Effective Inhibition of TNF-α/mTOR Axis-Mediated Liver Inflammation and Fibrosis Induced by TAA Using a Combination of Metformin and Resveratrol in Association with the Inhibition of the Profibrotic Gene and Protein Expression

SUMMARY: The response of the immune system to harmful stimuli leads to inflammation, and the adverse effects of the toxic hepatitis chemical, thioacetamide (TAA) on the human body are well documented. This article investigated the degree of protection provided by the combined pleotropic drug, metformin (Met) and the plant polyphenolic and the antiinflammatory compound, resveratrol (Res) on liver tissue exposed to TAA possibly via the inhibition of the inflammatory cytokine, tumor necrosis factor-α (TNF-α) / mammalian target of rapamycin (mTOR) axis-mediated liver fibrosis, as well as amelioration of profibrotic gene and protein expression. Rats were either given TAA (200 mg/kg via intraperitoneal injection) for 8 weeks beginning at the third week (experimental group) or received during the first two weeks of the experiment combined doses of metformin (200 mg/kg) and resveratrol (20 mg/kg) and continued receiving these agents and TAA until experiment completion at week 10 (treated group). A considerable damage to hepatic tissue in the experimental rats was observed as revealed by tissue collagen deposition in the portal area of the liver and a substantial increase (p<0.0001) in hepatic levels of the inflammatory marker, tumor necrosis factor-α (TNF-α), as well as blood levels of hepatocellular injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). TAA also augmented hepatic tissue levels of the signalling molecule that promotes liver fibrosis (mTOR), and profibrogenic markers; alpha-smooth muscle actin (α-SMA) protein, tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA, and matrix metalloproteinase-9 (MMP-9) mRNA. All these parameters were protected (p≤0.0016) by Met+Res. In addition, a significant correlation was detected between liver fibrosis score and inflammation, liver injury enzymes, mTOR, and profibrogenesis markers. Thus, these findings suggest that Met+Res effectively protect the liver against damage induced by thioacetamide in association with the downregulation of the TNF-α/mTOR/fibrosis axis.

La respuesta del sistema inmunológico a estímulos dañinos conduce a la inflamación y los efectos adversos de la tioacetamida (TAA), una sustancia química tóxica para el hígado, están bien documentadas. Este artículo investigó el grado de protección proporcionado por el fármaco pleotrópico combinado metformina (Met), el polifenólico vegetal y el compuesto antiinflamatorio resveratrol (Res) en el tejido hepático expuesto a TAA, posiblemente a través de la inhibición de la citoquina inflamatoria, factor de necrosis tumoral α (TNF-α)/objetivo de la fibrosis hepática mediada por el eje de rapamicina (mTOR), así como mejora de la expresión de genes y proteínas profibróticas. Las ratas recibieron TAA (200 mg/kg mediante inyección intraperitoneal) durante 8 semanas a partir de la tercera semana (grupo experimental) o recibieron durante las dos primeras semanas del experimento dosis combinadas de metformina (200 mg/kg) y resveratrol (20 mg/kg) y continuaron recibiendo estos agentes y TAA hasta completar el experimento en la semana 10 (grupo tratado). Se observó un daño considerable al tejido hepático en las ratas experimentales, como lo revela el depósito de colágeno tisular en el área portal del hígado y un aumento sustancial (p<0,0001) en los niveles hepáticos del marcador inflamatorio, el factor de necrosis tumoral-α (TNF- α), así como los niveles sanguíneos de biomarcadores de lesión hepatocelular, alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST). TAA también aumentó los niveles en el tejido hepático de la molécula de señalización que promueve la fibrosis hepática (mTOR) y marcadores profibrogénicos; proteína actina del músculo liso alfa (α- SMA), inhibidor tisular de las metaloproteinasas-1 (TIMP-1) mRNA y matriz metaloproteinasa-9 (MMP-9) mRNA. Todos estos parámetros fueron protegidos (p≤0.0016) por Met+Res. Además, se detectó una correlación significativa entre la puntuación de fibrosis hepática y la inflamación, las enzimas de lesión hepática, mTOR y los marcadores de profibrogénesis. Por lo tanto, estos hallazgos sugieren que Met+Res protege eficazmente el hígado contra el daño inducido por la tioacetamida en asociación con la regulación negativa del eje TNF-α/mTOR/fibrosis.

Accuracy of Neutrophil-to-Lymphocyte Ratio in Predicting the Severity of Acute Appendicitis: A Single-Center Retrospective Study.

OBJECTIVE:  Investigate the potential use of the neutrophil-to-lymphocyte ratio (NLR) in the identification and differentiation of acute appendicitis patients, specifically between simple and complicated presentations. METHODS:  An observational retrospective cohort study was conducted in Aseer Central Hospital, Saudi Arabia. RESULTS: In total, 103 patients were included in this study, in which males (50.5%) were more common than females (49.5%), and the most common age group was found to be 36-45 years (56.3%), followed by 18-25 years (23.3%). All patients (100%) had a diagnosis of acute appendicitis. The means of neutrophils, lymphocytes, and NLR were found to be 68.970%, 22.067%, and 5.020, respectively. The majority (69%) had non-complicated appendicitis, while (31%) had complications. A significant association was seen between NLR and the occurrence of complications (p-value = 0.00001). CONCLUSION: This study can comprehensively support the evidence presented in the literature review. The use of the NLR demonstrates a notable level of accuracy in diagnosing acute appendicitis and differentiating between complex and uncomplicated cases.

A Study of Misconceptions About Appendicitis Among the Resident Population of the Aseer Region.

BACKGROUND: Appendicitis is a common abdominal emergency requiring swift medical intervention. Misconceptions about this condition can lead to delayed diagnosis and potentially life-threatening complications. In the Aseer region of Saudi Arabia, where healthcare accessibility and awareness levels vary, addressing such misconceptions is of paramount importance. The aim of this study is to investigate and identify the prevalent misconceptions regarding appendicitis among the resident population of the Aseer region. Understanding the prevalent misconceptions and knowledge gaps is essential to develop targeted educational interventions and enhance public awareness. METHODS: This study utilized a cross-sectional study design to investigate misconceptions about appendicitis among residents in the Aseer region. Over a period of three months, 329 Aseer region resident population were interviewed. The symptoms, causes, diagnosis, treatment, and preventive measures of appendicitis were all covered in a questionnaire that was created to gather information on people's knowledge of appendicitis. Data were collected using an online questionnaire. Descriptive analysis was performed using frequencies and percentages, while inferential analysis employed appropriate statistical tests such as chi-square. RESULTS:  The study's 329 participants were made up of 56% men and 44% women. 40% of the sample size was between the ages of 18 and 30, 26% were between the ages of 31 and 40, 15% were between the ages of 41 and 50, and 10% were above 50 years, with those under the age of 18 years accounting for the smallest proportion (9%). The majority of the respondents (37%) were college graduates, 25% were college students, 23% were in high school and 15% were in middle school. Chi-square tests were conducted to examine the associations between background knowledge and pain area, as well as between background knowledge and source of information. For the association between background knowledge and pain area, the Chi-square test yielded a significant result (X² = 9.104, p = 0.028); the Chi-square test also revealed a significant result (X² = 8.078, p = 0.044) between background knowledge and the source of information about appendicitis. CONCLUSION: The analysis suggests a notable knowledge gap among the participants, with a significant portion displaying limited understanding or responding with "I don't know" when queried about appendicitis. It is important to note that this observation includes middle school students, who may be too young to be expected to possess knowledge about medical conditions. Additionally, there appears to be gender-related variation in opinions, misconceptions, and understanding regarding appendicitis.

Drainage vs. non-drainage after cholecystectomy for acute cholecystitis: a retrospective study.

Many surgeons practice prophylactic drainage after cholecystectomy without reliable evidence. This study was conducted to answer the question whether to drain or not to drain after cholecystectomy for acute calculous cholecystitis. A retrospective review of all patients who had cholecystectomy for acute cholecystitis in Aseer Central Hospital, Abha, Saudi Arabia, was conducted from April 2010 to April 2012. Data were extracted from hospital case files. Preoperative data included clinical presentation, routine investigations and liver function tests. Operative data included excessive adhesions, bleeding, bile leak, and drain insertion. Complicated cases such as pericholecystic collections, mucocele and empyema were also reported. Patients who needed therapeutic drainage were excluded. Postoperative data included hospital stay, volume of drained fluid, time of drain removal, and drain site problems. The study included 103 patients allocated into two groups; group A (n  =  38) for patients with operative drain insertion and group B (n  =  65) for patients without drain insertion. The number of patients with preoperative diagnosis of acute non-complicated cholecystitis was significantly greater in group B (80%) than group A (36.8%) (P < 0.001). Operative time was significantly longer in group A. All patients who were converted from laparoscopic to open cholecystectomy were in group A. Multivariate analysis revealed that hospital stay was significantly (P < 0.001) longer in patients with preoperative complications. There was no added benefit for prophylactic drain insertion after cholecystectomy for acute calculous cholecystitis in non-complicated or in complicated cases.