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The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats. [ABSTRACT FROM AUTHOR]

ABSTRACT: Background and Aim: Non-alcohol fatty liver disease (NAFLD) is a metabolic disorder that represents the hepatic manifestation of systemic process, and is a strong risk factor for diabetes Meletus, whereas the presence of DM increases the severity of NAFLD/NASH and its progression. Data on the impact of diabetes on NASH phenotype is sparse from northern India. We studied and compared the clinical profile of NALFD in the presence and absence of DM and the effect of diabetes on NASH. Methods: We did a cross-sectional analysis of data from NAFLD patients (n = 90) who were divided into diabetic and non-diabetic cohorts and their respective demographic, biochemical, imaging and histological features were recorded and compared. Results: Out of 90 patients, 53.3% were females with a mean age of 44 ± 12 years. The mean BMI and WHR of the study cohort were 28.9 ± 3.4 and 1.01 ± 0.15, respectively. The current study showed that 35.8% were diabetics. The mean age and WHR were 52 ± 11 years vs 40 ± 10 years and 1.1 ± 0.17 vs 0.99 ± 0.09, respectively, in diabetic and non-diabetic NAFLD patients. Non-invasive fibrosis scores, including BARD (2.8 vs 1.73), FIB-4 (3.4 vs 2.2) and NFS (0.97 vs −1.13), were significantly higher in diabetic NAFLD compared to non-diabetic NAFLD (P < 0.03). The histological grade of steatosis and fibrosis as depicted by the mean NAS score (5.7 ± 1.2 vs 4.63 ± 0.8) was higher in diabetic NAFLD vs non-diabetic NAFLD; however, only the fibrosis stage was statistically significant between the groups (P < 0.001). Conclusion: Despite the small no of cases, we should conclude that there is a bidirectional relationship between NAFLD and DM where the progression of one increases the rate of progression of other. Diabetic patients have higher risk of NASH and hence increased risk of liver related mortality and should be screened early for NAFLD/NASH. [ABSTRACT FROM AUTHOR]

During the last two decades, nonalcoholic fatty liver disease (NAFLD) has emerged as the most common hepatic disease in pediatrics, mainly owing to the rising prevalence of pediatric obesity. Epidemiological studies have shown that the progressive increase in NAFLD prevalence is associated not only with obesity but also with changes in dietary habits experienced by all age groups, characterized by the increased intake of added sugars and certain fatty acids. In this review article, we focus on the effect of oxidized fatty acids deriving from linoleic acid and arachidonic acid on the pathogenesis and progression of NAFLD in youth. [ABSTRACT FROM AUTHOR]

Introduction: Trimethylamine (TMA), produced by gut microbiota, is the precursor of trimethylamine-N-oxide (TMAO), a uremic toxin that accumulates in patients with chronic kidney disease (CKD). Elevated TMAO plasma levels are associated with cardiovascular complications and CKD progression., Objective: To evaluate the association between gut microbiota composition and TMAO plasma levels in CKD patients undergoing hemodialysis (HD)., Methods: This is a cross-sectional study with 25 patients evaluated (60% female, 53 (18) years, body mass index (BMI) 25.8 (6.75) Kg/m 2 ). They were divided into two groups according to their TMAO plasma levels: normal (≤ 7.4 μM) and high (> 7.4 μM). Uremic toxins such as indoxyl sulfate (IS), p-cresyl sulfate (pCS), and indol acetic acid (IAA) were measured with RP-HPLC, and TMAO plasma levels were quantified using LC-MS/MS. Fecal DNA was extracted with a commercial kit, PCR amplified the V4 region of the 16S rRNA gene, and short-read sequencing was performed on the Illumina platform. Dietary intake, anthropometric measurements, and inflammation markers were also evaluated. Nrf2, NF-κB, IL-1β, and NLRP3 mRNA expressions were measured from peripheral blood mononuclear cells (PBMC) using quantitative real-time polymerase chain reaction (qPCR)., Results: There were significant positive correlations between TMAO and plasma levels of pCS, NLPR3 inflammasome mRNA expression, serum phosphorus levels, and negative correlations with dietary lipid intake. The group with TMAO > 7.4 μM showed an increase in the microbiome abundance of Saccharibacteria (genus incertae sedis), Colidextribacter, Dorea, and Staphylococci genera, and a decrease in abundance in the genera Lachnospira, Lactobacilli, and Victivallis. TMAO plasma level was positively correlated with the abundance of bacteria of the genera Colidextribacter and Helicobacter and was negatively correlated with Sphingomanos, Lachnospira, Streptomyces, and Bacillus genera., Conclusion: Saccharibacteria (genus incertae sedis), Colidextribacter, Dorea, and Staphylococci genera showed higher abundance in patients with high TMAO levels. In addition, we observed that elevated plasma TMAO levels are associated with inflammation markers, dietary lipid intake, and serum phosphorus levels in patients undergoing HD., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Therapeutic resistance in cancer is responsible for numerous cancer deaths in clinical practice. While target mutations are well recognized as the basis of genetic resistance to targeted therapy, nontarget mutation resistance (or nongenetic resistance) remains poorly characterized. Despite its complex and unintegrated mechanisms in the literature, nongenetic resistance is considered from our perspective to be a collective response of innate or acquired resistant subpopulations in heterogeneous tumors to therapy. These subpopulations, e.g., cancer stem-like cells, cancer cells with epithelial-to-mesenchymal transition, and drug-tolerant persisters, are protected by their resistance traits at cellular and molecular levels. This review summarizes recent advances in the research on resistant populations and their resistance traits. NOTCH signaling, as a central regulator of nongenetic resistance, is discussed with a special focus on its canonical maintenance of resistant cancer cells and noncanonical regulation of their resistance traits. This novel view of canonical and noncanonical NOTCH signaling pathways is translated into our proposal of reshaping therapeutic strategies targeting NOTCH signaling in resistant cancer cells. We hope that this review will lead researchers to study the canonical and noncanonical arms of NOTCH signaling as an integrated resistant mechanism, thus promoting the development of innovative therapeutic strategies., Competing Interests: Compliance with ethics guidelines. Conflicts of interest Xianzhe Huang, Wenwei Chen, Yanyan Wang, Dmytro Shytikov, Yanwen Wang, Wangyi Zhu, Ruyi Chen, Yuwei He, Yanjia Yang, and Wei Guo declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee., (© 2024. Higher Education Press.)