Immune stimulatory effect of Nigella sativa in healthy animal models: A systematic review and meta-analysis.

The immune-modulatory effects of black seeds (Nigella sativa seeds, NSS) are well documented, but the overall in vivo impact of this important natural medicinal product on immune system function has yet to be established. Here we systematically reviewed and meta-analyzed the effects of NSS on humoral [serum titers of immunoglobulins including IgG, IgM, anti-Newcastle virus disease (anti-NDV), and sheep red blood cell antigen (anti-SRBC)] and cellular immunity [total white blood cell (WBC) count and percentages of monocytes, lymphocytes, basophils, neutrophils, and eosinophils] in healthy animals. The PubMed, ScienceDirect, Web of Science, and Scopus databases were searched according to predefined eligibility criteria. Meta-analyses were performed to estimate the final effect size using RevMan software. Seventeen animal studies were eligible for analysis. For humoral immunity, the overall pooled effect size (ES) of NSS on serum titers of IgM and anti-NVD antibodies was not significantly different [mean difference (MD) 75.27, 95% CI: -44.76 to 195.30, p = 0.22 (I2 = 89%, p = 0.003), and -0.01, 95% CI: -0.27 to 0.25, p = 0.94 (I2 = 74%, p = 0.02), respectively]. However, NSS significantly increased serum titers of IgG and anti-SRBC antibodies [MD 3.30, 95% CI: 2.27 to 4.32, p = 0.00001 (I2 = 0%, p = 0.97), and 1.15, 95% CI: 0.74 to 1.56, p = 0.00001 (I2 = 0%, p = 0.43), respectively]. For cellular immunity, the ES of NSS on WBCs, monocytes, and lymphocytes were not significantly different [MD 0.29, 95% CI: -0.55 to 1.13, p = 0.50, (I2 = 14%, p = 0.32), - 0.01, 95% CI: -0.45 to 0.44, p = 0.97 (I2 = 0%, p = 0.77), and 4.73, 95% CI: -7.13 to 16.59, p = 0.43, (I2 = 99%, p = 0.00001), respectively]. In conclusion, black seeds enhance humoral immunity in healthy animals but do not affect cellular immunity.

Psychological Toll of the COVID-19 Pandemic: An In-Depth Exploration of Anxiety, Depression, and Insomnia and the Influence of Quarantine Measures on Daily Life.

The COVID-19 pandemic, on a global scale, has prompted multifaceted challenges, including a notable psychological toll on the general population. This study uses mixed-method approach for a nuanced exploration of these experiences. Using a phenomenological strategy, qualitative responses from 999 participants were analyzed regarding their pandemic-induced anxiety and the influence of quarantine measures on their lives. Quantitative measures, including the revised Impact of Event Scale (IES-R), patient health questionnaire-9 (PHQ-9), the seven-item generalized anxiety disorder assessment (GAD-7), and Insomnia Severity Index (ISI), were used to quantify trauma, depression, anxiety, and insomnia attributed to COVID-19. Partial least squares structural equation modeling (PLS-SEM) was utilized for quantitative data analysis. The anxiety-related responses were mainly clustered into four themes: life threats, support shortage, economic consequences, and disruptions to family and social life. Subthemes that addressed the perceived effects encapsulated disruptions to academic and professional lives, familial and social relationships, psychopathological stress, and movement limitations. The findings from quantitative analysis revealed the significant associations between COVID-19-related trauma and symptoms of anxiety, depression, and insomnia, as indicated by coefficients exceeding 0.10 (all z-values > 1.96; p-values < 0.05). In conclusion, the findings underscore COVID-19's role in escalating anxiety, influenced by various factors, and its disruptive effects on daily life due to quarantine measures. The strong associations between the pandemic and the symptoms of depression, anxiety, and insomnia underscore the urgency of comprehensive psychological and public health interventions to alleviate these impacts.

A cross-sectional study on the impact of the COVID-19 pandemic on psychological outcomes: Multiple indicators and multiple causes modeling.

Although the psychological impact of coronavirus disease 2019 (COVID-19) has been evaluated in the literature, further research is needed, particularly on post-traumatic stress disorder (PTSD) and psychological outcomes, is needed. This study aims to investigate the effect of the COVID-19 pandemic on psychological outcomes (depression, anxiety, and insomnia). A cross-sectional study using an online survey was conducted using the following instruments: Impact of Event Scale-Revised (IES-R), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder (GAD-7), and Insomnia Severity Index (ISI). Confirmatory factor analysis (CFA), structural equation model (SEM), multiple indicators and multiple causes (MIMIC) modeling, and differential item functioning (DIF) were performed to analyze the collected data. According to the results, participants with PTSD (n = 360) showed a higher level of depression, anxiety, and insomnia than those without PTSD (n = 639). Among the participants, 36.5% experienced moderate to severe symptoms of depression, and 32.6% had mild depressive symptoms. Moreover, 23.7% of participants experienced moderate to severe anxiety symptoms, and 33.1% had mild anxiety symptoms. In addition, 51.5% of participants experienced symptoms of insomnia. In conclusion, the PTSD caused by COVID-19 is significantly associated with depression, anxiety, and insomnia at the level of latent constructs and observed variables.

Rasch Modeling and Multilevel Confirmatory Factor Analysis for the Usability of the Impact of Event Scale-Revised (IES-R) during the COVID-19 Pandemic.

BACKGROUND: Several instruments are currently used to assess Coronavirus Disease 2019 (COVID-19) -induced psychological distress, including the 22-item Impact of Event Scale-Revised (IES-R). The IES-R is a self-administered scale used to assess post-traumatic stress disorder (PTSD). The current study aimed to examine the construct validity of the IES-R, based on the Rasch model, with COVID-19-related data, as well as to test the multilevel construct validity of the IES-R within and among countries during the pandemic crisis. METHODS: A multi-country web-based cross-sectional survey was conducted utilizing the 22-item IES-R. A total of 1020 participants enrolled in our survey, of whom 999 were included in the analyses. Data were analyzed using Rasch modeling and multilevel confirmatory factor analysis (MCFA). RESULTS: The Rasch modeling results of the IES-R demonstrated that the IES-R is a satisfactory instrument with the five-point Likert scale, asserting that its 22 items are significant contributors to assessing PTSD as a unidimensional construct covered by the items of the IES-R. The MCFA confirmed that the 22-item IES-R, with its three factors, including intrusion, avoidance, and hyperarousal, demonstrates adequate construct validity at the within- and among-country levels. However, the results of the Akaike information criterion (AIC) model determined that the 16-item IES-R is better than the 22-item IES-R. CONCLUSION: The results suggested that the 22-item IES-R is a reliable screening instrument for measuring PTSD related to the COVID-19 pandemic, and can be utilized to provide timely psychological health support, when needed, based on the screening results.

A Comparison of the Gene Expression Profiles of Non-Alcoholic Fatty Liver Disease between Animal Models of a High-Fat Diet and Methionine-Choline-Deficient Diet.

Non-alcoholic fatty liver disease (NAFLD) embraces several forms of liver disorders involving fat disposition in hepatocytes ranging from simple steatosis to the severe stage, namely, non-alcoholic steatohepatitis (NASH). Recently, several experimental in vivo animal models for NAFLD/NASH have been established. However, no reproducible experimental animal model displays the full spectrum of pathophysiological, histological, molecular, and clinical features associated with human NAFLD/NASH progression. Although methionine-choline-deficient (MCD) diet and high-fat diet (HFD) models can mimic histological and metabolic abnormalities of human disease, respectively, the molecular signaling pathways are extremely important for understanding the pathogenesis of the disease. This review aimed to assess the differences in gene expression patterns and NAFLD/NASH progression pathways among the most common dietary animal models, i.e., HFD- and MCD diet-fed animals. Studies showed that the HFD and MCD diet could induce either up- or downregulation of the expression of genes and proteins that are involved in lipid metabolism, inflammation, oxidative stress, and fibrogenesis pathways. Interestingly, the MCD diet model could spontaneously develop liver fibrosis within two to four weeks and has significant effects on the expression of genes that encode proteins and enzymes involved in the liver fibrogenesis pathway. However, such effects in the HFD model were found to occur after 24 weeks with insulin resistance but appear to cause less severe fibrosis. In conclusion, assessing the abnormal gene expression patterns caused by different diet types provides valuable information regarding the molecular mechanisms of NAFLD/NASH and predicts the clinical progression of the disease. However, expression profiling studies concerning genetic variants involved in the development and progression of NAFLD/NASH should be conducted.

Cathinone: An alkaloid of Catha edulis (Khat) exacerbated hyperglycemia in diabetes-induced rats.

Cathinone, the main bioactive alkaloid of Catha edulis (khat), slightly increased the blood sugar levels of healthy animals, while its effect on blood sugar levels of diabetic animals has not yet been reported. This study investigated the in vitro inhibition of cathinone on α-amylase and α-glucosidase as well as its in vivo glycemic effects in diabetes-induced rats. Rats were fed on a high fat diet for five weeks, which then intraperitoneally injected with streptozotocin (30 mg/kg). Diabetic rats were distributed randomly into diabetic control (DC, n = 5), 10 mg/kg glibenclamide-treated group (DG, n = 5), and 1.6 mg/kg cathinone-treated group (CAD, n = 5). Additional healthy untreated rats (n = 5) served as a nondiabetic negative control group. Throughout the experiment, fasting blood sugar (FBS), caloric intake and body weight were recorded weekly. By the 28th day of treatment, rats were euthanized to obtain blood samples and pancreases. The results demonstrated that cathinone exerted a significantly less potent in vitro inhibition than α-acarbose against α-amylase and α-glucosidase. As compared to diabetic control group, cathinone significantly increased FBS of diabetic rats, while insulin levels of diabetic rats significantly decreased. In conclusion, cathinone was unable to induce a substantial in vitro inhibition on α-amylase and α-glucosidase, while it exacerbated the hyperglycemia of diabetes-induced rats.

Efficacy of Interventional Programs in Reducing Acculturative Stress and Enhancing Adjustment of International Students to the New Host Educational Environment: A Systematic Review and Meta-Analysis.

This review aimed to systematically outline and meta-analyze the efficacy of psychoeducational, cultural orientation, socio-cultural, and peer-pairing programs in reducing acculturative stress and enhancing adjustment among international students worldwide. The consulted databases were PubMed, Scopus, Web of Science, ScienceDirect, EBSCO, and ProQuest. Eligibility criteria allowed the inclusion of randomized controlled trials (RCTs) and quasi-experimental trials without applying language, country, publication type or time restrictions. The quality of the eligible studies was appraised by the RoB2 tool of Cochrane for RCTs and JBI critical appraisal tools for quasi-experimental trials. Data items were collected based on PICO acronym by two investigators and reviewed for accuracy by a third one. The evidence was narratively synthesized and validated by proceeding with a random model meta-analysis using Cochrane RevMan software(Version 5.4). The quality of the pooled evidence from meta-analysis was assessed using the tool of GRADE. Out of 29,975 retrieved records, 14 studies (six RCTs and eight quasi-experimental trials) were included. The psychoeducational program significantly reduced acculturative stress and enhanced adjustment. In contrast, cultural orientation and peer-pairing programs significantly enhanced adjustment, but could not reduce acculturative stress. In meta-analysis, acculturative stress was significantly reduced in the psychoeducational intervention versus controls [overall pooled size effect = -3.89 (95% CI: -5.42, -2.53) at p < 0.001]. Similarly, adjustment was significantly enhanced in the psychoeducation and socio-cultural interventions versus control [overall pooled size effect = 3.10 (95% CI: 2.35, 3.85) at p < 0.001]. In conclusion, the psychoeducational program demonstrated superior efficacy in reducing acculturative stress and enhancing adjustment compared to the other interventional programs. However, socio-cultural programs have still been effective in enhancing adjustment. This systematic review is registered in PROSPERO (CRD42018104211).

Efficacy of Edible Bird's Nest on Cognitive Functions in Experimental Animal Models: A Systematic Review.

Edible bird's nest (EBN) is constructed from saliva of swiftlets birds and consumed largely by Southeast and East Asians for its nutritional value and anti-aging properties. Although the neuroprotection of EBN in animals has been reported, there has not been yet systemically summarized. Thus, this review systemically outlined the evidence of the neuroprotective activity of EBN in modulating the cognitive functions of either healthy or with induced-cognitive dysfunction animals as compared to placebos. The related records from 2010 to 2020 were retrieved from PubMed, Scopus, Web of Science and ScienceDirect using pre-specified keywords. The relevant records to the effect of EBN on cognition were selected according to the eligibility criteria and these studies underwent appraisal for the risk of bias. EBN improved the cognitive functions of induced-cognitive dysfunction and enhanced the cognitive performance of healthy animals as well as attenuated the neuroinflammations and neuro-oxidative stress in the hippocampus of these animals. Malaysian EBN could improve the cognitive functions of experimental animals as a treatment in induced cognitive dysfunction, a nutritional cognitive-enhancing agent in offspring and a prophylactic conservative effect on cognition against exposure to subsequent noxious cerebral accidents in a dose-depended manner through attenuating neuroinflammation and neuro-oxidative stress. This systemic review did not proceed meta-analysis.

Efficacy of Afatinib in the Treatment of Patients with Non-Small Cell Lung Cancer and Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.

Several randomized controlled trials (RCTs) evaluated the afatinib efficacy in patients with advanced non-small cell lung cancer (NSCLC) and recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). This review systemically outlined and meta-analyzed the afatinib efficacy in NSCLC and R/M HNSCC in terms of overall survival (OS) and progression-free survival (PFS) endpoints. Records were retrieved from PubMed, Web of Science, and ScienceDirect from 2011 to 2020. Eight afatinib RCTs were included and assessed for the risk of bias. In meta-analysis, overall pooled effect size (ES) of OS in afatinib group (AG) significantly improved in all RCTs and NSCLC-RCTs [hazard ratios (HRs): 0.89 (95% CI: 0.81-0.98, p = 0.02); I2 = 0%, p = 0.71/ 0.86 (95% CI: 0.76-0.97; p = 0.02); I2 = 0%, p = 0.50, respectively]. ES of PFS in AG significantly improved in all RCTs, NSCLC-RCTs, and HNSCC-RCTs [HRs: 0.75 (95% CI: 0.68-0.83; p < 0.00001); I2 = 26%, p = 0.24; 0.75 (95% CI: 0.66-0.84; p < 0.00001); I2 = 47%, p = 0.15/0.76 (95% CI: 0.65-88; p = 0.0004); I2 = 34%, p = 0.0004, respectively]. From a clinical viewpoint of severity, interstitial lung disease, dyspnea, pneumonia, acute renal failure, and renal injury were rarely incident adverse events in the afatinib group. In conclusion, first- and second-line afatinib monotherapy improved the survival of patients with NSCLC, while second-line afatinib monotherapy could be promising for R/M HNSCC. The prospective protocol is in PROSPERO (ID = CRD42020204547).

Correlation of Mortality Burdens of Cerebrovascular Disease and Diabetes Mellitus with Domestic Consumption of Soya and Palm Oils.

BACKGROUND: Cerebrovascular diseases (CBVDs) and diabetes mellitus (DM) are interrelated and cumbersome global health burdens. However, the relationship between edible oils consumption and mortality burdens of CBVDs and DM has not yet been evaluated. This review aims to explore correlations between per capita mortality burdens of CBVDs and DM, as well as food consumption of palm or soya oils in 11 randomly selected countries in 2005, 2010, and 2016. METHODS: After obtaining data on food consumption of palm and soya oils and mortality burdens of CBVDs and DM, correlations between the consumption of oils and mortality burdens of diseases were explored. RESULTS: There was a positive correlation between the consumption of soya oil with the mortality burden of CBVDs in Australia, Switzerland, and Indonesia, as well as the mortality burden of DM in the USA. The consumption of palm oil had a positive correlation with the mortality burden of DM in Jordan only. CONCLUSIONS: Food consumption of soya oil in several countries possibly contributes to the mortality burden of CBVDs or DM more than food consumption of palm oil, which could be a possible risk factor in the mortality burdens of CBVDs and DM.

Safety and Neuroprotective Efficacy of Palm Oil and Tocotrienol-Rich Fraction from Palm Oil: A Systematic Review.

BACKGROUND: Several natural products have been reported to elicit beneficial effects against neurodegenerative disorders due to their vitamin E contents. However, the neuroprotective efficacy of palm oil or its tocotrienol-rich fraction (TRF) from the pre-clinical cell and animal studies have not been systematically reviewed. METHODS: The protocol for this systematic review was registered in "PROSPERO" (CRD42019150408). This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The Medical Subject Heading (MeSH) descriptors of PubMed with Boolean operators were used to construct keywords, including ("Palm Oil"[Mesh]) AND "Nervous System"[Mesh], ("Palm Oil"[Mesh]) AND "Neurodegenerative Diseases"[Mesh], ("Palm Oil"[Mesh]) AND "Brain"[Mesh], and ("Palm Oil"[Mesh]) AND "Cognition"[Mesh], to retrieve the pertinent records from PubMed, Scopus, Web of Science and ScienceDirect from 1990 to 2019, while bibliographies, ProQuest and Google Scholar were searched to ensure a comprehensive identification of relevant articles. Two independent investigators were involved at every stage of the systematic review, while discrepancies were resolved through discussion with a third investigator. RESULTS: All of the 18 included studies in this review (10 animal and eight cell studies) showed that palm oil and TRF enhanced the cognitive performance of healthy animals. In diabetes-induced rats, TRF and α-tocotrienol enhanced cognitive function and exerted antioxidant, anti-apoptotic and anti-inflammatory activities, while in a transgenic Alzheimer's disease (AD) animal model, TRF enhanced the cognitive function and reduced the deposition of ß-amyloid by altering the expression of several genes related to AD and neuroprotection. In cell studies, simultaneous treatment with α-tocotrienols and neurotoxins improved the redox status in neuronal cells better than ϒ- and δ-tocotrienols. Both pre-treatment and post-treatment with α-tocotrienol relative to oxidative insults were able to enhance the survival of neuronal cells via increased antioxidant responses. CONCLUSIONS: Palm oil and its TRF enhanced the cognitive functions of healthy animals, while TRF and α-tocotrienol enhanced the cognitive performance with attenuation of oxidative stress, neuroinflammation and apoptosis in diabetes-induced or transgenic AD animal models. In cell studies, TRF and α-tocotrienol exerted prophylactic neuroprotective effects, while α-tocotrienol exerted therapeutic neuroprotective effects that were superior to those of ϒ- and δ-tocotrienol isomers.

Prenatal developmental toxicity evaluation of Verbena officinalis during gestation period in female Sprague-Dawley rats.

Verbena officinalis is widely used by women for maintaining general health and treating various gynaecological disorders during pregnancy. A case report has indicated that the consumption of V. officinalis induced an abortifacient effect. Hence, this study aimed to investigate the prenatal developmental toxicity of this plant according to OECD guideline (no. 414). A total of 50 pregnant female rats (dams) were distributed into five groups (n = 10); 500 mg/kg 1000 mg/2000 mg/kg and 3000 mg/kg of V. offcinalis extracts and the fifth group served as a normal control. All dams received their respective oral single daily treatment from the 6th to the 20th day of gestation. Maternal clinical toxicity signs, body weight and weight gain were recorded. Caesarean sections were performed on day 21 to evaluate embryo-foetal developmental toxicity. For dams, ovaries were harvested and weighed. The number of corpora lutea, implantation sites, and resorptions were recorded. No mortality was observed in dams, but their body weight gain was significantly reduced particularly in dams treated with 2000 and 3000 mg/kg V. officinalis. Asymmetrical distribution of implantation sites and embryos were observed. Embryo-fetotoxicity retardation was observed as evident by the decrease in foetal weight, head cranium, tail length, and higher incidence in the pre-and post-implantation loss. Some foetal skeleton abnormalities such as incomplete ossification of skull, sternebrae, and metatarsal bones were observed in foetuses of the 2000 and 3000 mg/kg V. officinalis-treated dams. LC/MS analysis identified the major constituents including geniposidic acid, tuberonic acid glucoside, luteolin 7, 3'-digalacturonide, iridotrial and apigenin. The glycosylated flavonoids such as apigenin and luteolin could be responsible for the reported prenatal developmental toxicity. In conclusion, the use of V. officinalis during pregnancy is not safe indicating evidence-based toxic effects on the reproductive performance of dams and dose-dependent risk potentials to the foetuses.

Mutagenicity and genotoxicity effects of Verbena officinalis leaves extract in Sprague-Dawley Rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, Verbena officinalis L. has been used for reproductive and gynaecological purposes. However, the mutagenicity and genotoxicity of V. officinalis have not been extensively investigated. AIM OF THE STUDY: To assess the in vitro mutagenicity and in vivo genotoxicity of aqueous extract of V. officinalis leaves using a modified Ames test and rat bone marrow micronucleus assay according to OECD guidelines. MATERIALS AND METHODS: In vitro Ames test was carried out using different strains of Salmonella (TA97a, TA98, TA100, and TA1535) and Escherichia coli WP2 uvrA (pKM101) in the presence or absence of metabolic activation (S9 mixture). For micronucleus experiment, male and female Sprague-Dawley rats (n = 6/group) were received a single oral daily dose of 500, 1000, and 2000 mg/kg of V. officinalis extract for three days. Negative and positive control rats were received distilled water or a single intraperitoneal injection of 50 mg/kg of cyclophosphamide, respectively. Following dissection, femurs were collected and bone marrow cells were stained with May-Grünwald-Giemsa solution for micronucleus assessment. RESULTS: Ames test results demonstrated that 5, 2.5, 1.25 and 0.625 mg/ml of V. officinalis extract induced a significant mutagenic effect against TA100 and TA98 strains (with and without metabolic activation). Findings of the animal study showed there were no significant increase in the micronucleated polychromatic erythrocytes (MNPE) and no significant alterations in the polychromatic erythrocytes (PCE) to normochromatic erythrocytes (NCE) ratio of treated rats as compared with their negative control. Meanwhile, significantly increased in the MNPEs was seen in the cyclophosphamide-treated group only. CONCLUSION: Aqueous extract of V. officinalis has mutagenic effect against TA98 and TA100 strains as demonstrated by Ames test, however, there is no in vivo clastogenic and myelotoxic effect on bone marrow micronucleus of rats indicating that the benefits of using V. officinalis in traditional practice should outweigh risks.

Effect of Catha edulis (khat) on pancreatic functions in streptozotocin-induced diabetes in male Sprague-Dawley rats.

People consume Catha edulis (khat) for its euphoric effect, and type 1 diabetics have claimed that khat could reduce elevated levels of blood sugar. However, khat has been suggested to provoke diabetes mellitus through destruction of pancreatic ß-cells. This study investigated the effect of an ethanolic khat extract on pancreatic functions in type 1 diabetes (T1DM)-induced male Sprague-Dawley rats and to assess its in vitro cytotoxicity in rat pancreatic ß-cells (RIN-14B). T1DM was induced in a total of 20 rats with a single intraperitoneal injection of 75 mg/kg of streptozotocin. The rats were distributed into four groups (n=5): the diabetic control, 8 IU insulin-treated, 200 mg/kg khat-treated, and 400 mg/kg khat-treated groups. Another 5 rats were included as a nondiabetic control. Body weight, fasting blood sugar, and caloric intake were recorded weekly. Four weeks after treatment, the rats were sacrificed, and blood was collected for insulin, lipid profile, total protein, amylase, and lipase analysis, while pancreases were harvested for histopathology. In vitro, khat exerted moderate cytotoxicity against RIN-14B cells after 24 and 48 h but demonstrated greater inhibition against RIN-14B cells after 72 h. Neither 200 mg/kg nor 400 mg/kg of khat produced any significant reduction in blood sugar; however, 200 mg/kg khat extract provoked more destruction of pancreatic ß-cells as compared with the diabetic control. Ultimately, neither 200 mg/kg nor 400 mg/kg of khat extract could produce a hypoglycemic effect in T1DM-induced rats. However, 200 mg/kg of khat caused greater destruction of pancreatic ß-cells, implying that khat may cause a direct cytotoxic effect on pancreatic ß-cells in vitro.

Evaluation of the glycemic effect of Ceratonia siliqua pods (Carob) on a streptozotocin-nicotinamide induced diabetic rat model.

BACKGROUND: Ceratonia siliqua pods (carob) have been nominated to control the high blood glucose of diabetics. In Yemen, however, its antihyperglycemic activity has not been yet assessed. Thus, this study evaluated the in vitro inhibitory effect of the methanolic extract of carob pods against α-amylase and α-glucosidase and the in vivo glycemic effect of such extract in streptozotocin-nicotinamide induced diabetic rats. METHODS: 2,2-diphenyl-1-picrylhydrazyl (DPPH) and Ferric reducing antioxidant power assay (FRAP) were applied to evaluate the antioxidant activity of carob. In vitro cytotoxicity of carob was conducted on human hepatocytes (WRL68) and rat pancreatic ß-cells (RIN-5F). Acute oral toxicity of carob was conducted on a total of 18 male and 18 female Sprague-Dawley (SD) rats, which were subdivided into three groups (n = 6), namely: high and low dose carob-treated (CS5000 and CS2000, respectively) as well as the normal control (NC) receiving a single oral dose of 5,000 mg kg-1 carob, 2,000 mg kg-1 carob and 5 mL kg-1 distilled water for 14 days, respectively. Alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, creatinine and urea were assessed. Livers and kidneys were harvested for histopathology. In vitro inhibitory effect against α-amylase and α-glucosidase was evaluated. In vivo glycemic activity was conducted on 24 male SD rats which were previously intraperitoneally injected with 55 mg kg-1 streptozotocin (STZ) followed by 210 mg kg-1nicotinamide to induce type 2 diabetes mellitus. An extra non-injected group (n = 6) was added as a normal control (NC). The injected-rats were divided into four groups (n = 6), namely: diabetic control (D0), 5 mg kg-1glibenclamide-treated diabetic (GD), 500 mg kg-1 carob-treated diabetic (CS500) and 1,000 mg kg-1 carob-treated diabetic (CS1000). All groups received a single oral daily dose of their treatment for 4 weeks. Body weight, fasting blood glucose (FBG), oral glucose tolerance test, biochemistry, insulin and hemostatic model assessment were assessed. Pancreases was harvested for histopathology. RESULTS: Carob demonstrated a FRAP value of 3191.67 ± 54.34 µmoL Fe++ and IC50 of DPPH of 11.23 ± 0.47 µg mL-1. In vitro, carob was non-toxic on hepatocytes and pancreatic ß-cells. In acute oral toxicity, liver and kidney functions and their histological sections showed no abnormalities. Carob exerted an in vitro inhibitory effect against α-amylase and α-glucosidase with IC50 of 92.99 ± 0.22 and 97.13 ± 4.11 µg mL-1, respectively. In diabetic induced rats, FBG of CS1000 was significantly less than diabetic control. Histological pancreatic sections of CS1000 showed less destruction of ß-cells than CS500 and diabetic control. CONCLUSION: Carob pod did not cause acute systemic toxicity and showed in vitro antioxidant effects. On the other hand, inhibiting α-amylase and α-glucosidase was evident. Interestingly, a high dose of carob exhibits an in vivo antihyperglycemic activity and warrants further in-depth study to identify the potential carob extract composition.

Altered circulating concentrations of active glucagon-like peptide (GLP-1) and dipeptidyl peptidase 4 (DPP4) in obese subjects and their association with insulin resistance.

OBJECTIVES: Soluble DPP4 (sDPP4) is a novel adipokine that degrades glucagon-like peptide (GLP-1). We evaluated the fasting serum levels of active GLP-1 and sDPP4 in obese, overweight and normal weight subjects to assess the association between sDPP4 levels, active GLP-1 levels and insulin resistance in obese subjects. METHODS: The study involved 235 Malaysian subjects who were randomly selected (66 normal weight subjects, 97 overweight, 59 obese subjects, and 13 subjects who were underweight). Serum sDPP4 and active GLP-1 levels were examined by enzyme-linked immunosorbent assay (ELISA). Also, body mass index kg/m2 (BMI), lipid profiles, insulin and glucose levels were evaluated. Insulin resistance (IR) was estimated via the homeostasis model assessment for insulin resistance (HOMA-IR). RESULTS: Serum sDPP4 levels were significantly higher in obese subjects compared to normal weight subjects (p=0.034), whereas serum levels of active GLP-1 were lower (p=0.021). In obese subjects, sDPP4 levels correlated negatively with active GLP-1 levels (r2=-0.326, p=0.015). Furthermore, linear regression showed that sDPP4 levels were positively associated with insulin resistance (B=82.28, p=0.023) in obese subjects. CONCLUSION: Elevated serum sDPP4 levels and reduced GLP-1 levels were observed in obese subjects. In addition, sDPP4 levels correlated negatively with active GLP-1 levels but was positively associated with insulin resistance. This finding provides evidence that sDPP4 and GLP-1 may play an important role in the pathogenesis of obesity, suggesting that sDPP4 may be valuable as an early marker for the augmented risk of obesity and insulin resistance.

Khat (Catha edulis) and Obesity: A Scoping Review of Animal and Human Studies.

BACKGROUND: Khat (Catha edulis) is a plant that is deeply rooted in the cultural life of East African and Southwestern Arabian populations. Prevalent traditional beliefs about khat are that the plant has an effect on appetite and body weight. SUMMARY: This review assesses the accumulated evidences on the mutual influence of monoamines, hormones and neuropeptides that are linked to obesity. A few anti-obesity drugs that exert their mechanisms of action through monoamines are briefly discussed to support the notion of monoamines being a critical target of drug discovery for new anti-obesity drugs. Subsequently, the review provides a comprehensive overview of central dopamine and serotonin changes that are associated with the use of khat or its alkaloids. Then, all the studies on khat that describe physical, biochemical and hormonal changes are summarised and discussed in depth. CONCLUSION: The reviewed studies provide relatively acceptable evidence that different khat extracts or cathinone produces changes in terms of weight, fat mass, appetite, lipid biochemistry and hormonal levels. These changes are more pronounced at higher doses and long durations of intervention. The most suggested mechanism of these changes is the central action that produces changes in the physiology of dopamine and serotonin. Nonetheless, there are a number of variations in the study design, including species, doses and durations of intervention, which makes it difficult to arrive at a final conclusion about khat regarding obesity, and further studies are necessary in the future to overcome these limitations.

Conflicting reports on the role of the glycemic effect of Catha edulis (Khat): A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, the leaves of Catha edulis Forsskal (Khat) are consumed by the people of Yemen primarily for its recreational effect, and secondarily, for achieving certain tasks. Additionally, Yemeni diabetics chew such leaves in the belief that this can control their elevated blood glucose level. AIMS: This review focuses on outlining the findings of studies that have been conducted to display the glycemic effect of Catha edulis, while trying to balance it with findings of the association of its chewing with the development of type 2 diabetes mellitus (DM). MATERIALS AND METHODS: The search strategy adopted was based on a comprehensive research in Medline, PubMed, Web of Science, JSTOR, Scopus and Cochrane for articles, proceeding abstracts and theses to identify complete reports written in the English language about the glycemic effect of Catha edulis in humans and animals from 1976 to 2016. In addition, bibliographies were also reviewed to find additional reports not otherwise published. Thirty seven records were identified of which, 25 eligible studies were included in the meta-analysis using blood glucose as an outcome measurement. Studies were divided into four subgroups according to the experimental model, namely; non-diabetic animals, diabetic animals, non-diabetic humans and diabetic humans. The pooled mean difference (MD) of blood glucose between experimental and control were calculated using random effects model of the weighted mean difference of blood glucose with 95% confidence interval (CI). Heterogeneity between studies was tested using I(2) statistic and a value of P<0.05 was considered to indicate statistical significance. RESULTS: The scientific reports in the literature prevailed that the glycemic effect of Catha edulis were greatly conflicting with the majority of studies indicating that Catha edulis has a mild hypoglycemic effect. However, the meta-analysis indicted that the overall result showed an insignificant reduction in blood glucose (MD=-9.70, 95% CI: -22.17 to 2.76, P=0.13, with high heterogeneity between subgroups, I(2)=88.2%, P<0.0001). In addition, pooled mean difference of blood glucose of non-diabetic animals, diabetic animals and non-diabetic humans showed an insignificant reduction in blood glucose (MD=-18.55, 95% CI: -39.55 to 2.50, P<0.08, MD=-52.13%, 95% CI: -108.24 to 3.99, P=0.07 and MD=-2.71%, 95% CI: -19.19 to -13.77, P=0.75) respectively. Conversely, a significant elevation in the pooled mean difference of blood glucose in diabetic humans was indicated (MD=67.18, 95% CI: 36.93-97.43, P<0.0001). The conflict shown in the glycemic effect of Catha edulis is thought to be cultivar-related, while demographic and epidemiological reports suggested that chewing Catha edulis might be a predisposing factor contributing to the development of type 2 DM. CONCLUSION: It was difficult to draw a meaningful conclusion from both the systematic and the meta-analysis with respect to the glycemic effect of Catha edulis since the meta-analysis results were insignificant with high heterogeneity among subgroups and are greatly conflicting. The variation is most likely due to unadjusted experimental factors or is related to Catha edulis itself, such as the differences in the phytochemical composition. Therefore, it is highly recommended that further studies of the glycemic effect of the cultivar of Catha edulis being studied should come with the identification and quantification of phytochemical content so that a meaningful assessment can be made with regard to its hypoglycemic properties. In addition, well-controlled clinical studies should be conducted to confirm whether or not chewing Catha edulis is associated with the development of type 2 DM, since this would be a source of concern seeing that the plant is widely consumed in certain populations.

Apoptosis induction, cell cycle arrest and in vitro anticancer activity of gonothalamin in a cancer cell lines.

Cancer is one of the major health problems worldwide and its current treatments have a number of undesired adverse side effects. Natural compounds may reduce these. Currently, a few plant products are being used to treat cancer. In this study, goniothalamin, a natural occurring styryl-lactone extracted from Goniothalamus macrophyllus, was investigated for cytotoxic properties against cervical cancer (HeLa), breast carcinoma (MCF-7) and colon cancer (HT29) cells as well as normal mouse fibroblast (3T3) using MTT assay. Fluorescence microscopy showed that GTN is able to induce apoptosis in HeLa cells in a time dependent manner. Flow cytometry further revealed HeLa cells treated with GTN to be arrested in the S phase. Phosphatidyl serine properties present during apoptosis enable early detection of the apoptosis in the cells. Using annexin V/PI double staining it could be shown that GTN induces early apoptosis on HeLa cells after 24, 48 and 72 h. It could be concluded that goniothalamin showing a promising cytotoxicity effect against several cancer cell lines including cervical cancer cells (HeLa) with apoptosis as the mode of cell death induced on HeLa cells by Goniothalamin was.

Toxicological Features of Catha edulis (Khat) on Livers and Kidneys of Male and Female Sprague-Dawley Rats: A Subchronic Study.

Hepato- and nephrotoxicity of Khat consumption (Catha edulis Forskal) have been evoked. Therefore, this study was conducted to evaluate such possible hepatorenal toxicity in female and male Sprague-Dawley rats (SD rats) focusing primarily on liver and kidney. In addition, female and male rats were investigated separately. Accordingly, forty-eight SD-rats (100-120 g) were distributed randomly into four groups of males and female (n = 12). Normal controls (NCs) received distilled water, whereas test groups received 500 mg/kg (low dose (LD)), 1000 mg/kg (medium dose (MD)), or 2000 mg/kg (high dose (HD)) of crude extract of Catha edulis orally for 4 weeks. Then, physical, biochemical, hematological, and histological parameters were analyzed. Results in Khat-fed rats showed hepatic enlargement, abnormal findings in serum aspartate aminotransferase (AST), and alkaline phosphatase (ALP) of male and female SD-rats and serum albumin (A) and serum creatinine (Cr) of female as compared to controls. In addition, histopathological abnormalities confirmed hepatic and renal toxicities of Khat that were related to heavy Khat consumption. In summary, Khat could be associated with hepatic hypertrophy and hepatotoxicity in male and female SD-rats and nephrotoxicity only in female SD-rats.