Particulate matter exposure has been known as a potential risk for the global burden of disease, such as respiratory and cardiovascular diseases. Accumulating evidence suggests that PM2.5 (particulate matter with a diameter less than 2.5 μm) is associated with increased risk of kidney disease, but the mechanisms underlying the renal injury caused by PM2.5 remain to be elucidated. This study investigated the effects of PM2.5 on human proximal tubular epithelial (HK-2) cells by monolayer and 3D spheroid cultures and explored the potential mechanisms. The typical morphology of HK-2 cells showed epithelial–mesenchymal transition (EMT), resulting in reduced adhesion and enhanced migration after PM2.5 exposure, and was accompanied by decreased E-cadherin expression and increased vimentin and α-SMA expressions. Exposure to PM2.5 in the HK-2 cells could lead to an increase in interleukin-6 (IL-6) levels and cause the activation of signal transducer and activator of transcription 3 (STAT3), which is involved in EMT features of HK-2 cells. Furthermore, blocking IL-6/STAT3 signaling by an IL-6 neutralizing antibody or STAT3 inhibitor was sufficient to reverse PM2.5-induced EMT characteristics of the HK-2 cells. Our study suggests that PM2.5 could induce early renal tubule cell injury, contributing to EMT change, and the induction of IL-6/STAT3 pathway may play an important role in this process.

The tripartite motif-containing protein 28 (TRIM28) is a transcription corepressor, interacting with histone deacetylase and methyltransferase complexes. TRIM28 is a crucial regulator in development and differentiation. We would like to investigate its function and regulation in adipogenesis. Knockdown of Trim28 by transducing lentivirus-carrying shRNAs impairs the differentiation of 3T3-L1 preadipocytes, demonstrated by morphological observation and gene expression analysis. To understand the molecular mechanism of Trim28-mediated adipogenesis, the RNA-seq was performed to find out the possible Trim28-regulated genes. Dlk1 (delta-like homolog 1) was increased in Trim28 knockdown 3T3-L1 cells both untreated and induced to differentiation. Dlk1 is an imprinted gene and known as an inhibitor of adipogenesis. Further knockdown of Dlk1 in Trim28 knockdown 3T3-L1 would rescue cell differentiation. The epigenetic analysis showed that DNA methylation of Dlk1 promoter and differentially methylated regions (DMRs) was not altered significantly in Trim28 knockdown cells. However, compared to control cells, the histone methylation on the Dlk1 promoter was increased at H3K4 and decreased at H3K27 in Trim28 knockdown cells. Finally, we found Trim28 might be recruited by transcription factor E2f1 to regulate Dlk1 expression. The results imply Trim28-Dlk1 axis is critical for adipogenesis.

Short noncoding endogenous RNAs, including microRNAs (miRNAs), are associated with the development and metastasis of multiple cancers. Epigallocatechin gallate (EGCG), the most active and abundant polyphenol in green tea, plays a crucial role in the modulation of miRNA expression, which is related to changes in cancer progression. In the present study, we explore whether EGCG exerts its suppressive effects on nasopharyngeal carcinoma (NPC) cells through miRNA regulation. The anoikis-resistant sphere-forming NPC cells grown under anchorage-independent conditions exhibit enhanced migratory properties, which were inhibited by EGCG treatment. The miR-296 level was lower in the anoikis-resistant cells than in the monolayer parental cells; however, miR-296 was significantly upregulated after EGCG treatment. We demonstrate that miR-296 is involved in the inhibitory effects of EGCG on the anoikis-resistant NPC cells through the downregulation of signal transducer and activator of transcription 3 (STAT3) activation. Our study is the first to demonstrate that EGCG inhibited the migratory properties of anoikis-resistant cells by modulating the expression of miRNA in NPC cells. Our results indicate the novel effects of EGCG on miRNA regulation to inhibit an invasive phenotype of NPC as well as the regulatory role of miR-296.

With advances in the understanding of characteristics of molecules, specific antigens on the surface of hematological malignant cells were identified and multiple therapies targeting these antigens as neoplasm treatments were developed. Among them, chimeric antigen receptor (CAR) T-cell therapy, which got United States Food and Drug Administration (FDA) approval for relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) as well as for recurrent acute lymphoblastic leukemia (ALL) within the past five years, and for r/r mantle cell lymphoma (MCL) this year, represents one of the most rapidly evolving immunotherapies. Nevertheless, its applicability to other hematological malignancies, as well as its efficacy and persistence are fraught with clinical challenges. Currently, more than one thousand clinical trials in CAR T-cell therapy are ongoing and its development is changing rapidly. This review introduces the current status of CAR T-cell therapy in terms of the basic molecular aspects of CAR T-cell therapy, its application in hematological malignancies, adverse reactions during clinical use, remaining challenges, and future utilization.

Objectives This study aimed to evaluate the real-world effectiveness of tofacitinib for treating moderate-to-severe ulcerative colitis (UC). Design Systematic review and meta-analysis. Data sources PubMed, EMBASE and Cochrane CENTRAL databases were searched from inception up to 18 July 2023. Reference lists of included studies were manually searched to identify potentially relevant studies not found in the databases. Eligibility criteria Eligible studies included real-world observational studies, reported in English, on patients with moderate-to-severe UC treated with tofacitinib, defined by the Partial Mayo Score. Excluded were clinical trials, reviews, letters, conference abstracts, case reports and studies involving patients with mixed Crohn’s disease. Data extraction and synthesis Two independent reviewers extracted data and recorded it in Excel. Quality assessment was performed using the Newcastle-Ottawa scale. Meta-analysis was performed using random-effects models due to high heterogeneity across studies. Results 19 studies containing a total of 2612 patients were included. Meta-analysis revealed that clinical response rates were 58% at week 8, 61% at weeks 12–16, 51% at weeks 24–26 and 51% at week 52. Clinical remission rates were 39% at week 8, 43% at weeks 12–16, 40% at weeks 24–26 and 43% at week 52. Corticosteroid-free clinical remission rates were 33% at week 8, 37% at weeks 12–16, 32% at weeks 24–26 and 40% at week 52. Conclusion This meta-analysis of real-world studies indicates that treatment of UC with tofacitinib is associated with favourable clinical response and remission rates in the induction and maintenance phases.

Maintaining mesothelial cell viability is critical to long-term successful peritoneal dialysis (PD) treatment. To clarify the viability mechanism of peritoneal mesothelial cells under PD solutions exposure, we examined the mechanisms of cellular response to this stress conditions. Here we report that the proteasome activity is inhibited when treated with PD solutions. Proteasome inhibition-mediated activation of salt-inducible kinase 2 (SIK2), an endoplasmic reticulum-resident protein, is important for mesothelial cell viability. SIK2 is mobilized to promote autophagy and protect the cells from apoptosis under PD solution or MG132 treatment. Immunofluorescence staining showed that SIK2 is colocalized with LC3B in the autophagosomes of mesothelial cells treated with PD solution or derived from patients undergoing PD treatment. SIK2 activation is likely via a two-step mechanism, upstream kinases relieving the autoinhibitory conformation of SIK2 molecule followed by autophosphorylation of Thr175 and activation of kinase activity. These results suggest that activation of SIK2 is required for the cell viability when proteasome activity is inhibited by PD solutions. Maintaining or boosting the activity of SIK2 may promote peritoneal mesothelial cell viability and evolve as a potential therapeutic target for maintaining or restoring peritoneal membrane integrity in PD therapy.