the ethnopharmacological use of grape preparations in cardiovascular diseases. Furthermore, grape compounds and GSPE, by exerting a beneficial effect on the BBB, may also be considered in the treatment of obesity after validation in clinical trials.

Oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, synthetic peptide leptin mimetics: Immunofluorescent localization in the mouse hypothalamus.

This study describes the localization of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, synthetic peptide leptin mimetics, in the hypothalamus of Swiss Webster and C57BL/6J wild-type mice, leptin-deficient ob/ob mice, and leptin-resistant diet-induced obese (DIO) mice. The mice were given [D-Leu-4]-OB3 or MA-[D-Leu-4]-OB3 in 0.3% dodecyl maltoside by oral gavage. Once peak serum concentrations were reached, the mice received a lethal dose of pentobarbital and were subjected to intracardiac perfusion fixation. The brains were excised, post-fixed in paraformaldehyde, and cryo-protected in sucrose. Free-floating frozen coronal sections were cut at 25-µm and processed for imaging by immunofluorescence microscopy. In all four strains of mice, dense staining was concentrated in the area of the median eminence, at the base and/or along the inner wall of the third ventricle, and in the brain parenchyma at the level of the arcuate nucleus. These results indicate that [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 cross the blood-brain barrier and concentrate in an area of the hypothalamus known to regulate energy balance and glucose homeostasis. Most noteworthy is the localization of [D-Leu-4]-OB3 immunoreactivity within the hypothalamus of DIO mice via a conduit that is closed to leptin in this rodent model, and in most cases of human obesity. Together with our previous studies describing the effects of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on energy balance, glucose regulation, and signal transduction pathway activation, these findings are consistent with a central mechanism of action for these synthetic peptide leptin mimetics, and suggest their potential usefulness in the management of leptin-resistant obesity and type 2 diabetes in humans.

Inhibiting Microglia Expansion Prevents Diet-Induced Hypothalamic and Peripheral Inflammation.

Cell proliferation and neuroinflammation in the adult hypothalamus may contribute to the pathogenesis of obesity. We tested whether the intertwining of these two processes plays a role in the metabolic changes caused by 3 weeks of a high-saturated fat diet (HFD) consumption. Compared with chow-fed mice, HFD-fed mice had a rapid increase in body weight and fat mass and specifically showed an increased number of microglia in the arcuate nucleus (ARC) of the hypothalamus. Microglia expansion required the adequate presence of fats and carbohydrates in the diet because feeding mice a very high-fat, very low-carbohydrate diet did not affect cell proliferation. Blocking HFD-induced cell proliferation by central delivery of the antimitotic drug arabinofuranosyl cytidine (AraC) blunted food intake, body weight gain, and adiposity. AraC treatment completely prevented the increase in number of activated microglia in the ARC, the expression of the proinflammatory cytokine tumor necrosis factor-α in microglia, and the recruitment of the nuclear factor-κB pathway while restoring hypothalamic leptin sensitivity. Central blockade of cell proliferation also normalized circulating levels of the cytokines leptin and interleukin 1ß and decreased peritoneal proinflammatory CD86 immunoreactive macrophage number. These findings suggest that inhibition of diet-dependent microglia expansion hinders body weight gain while preventing central and peripheral inflammatory responses due to caloric overload.

Central leptin resistance and hypothalamic inflammation are involved in letrozole-induced polycystic ovary syndrome rats.

Accumulating evidence indicates that leptin acts as an important mediator in energy homeostasis and reproduction. Since dysfunction of reproduction and metabolism are major characteristics of polycystic ovarian syndrome (PCOS), the role of leptin in pathogenesis of PCOS needs further research. Many studies have shown that central leptin resistance existed in obesity rats through leptin intracerebroventricular (icv) injection; however, central leptin resistance in PCOS rats has not been reported. This study aimed to investigate whether there was a state of central leptin resistance in PCOS rats, as well as explore the possible association of hypothalamic inflammation with central leptin resistance. First, letrozole was used to induce the PCOS model, 24 h food intake, 24 h body weight changes and the expression of p-STAT3 were determined following leptin or artificial cerebrospinal fluid (aCSF) icv injection in rats. Second, we further evaluated the expressions of IL-1ß, IL-6, TNF-α, p-IKKß, NF-κB, p-NF-κB, IκBα, p-IκBα and SOCS3 in hypothalamus. The results showed that 24 h food intake and body weight were decreased, while the expression of p-STAT3 was increased in control group rats following leptin icv injection compared with aCSF icv injection; however, both of them showed no significant difference in PCOS rats. Furthermore, inflammatory markers were upregulated in the hypothalami of PCOS rats. Taken together, our data indicated that there was a state of chronic low-grade inflammation in hypothalamus which might be the possible mechanism for central leptin resistance in PCOS rats.

Effect of Electroacupuncture on Inflammation in the Obese Zucker Fatty Rat Model of Metabolic Syndrome.

Chronic inflammation is known to be associated with visceral obesity and insulin resistance and is characterized by altered levels of production of adipokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6, leptin, and adiponectin. Metabolic syndrome (MetS) is a major and escalating public health and clinical challenge worldwide, and patients with MetS have an increased risk of developing cardiovascular disease and type 2 diabetes mellitus. Electroacupuncture (EA) was tested as a means of decreasing inflammation in genetically obese Zucker fatty rats, which serve as a model of MetS. Repeated application of EA at the Zhongwan/Guanyuan acupoints decreased serum TNF-α, but produced no significant alterations in serum leptin, adiponectin, or IL-10. EA had no significant effect on the levels of these four adipokines in white adipose tissue. These findings are consistent with the supposition that EA inhibits proliferation and/or infiltration of macrophages into the adipose tissue of obese rats and stimulates the release of IL-10 from the decreased numbers of macrophages present in adipose tissue. Compared with the control animals, no significant change in body weight occurred. The blood glucose (BG) level over a 30-minute interval in Week 2 was relatively the same as that in Week 1, suggesting that EA treatment does not increase the likelihood of developing hyperglycemia.

PI3K signaling in the pathogenesis of obesity: The cause and the cure.

With the steady rise in the incidence of obesity and its associated comorbidities, in the last decades research aimed at understanding molecular mechanisms that control body weight has gained new interest. Fat gain is frequently associated with chronic adipose tissue inflammation and with peripheral as well as central metabolic derangements, resulting in an impaired hypothalamic regulation of energy homeostasis. Recent attention has focused on the role of phosphatidylinositol 3-kinase (PI3K) in both immune and metabolic response pathways, being involved in the pathophysiology of obesity and its associated metabolic diseases. In this review, we focus on distinct PI3K isoforms, especially class I PI3Ks, mediating inflammatory cells recruitment to the enlarged fat as well as intracellular responses to key hormonal regulators of fat storage, both in adipocytes and in the central nervous system. This integrated view of PI3K functions may ultimately help to develop new therapeutic interventions for the treatment of obesity.

Evaluation of yellow pea fibre supplementation on weight loss and the gut microbiota: a randomized controlled trial.

BACKGROUND: Fibre intake among North Americans is currently less than half the recommended amount. Consumers are interested in food products that could promote weight loss and improve health. Consequently, evaluation of unique fibre sources with potential gut-mediated benefits for metabolic health warrants investigation. Our objective is to assess the effects of yellow pea fibre supplementation on weight loss and gut microbiota in an overweight and obese adult population. METHODS/DESIGN: In a double blind, placebo controlled, parallel group study, overweight and obese (BMI = 25-38) adults will be randomized to either a 15 g/d yellow pea fibre supplemented group or isocaloric placebo group for 12 weeks (n = 30/group). The primary outcome measure is a change in body fat from baseline to 12 weeks. Secondary outcomes include glucose tolerance, appetite regulation, serum lipids and inflammatory markers. Anthropometric data (height, weight, BMI, and waist circumference) and food intake (by 3-day weighed food records) will be measured at baseline and every 4 weeks thereafter. Subjective ratings of appetite will be recorded by participants at home on a weekly basis using validated visual analogue scales. At week 0 and at the end of the study (week 12), an ad libitum lunch buffet protocol for objective food intake measures and dual-energy X-ray absorptiometry (DXA) scan for body composition will be completed. Participants will be instructed not to change their exercise habits during the 12 week study. Glucose and insulin will be measured during an oral glucose tolerance test at weeks 0 and 12. Levels of lipids and CRP will be measured and inflammatory markers (adiponectin, leptin, TNF-α, IL-6 and IL-8) in the serum will be quantified using Milliplex kits. Mechanisms related to changes in gut microbiota, serum and fecal water metabolomics will be assessed. DISCUSSION: Globally the development of functional foods and functional food ingredients are critically needed to curb the rise in metabolic disease. This project will assess the potential of yellow pea fibre to improve weight control via gut-mediated changes in metabolic health in overweight and obese adults. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01719900) Registered October 23, 2012.

Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice.

Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer.

Effect of immune stress on body weight regulation is altered by ovariectomy in female rats.

It has been suggested that obesity and loss of ovarian function alter the inflammatory response to immune stress. Ovariectomized (OVX) rats, which are used as a model of human menopause, exhibit both hyperphagia-induced obesity and gonadal steroid deficiency. To evaluate the effects of ovariectomy on inflammatory responses, we compared the anorectic response to LPS in OVX rats and gonad intact female rats. As leptin and hypothalamic interleukin-1ß (IL1ß) play pivotal roles in the anorectic response to immune stress, these factors were also measured. It was found that the OVX rats exhibited an increased anorectic response to LPS compared with the sham-operated rats. The OVX rats showed higher serum leptin concentrations and a greater increase in hypothalamic IL1ß mRNA expression after LPS injection. In addition, in order to determine whether gonadal steroid deficiency contributes to the changes in the inflammatory responses of OVX rats, we compared responses between OVX rats treated with gonadal steroids and untreated OVX rats. There were no differences in appetite, the serum leptin level, and hypothalamic IL1ß mRNA expression between the two groups after LPS injection. These findings suggest that the loss of ovarian function increases the induction of leptin and hypothalamic IL1ß synthesis and consequently increases the anorectic response under immune stress conditions. It is possible that these alterations are caused by OVX-induced obesity rather than the direct effects of gonadal steroid deficiency.

Effect of bacterial lipopolysaccharide on the reproductive axis of prepubertal and peripubertal female rats. Ontogenic changes in the immune-neuroendocrine interactions.

The immune, endocrine and nervous systems are closely interrelated, which allows the organism to respond to different types of stress such as infection. Chronic infectious and inflammatory conditions are often accompanied by an impaired reproductive function. Leptin, a hormone produced by adipose tissue, exerts a regulatory function on the reproductive axis. It has homology with other proinflammatory cytokines and could be modified by lipopolysaccharide (LPS). Therefore, these studies were designed to investigate the effect of LPS administration on the neuroendocrine mechanisms involved in the regulation of the reproductive axis during sexual maturation. Fifteen- and 30-day-old female rats were injected with a single dose of LPS 250 microg/kg (i.p.) and then nitric oxide synthase (NOS) activity, hypothalamic excitatory/inhibitory amino acids and Gn-RH content, serum LH and leptin concentration were studied. In 15-day-old female rats LPS treatment did not modify hypothalamic inducible (iNOS) and constitutive (cNOS) NOS activity, Gn-RH, glutamate (GLU) and GABA content. Also serum LH and leptin levels were not modified. In 30-day-old rats LPS increased iNOS and cNOS activity (p < 0.001) and hypothalamic Gn-RH content (p < 0.001). At this age hypothalamic GABA content was significantly decreased (p < 0.001) without changes in GLU content, and serum LH (p < 0.001) and leptin (p < 0.0001) decreased significantly. In summary, current studies have demonstrated that LPS administration to 15- and 30-day-old female rats results in a different response of the hypothalamus-pituitary-gonadal axis and of the adipose tissue, demonstrating an ontogenic response of the immune-neuroendocrine system to LPS administration.

Effect of intestinal ischemia-reperfusion injury on protein levels of leptin and orexin-A in peripheral blood and central secretory tissues.

AIM: To explore the effect of intestinal ischemia-reperfusion injury on protein levels of leptin and orexin-A in peripheral blood and their central secretory tissues and to find out the role leptin and orexin-A play in acute inflammatory responses. METHODS: An intestinal ischemia-reperfusion (I/R) injury model of rats was established and rats were divided randomly into six groups: sham-operation group, 60 min ischemia/30 min reperfusion group (I60'R30'), I60'R90', I60'R150', I60'R240' and I60'R360', 9 rats each group. Two highly-sensitive radioimmunoassays for leptin and orexin-A were established and used to check the change of their concentrations in peripheral blood and central secretory tissues before and after intestinal I/R injury. RESULTS: Compared with the serum leptin level before injury, it decreased significantly in I60'R30' group and increased significantly in I60'R360' group; compared to sham-operation group after injury, serum leptin level increased significantly in I60'R360' group; compared to sham-operation group after injury, adipose leptin levels decreased significantly in I60'R30' and I60'R90' groups, while increased significantly in I60'R360' group. There was no significant difference between the expression levels of orexin-A before and after I/R injury. CONCLUSION: Leptin has a time-dependent response and orexin-A has a delayed response to acute inflammatory stimuli such as intestinal I/R injury and they may participate in metabolic disorders in injury as inflammatory cytokines.

Circulating leptin mediates lipopolysaccharide-induced anorexia and fever in rats.

Anorexia and fever are important features of the host's response to inflammation that can be triggered by the bacterial endotoxin lipopolysaccharide (LPS) and the appetite suppressant leptin. Previous studies have demonstrated that LPS induces leptin synthesis and secretion in the periphery, and that the action of leptin on appetite suppression and fever are dependent on brain interleukin (IL)-1beta. However, the role of leptin as a neuroimmune mediator of LPS-induced inflammation has not been fully elucidated. To address this issue, we neutralized circulating leptin using a leptin antiserum (LAS) and determined how this neutralization affected LPS-induced anorexia, fever and hypothalamic IL-1beta. Adult male rats were separated into four treatment groups, namely LPS + normal sheep serum (NSS), LPS + LAS, saline + LAS and saline + NSS. Intraperitoneal injection of LPS (100 microg kg(-1)) induced a significant reduction in food intake and body weight, which were significantly reversed in the presence of LAS (1 ml kg(-1)), 8 and 24 h after treatment. In addition, LPS-induced fever was significantly attenuated by LAS over the duration of the fever response (8 h). Lipopolysaccharide induced an increase of circulating IL-6, another potential circulating pyrogen, which was not affected by neutralization of leptin at 2 h. Interleukin-1beta mRNA at 1 and 8 h, and IL-1 receptor antagonist (ra) at 2 h were significantly upregulated in the hypothalamus of LPS-treated animals. The induction of these cytokines was attenuated in the presence of LAS. These results are the first to demonstrate that leptin is a circulating mediator of LPS-induced anorexia and fever, probably through a hypothalamic IL-1beta-dependent mechanism.