(p)ppGpp binds to RNA polymerase, causing stalling at damaged DNA sites and subsequent backtracking, which facilitates the recognition and removal of damaged DNA by repair proteins. Additionally, (p)ppGpp regulates DNA repair proteins involved in the Save Our Soul response and mutagenic strand break repair pathways, which are crucial for repairing damages induced by Ultraviolet light and other DNA-damaging agents, including antibiotics. Through these repair pathways, (p)ppGpp plays a vital role in mending strand breaks induced by ciprofloxacin, a fluoroquinolone antibiotic. (p)ppGpp mediates bacterial survival by inhibiting the transcription of mismatch repair proteins while simultaneously upregulating error-prone polymerases mediated by stress-induced sigma factors, thereby facilitating mutagenesis. The function of (p)ppGpp in fine-tuning DNA repair proteins to support bacterial survival against antibiotics via stress-induced mutagenesis is an emerging topic in the field of antibiotic resistance research. Currently, limited information is available on how (p)ppGpp interconnects the various DNA repair pathways that directly influence bacterial resistance to antibiotics. (p)ppGpp is also known to promote bacterial persistence against ofloxacin, another fluoroquinolone, by regulating proteins that induce membrane depolarization. The overlapping functions of (p)ppGpp as a master regulator in DNA repair during stress and bacterial persistence are yet to be fully elucidated. This review focuses on recent publications highlighting (p)ppGpp as a potential link connecting DNA repair pathways to bacterial survival strategies against fluoroquinolone antibiotics.

Obesity has become a global epidemic affecting diverse populations and leading to metabolic syndrome across different sexes and age groups. A significant aspect of obesity is the development of leptin resistance, primarily due to the inefficient transport of leptin across the blood-brain barrier and other mechanisms such as protein folding and dysregulation of leptin signaling in brain areas related to energy and adipose tissue metabolism. This hindrance in leptin delivery poses a challenge to using this adipokine as a potential therapy for obesity. Current research focuses on understanding the complex molecular pathways that link diet-induced obesity, characterized by increased levels of leptin, to the onset of metabolic syndrome. This syndrome encompasses various health issues, including type 2 diabetes mellitus, and involves intricate mechanisms primarily affecting pancreatic β-cells. This bioinformatics-assisted review describes key biological elements of known pathways, such as the forkhead box protein O1/leptin receptor and Janus kinase/signal transducer and activator of transcription 3, and discusses future directions that might contribute to understanding the relationship between obesity, leptin resistance, and metabolic complications (e.g., Rac1/cell division control protein 42 homolog), paving the way for future research on targeted therapeutic interventions.

Yersinia pseudotuberculosis (Yptb) causes intestinal infection and can spread to the liver, where the bacterium induces hemosiderosis, abscesses, and hepatitis. To evade the immune response of the host organism, Yptb expresses at least six plasmid-encoded Yersinia outer proteins belonging to the Type III secretion system, which suppress phagocytic activity. Recently, evidence has accumulated that chromosome-encoded protein toxins are also involved in the anti-phagocytic defense of Yptb. Most of these toxins have been found in isolates from patients with Far East scarlet-like fever, often accompanied by liver pathology. Yersinia proteins contribute to bacterial colonization of lymphoid organs through their effects on immune cells. A thorough understanding of the immunomodulatory effects of these toxic proteins on bacterial dissemination and colonization in the liver will contribute to the development of novel approaches to cure hepatic pathology during Yptb infection. The review aimed to summarize the current data on the mechanisms of effects of Yptb plasmid- and chromosome-encoded toxins on bacterial colonization in the liver. The review highlights the fine-tuning of immune system activity by toxins encoded by both a 70-kb plasmid and chromosomes, through various mechanisms of action of individual proteins and their interactions. The focus is on mechanisms that promote bacterial survival in macrophages, including those that facilitate bacterial-induced macrophage polarization towards the M2 phenotype. The role of a type of phagocyte death in bacterial dissemination and colonization in the organs is also discussed.

With the improvement of living standards in recent years, up to 90% of obese patients have nonalcoholic fatty liver disease (NAFLD). The number of nonalcoholic steatohepatitis (NASH)-related deaths will gradually increase, and NASH is expected to be the most common cause of liver-related deaths in the future. Therefore, there is an urgent need to find effective and reliable serum biomarkers to distinguish simple hepatic steatosis (SS) from NASH. Liver cell regeneration, oxidative stress-induced DNA methylation, and biliary epithelial cell proliferation were reported to increase serum alpha-fetoprotein (AFP) levels. AFP has long been used as a tool to monitor liver cancer. However, the function of AFP in NAFLD, especially NASH, has not been clarified. Moreover, whether an elevated AFP level indicates the occurrence of NASH or serves as a serum biomarker remains to be elucidated. The miRNA-122 pathway, DNA methylation and DNA damage, and activation of resident stem cells and/or progenitor cells in the liver, as well as necrosis, regeneration, and repair of liver cells, may contribute to slight increases in AFP levels in the development of NASH in patients with NAFLD. Furthermore, mildly elevated AFP levels may indicate the development of NASH. This review explores the role of elevated AFP levels in the development of NASH, with a specific focus on the underlying molecular mechanisms and the clinical significance.

Diabetes mellitus (DM) is an established risk for biliary tract cancer (BTC). Metformin, an anti-diabetes medication, has been reported for its association with a reduced risk of BTC. However, the controversy about metformin’s benefit among epidemiological studies is unresolved. This study is to investigate metformin’s effects on the development and progression of BTC.

Literature searches were performed, without language restriction, in Pubmed, Embase, and Web of Science, from their respective inceptions to February 28, 2023. All studies were screened by two researchers using Covidence. Quality assessment was performed using the Newcastle-Ottawa Scale. Meta-analyses were performed by a fixed and random-effect model using RevMan version 5.4.

Nine observational studies met the inclusion criteria and were included in the meta-analysis. With pooled samples of 24,743,526 individuals from 4 case-control and 2 cohort studies, metformin was not associated with a decreased risk of BTC (pooled RR: 0.82, 95% CI: 0.42–1.59, p = 0.56). Sub-group analyses in each study design also revealed a null effect of metformin. Meta-analysis of 3 cohort studies reporting the association between metformin and survival of patients with BTC with a pooled sample of 1,163 patients showed a marginally significant effect of metformin on survival outcome improvement in both fixed effect models (pooled RR: 0.83, 95% CI: 0.68–1.00, p = 0.05), and random-effect model (pooled RR: 0.83, 95% CI: 0.68–1.01, p = 0.07).

Meta-analyses of available observational studies show that metformin was neither significantly associated with decreased risk nor, survival improvement for BTC patients who had DM.

Nonalcoholic fatty liver disease (NAFLD) has become one of the most common and important chronic liver diseases worldwide. Some chronic infectious diseases are associated with the risk of NAFLD. These can induce abnormal glucose and lipid metabolism, insulin resistance, inflammatory activation and other responses, which increase the risk of progression of liver fibrosis. The present study describes the pathogenesis and management of NAFLD with chronic infectious diseases, such as hepatitis B virus, hepatitis C virus, Helicobacter pylori, and human immunodeficiency virus infections.

Coconut oil (CO) has anti-oxidative effects due to its composition of phenolics and tocopherols. This study aims to investigate the effect of coconut oil (CO) on steatosis and oxidative stress in rats fed a high-fat diet.

Three groups of male Wistar rats were used: the control group (CG, n = 10) received a standard diet for 50 days, the hyperlipidic group (HL, n = 10) received a high-fat diet with 50% lard for 50 days, and the hyperlipidic-CO group (HL+CO, n = 10) received a high-fat diet with 50% lard for 30 days followed by 25% lard and 25% CO for 20 days. Then, the animals were euthanized, and their blood, liver, and adipose tissue were collected for biochemical analyses.

The groups that received a high-fat diet had pronounced liver steatosis. Compared to the CG and HL groups, the HL+CO group had less weight gain, but liver fat and triglycerides were increased, with a significant reduction in liver cholesterol. Glutathione increased significantly and vitamin E decreased in the livers of the experimental groups compared to the control. Lipid peroxidation in the serum and liver was less in the HL+CO group compared to that in the HL group, but it was higher than that in the control group. CO caused significant accumulation of hepatic fat, triglycerides, and fat content, despite decreasing the hepatic cholesterol levels. There was a better hepatic antioxidant response in the CO group, especially compared with the HL group.

CO does not prevent or improve hepatic steatosis in rats fed a high-fat diet, although CO improved their antioxidant profile. Additional clinical studies are necessary to verify the efficacy and safety of different CO doses on both hepatic and lipid metabolism.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the leading causes of hepatic fibrosis and liver-related mortality worldwide, despite efficient hepatitis B and C antiviral therapies that have dramatically lowered the disease load. Although significant efforts have been exerted to understand the molecular basis of disease pathogenesis, there are currently few therapeutic alternatives available for NAFLD-associated fibrosis. Thus, NAFLD prevention is critical before the development of disease-related complications. In this context, there is a tremendous substantial global burden on public health systems to actively search for effective preventive and therapeutic targets for NAFLD. In this review, we highlight the current strategies to prevent progression and poor outcomes of NAFLD and to avoid complications associated with disease fibrosis, notably cirrhosis, portal hypertension, and liver cancer. We discuss different nonpharmacological measures, such as lifestyle modifications (weight loss, exercise, healthy diet) and other pharmacological interventions that could prevent NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed countries, contributing to ∼24% of cases worldwide and includes non-alcoholic steatohepatitis. High-throughput OMICS approaches have been used to characterize NAFLD conditions for the identification of potential molecular signatures or differentially regulated molecules (DEMs). The present study aims to perform a systematic review and meta-analysis from an omics perspective.

We analyzed the publically available data set (accession number: GSE63067) from the Gene Expression Omnibus (GEO) using the GEO2R program. The differentially expressed genes (DEGs) were filtered using the criteria where genes with p-value ≤0.05 and fold-change ≥2.0-fold (upregulated), and fold-change ≤0.5-fold (downregulated).

We identified 264 differentially expressed genes (DEGs) between NAFLD and normal liver tissue samples, where 211 were upregulated and 53 were downregulated in NAFLD. Additionally, we identified novel genes sphingomyelin synthase 2 and WNK lysine deficient protein kinase 3 that were not well understood in the molecular pathophysiology of NAFLD. Further gene ontology-based analysis revealed that among biological processes, cellular components, and molecular functions were also dysregulated in NAFLD.

Our study shows that meta-analysis of publicly available data is useful for the identification of DEGs and indication of dysregulated biological processes in NAFLD, which provide valuable insights into the molecular mechanisms of NAFLD.