Explore the vast range of titles available.

Damaged hyaline cartilage has no capacity for self-healing, making osteoarthritis (OA) “difficult-to-treat”. Cartilage destruction is central to OA patho-etiology and is mediated by matrix degrading enzymes. Here we report decreased expression of miR-17 in osteoarthritic chondrocytes and its deficiency contributes to OA progression. Supplementation of exogenous miR-17 or its endogenous induction by growth differentiation factor 5, effectively prevented OA by simultaneously targeting pathological catabolic factors including matrix metallopeptidase-3/13 (MMP3/13), aggrecanase-2 (ADAMTS5), and nitric oxide synthase-2 (NOS2). Single-cell RNA sequencing of hyaline cartilage revealed two distinct superficial chondrocyte populations (C1/C2). C1 expressed physiological catabolic factors including MMP2, and C2 carries synovial features, together with C3 in the middle zone. MiR-17 is highly expressed in both superficial and middle chondrocytes under physiological conditions, and maintains the physiological catabolic and anabolic balance potentially by restricting HIF-1α signaling. Together, this study identified dual functions of miR-17 in maintaining cartilage homeostasis and prevention of OA. Osteoarthritic (OA) is characterized by progressive destruction of joint cartilage. Here, the authors show that microRNA-17 plays a dual role in maintaining cartilage homeostasis and in the prevention of osteoarthritis, by targeting hypoxia-inducible factor-1α as well as multiple matrix-degrading enzymes.

PUMILIO (PUM) proteins belong to the highly conserved PUF family post-transcriptional regulators involved in diverse biological processes. However, their function in carcinogenesis remains under-explored. Here, we report that Pum1 and Pum2 display increased expression in human colorectal cancer (CRC). Intestine-specific knockout of Pum1 and Pum2 in mice significantly inhibits the progression of colitis-associated cancer in the AOM/DSS model. Knockout or knockdown of Pum1 and/or Pum2 in human CRC cells result in a significant decrease in the tumorigenicity and delayed G1/S transition. We identify p21/Cdkn1a as a direct target of PUM1. Abrogation of the PUM1 binding site in the p21 mRNA also results in decreased cancer cell growth and delayed G1/S transition. Furthermore, intravenous injection of nanoparticle-encapsulated anti- Pum1 and Pum2 siRNAs reduces colorectal tumor growth in murine orthotopic colon cancer models. These findings reveal the requirement of PUM proteins for CRC progression and their potential as therapeutic targets. RNA binding proteins can contribute to colorectal cancer (CRC) initiation and development. Here the authors show that PUMILIO proteins, PUM1 and PUM2 contribute to CRC growth by inhibiting p21 expression.

Targeted cancer therapy aims to achieve specific elimination of cancerous but not normal cells. Recently, PIWI proteins, a subfamily of the PAZ-PIWI domain (PPD) protein family, have emerged as promising candidates for targeted cancer therapy. PPD proteins are essential for small noncoding RNA pathways. The Argonaute subfamily partners with microRNA and small interfering RNA, whereas the PIWI subfamily partners with PIWI-interacting RNA (piRNA). Both PIWI proteins and piRNA are mostly expressed in the germline and best known for their function in transposon silencing, with no detectable function in mammalian somatic tissues. However, PIWI proteins become aberrantly expressed in multiple types of somatic cancers, thus gaining interest in targeted therapy. Despite this, little is known about the regulatory mechanism of PIWI proteins in cancer. Here we report that one of the four PIWI proteins in humans, PIWIL1, is highly expressed in gastric cancer tissues and cell lines. Knocking out the PIWIL1 gene (PIWIL1-KO) drastically reduces gastric cancer cell proliferation, migration, metastasis, and tumorigenesis. RNA deep sequencing of gastric cancer cell line SNU-1 reveals that KO significantly changes the transcriptome, causing the up-regulation ofmost of its associated transcripts. Surprisingly, few bona fide piRNAs exist in gastric cancer cells. Furthermore, abolishing the piRNA-binding activity of PIWIL1 does not affect its oncogenic function. Thus, PIWIL1 function in gastric cancer cells is independent of piRNA. This piRNA-independent regulation involves interaction with the UPF1-mediated nonsense-mediated mRNA decay (NMD) mechanism. Altogether, our findings reveal a piRNA-independent function of PIWIL1 in promoting gastric cancer.

Trace elements play important roles in human health, but little is known about their functions in humoral immunity. Here, we show an important role for iron in inducing cyclin E and B cell proliferation. We find that iron-deficient individuals exhibit a significantly reduced antibody response to the measles vaccine when compared to iron-normal controls. Mice with iron deficiency also exhibit attenuated T-dependent or T-independent antigen-specific antibody responses. We show that iron is essential for B cell proliferation; both iron deficiency and α-ketoglutarate inhibition could suppress cyclin E1 induction and S phase entry of B cells upon activation. Finally, we demonstrate that three demethylases, KDM2B, KDM3B and KDM4C, are responsible for histone 3 lysine 9 (H3K9) demethylation at the cyclin E1 promoter, cyclin E1 induction and B cell proliferation. Thus, our data reveal a crucial role of H3K9 demethylation in B cell proliferation, and the importance of iron in humoral immunity. The authors show an important role for iron in B cell proliferation via histone 3 lysine 9 (H3K9) demethylation at the cyclin E1 promoter. Using a measles vaccination murine model, they show that iron-deficient individuals have a significantly reduced antibody response to the vaccine when compared to iron-normal controls.

BackgroundCrohn’s disease (CD) is a chronic inflammatory disorder characterised by intestinal dysbiosis. While inflammation-induced leakage of host proteins is a known phenomenon in CD, how these proteins affect the gut microbiota and contribute to dysbiosis remains unclear. One hypothesis is that commensal bacteria hijack these proteins, exacerbating inflammation in CD.DesignTo investigate host-microbiota interactions in CD, we measured fatty acid-binding protein 2 (FABP2) levels in patients with CD and in mouse models of dextran sulfate sodium induced enteritis and interleukin 10 knockout spontaneous enteritis. Proteomic approaches, including bacterial pull-down and mass spectrometry, were employed to identify commensal targets of FABP2. Functional studies were conducted using wild type and EF3041-deficient Enterococcus faecalis strains, along with α-FABP2 antibody treatment, to assess their effects on intestinal inflammation and microbiota composition.ResultsFABP2 levels were elevated in plasma and faeces of patients with CD, as well as in the mouse models. This was accompanied by dysbiosis of gut commensal bacteria. E. faecalis hijacked luminal FABP2 to promote its proliferation via pheromone-binding protein EF3041, which activated quorum-sensing pathways. Deletion of EF3041 abolished this response, while complementation with EF3041 restored it. Injection of α-FABP2 antibody or transplantation of ΔEF3041 mutant strain significantly reduced epithelial damage, mitigated dysbiosis and alleviated inflammation and symptoms of enteritis in mice.ConclusionThis study reveals a novel mechanism by which commensal bacteria use host-derived FABP2 to drive dysbiosis and worsen CD pathology. Targeting the FABP2-EF3041 axis may offer new diagnostic and therapeutic avenues for managing CD.

Sepsis is defined as “a life‐threatening organ dysfunction caused by dysregulated host systemic inflammatory and immune response to infection.” At present, sepsis continues to pose a grave healthcare concern worldwide. Despite the use of supportive measures in treating traditional sepsis, such as intravenous fluids, vasoactive substances, and oxygen plus antibiotics to eradicate harmful pathogens, there is an ongoing increase in both the morbidity and mortality associated with sepsis during clinical interventions. Therefore, it is urgent to design specific pharmacologic agents for the treatment of sepsis and convert them into a novel targeted treatment strategy. Herein, we provide an overview of the molecular mechanisms that may be involved in sepsis, such as the inflammatory response, immune dysfunction, complement deactivation, mitochondrial damage, and endoplasmic reticulum stress. Additionally, we highlight important targets involved in sepsis‐related regulatory mechanisms, including GSDMD, HMGB1, STING, and SQSTM1, among others. We summarize the latest advancements in potential therapeutic drugs that specifically target these signaling pathways and paramount targets, covering both preclinical studies and clinical trials. In addition, this review provides a detailed description of the crosstalk and function between signaling pathways and vital targets, which provides more opportunities for the clinical development of new treatments for sepsis. In this review, we describe the possible pathogenesis of sepsis, summarize the main regulatory pathways that intervene in sepsis and the main regulatory target proteins of sepsis, and the recent exploration of the main intervention molecules in sepsis.

Background Immunotherapy is becoming a standard of care for non-small cell lung cancer (NSCLC). Checkpoint inhibitor-associated pneumonia (CIP) is a rare and potentially life-threatening event that can occur at any time during tumor immunotherapy. However, there may be differences in the radiological patterns and prognosis of CIP during different periods. This study aimed to investigate the radiographic features and prognosis of early- and late-onset immune-related pneumonitis. Methods We retrospectively analyzed the clinical data of 677 NSCLC patients receiving immunotherapy to identify 32 patients with CIP, analyzed the clinical and radiographic data, and summarized the radiological features and prognosis of early- and late-onset CIP. Results CIP had an incidence of 4.7%, a median onset time of 10 weeks, and a mortality of 28.1%. Among these, CIP included 14 early-onset cases, where grade ≥ 3 CIP accounted for 92.9%, main radiographic pattern was organizing pneumonia (OP)-like pattern, and mortality was 50.0%. We also identified 18 late-onset CIPs, where grade ≥ 3 CIP accounted for 50.0%, main radiographic pattern was nonspecific interstitial pneumonia (NSIP)-like pattern, and mortality was 11.1%. The overall survival rate of the early-onset group was significantly lower than that of the late-onset group ( P  < 0.05). Conclusion Early-onset CIP cases were higher in the Common Terminology Criteria for Adverse Events (CTCAE v5.0) grade and mainly presented with an OP-like radiographic pattern; whereas, late-onset CIP cases were lower in CTCAE grade and mainly presented with an NSIP-like radiographic pattern. Finally, the prognosis of the early-onset CIP group was poorer than that of the late-onset CIP group. We believe that this study will be helpful for clinicians for making early diagnosis and deciding treatment modalities for patients with CIP.

Background Endometriosis is a crippling, ongoing, chronic inflammatory condition. The management of these patients has been impacted by the current COVID-19 pandemic, which is still controversial. This study compared the clinical therapy outcomes and psychological scores between before and during- the epidemic. Method The data of patients who were diagnosed with endometriosis in the Department of Gynecology, Chongqing Traditional Chinese Medicine Hospital from January 2018 to December 2022 were collected. The patients were divided into pre- and intra-COVID groups. The treatment results and psychological status of the two groups were compared. Results A total of 1022 patients with endometriosis were enrolled, with a mean age of 33.16 ± 9.81 years and a BMI of 23.90 ± 3.04 kg/m 2 , of which 434 cases (434/1022, 42.5%) were in the pre-COVID group and 588 cases (588/1022, 57.5%) in the intra-COVID group. Both groups were well balanced for age, BMI, history of abdominopelvic surgery, family relationships, education level, and duration between initial diagnosis and admission. Compared to the Pre-COVID group, the intra-COVID group had a higher proportion of patients with chronic pelvic pain (297/434, 68.4% vs. 447/588, 76.0%, p = 0.007) and dysmenorrhea (249/434, 62.8% vs. 402/588, 70.0%, p < 0.001), more patients requiring surgery (93/434, 21.4% vs. 178/588, 30.3%, p = 0.002) and longer hospital stays (5.82 ± 2.24 days vs. 7.71 ± 2.15 days, p < 0.001). A total of 830 questionnaires were completed. In the Intra-COVID group, PHQ-2 (2 (2, 3) vs. 3 (2,4), p < 0.001), GAD-2 (2 (1, 2) vs. 3 (2, 3), p < 0.001), PHQ-4 (4 (3, 5) vs. 5 (4, 7), EHP-5 (20.26 ± 6.05 vs. 28.08 ± 7.95, p < 0.001) scores were higher than that in the pre-COVID group, while BRS (3.0 (2.2, 4.0) vs. 2.4 (1.8, 3.8), p = 0.470) were not significantly different. Conclusion During the COVID-19 epidemic, patients with endometriosis may have reduced visits to the hospital, more severe related symptoms, longer length of hospital stays, and worse quality of life, with the possible cause being a disturbance in hormone levels through increased anxiety and depression. This provides a valid clinical basis for optimizing the management of patients with endometriosis and for early psychological intervention during the epidemic.

Chronic inflammation promotes the tumorigenesis and cell stemness maintenance of colorectal cancer (CRC). However, the bridge role of long noncoding RNA (lncRNA) in linking chronic inflammation to CRC development and progression needs better understanding. Here, we elucidated a novel function of lncRNA GMDS-AS1 in persistently activated signal transducer and transcription activator 3 (STAT3) and Wnt signaling and CRC tumorigenesis. Interleukin-6 (IL-6) and Wnt3a induced lncRNA GMDS-AS1 expression, which was highly expressed in the CRC tissues and plasma of CRC patients. GMDS-AS1 knockdown impaired the survival, proliferation and stem cell-like phenotype acquisition of CRC cells in vitro and in vivo. We performed RNA sequencing (RNA-seq) and mass spectrometry (MS) to probe target proteins and identify their contributions to the downstream signaling pathways of GMDS-AS1. In CRC cells, GMDS-AS1 physically interacted with the RNA-stabilizing protein HuR, thereby protecting the HuR protein from polyubiquitination- and proteasome-dependent degradation. HuR stabilized STAT3 mRNA and upregulated the levels of basal and phosphorylated STAT3 protein, persistently activating STAT3 signaling. Our research revealed that the lncRNA GMDS-AS1 and its direct target HuR constitutively activate STAT3/Wnt signaling and promote CRC tumorigenesis, the GMDS-AS1-HuR-STAT3/Wnt axis is a therapeutic, diagnostic and prognostic target in CRC.