BACKGROUND:Arthritis represents a spectrum of chronic inflammatory conditions, with growing evidence linking metabolic dysregulation to disease pathogenesis. While composite metabolic indices have been proposed as potential markers for arthritis, their associations with specific disease subtypes and applicability across diverse ethnic populations remain insufficiently characterized. METHODS:This study analyzed data from 15,015 participants in the U.S. National Health and Nutrition Examination Survey (NHANES) and 3848 subjects from a Chinese hospital-based cohort. Associations between triglyceride-glucose (TyG) index/TyG-body mass index (TyG-BMI) and arthritis subtypes (osteoarthritis [OA], rheumatoid arthritis [RA], and gout) were assessed using multiple logistic regression and restricted cubic splines (RCS) with adjustment for age and gender. Mediation analysis evaluated the role of the systemic immune-inflammation index (SII). Predictive performance was compared using area under the curve (AUC). RESULTS:Elevated TyG and TyG-BMI were significantly associated with higher odds of multiple arthritis subtypes in both cohorts. In NHANES, the highest TyG quartile was linked to 26%-64% higher odds compared with the lowest quartile, while TyG-BMI showed stronger associations (ORs 2.25-2.76). Similarly, TyG-BMI was strongly associated with RA (OR = 4.77) and gout (OR = 5.46) in the Chinese cohort. Dose-response analyses confirmed significant nonlinear positive relationships between TyG/TyG-BMI levels and arthritis risk. Systemic inflammation mediated a substantial proportion of these associations (all p < 0.05). Predictive performance differed ethnically: TyG-BMI performed best in the U.S. cohort (AUCs 0.599-0.617), whereas the TyG index was superior in the Chinese cohort (AUCs 0.647-0.719). CONCLUSIONS:This cross-population study demonstrates that TyG and TyG-BMI indices are positively and dose-dependently associated with multiple arthritis subtypes, with systemic inflammation serving as a partial mediator. These findings underscore the utility of TyG and TyG-BMI indices in identifying at-risk individuals for targeted early intervention and personalized management of arthritis.
Myocarditis is characterized by inflammatory cell infiltration and myocardial injury, yet current treatments remain largely empirical and nonspecific. Given the heart's high energy demand and the essential role of mitochondria in cellular metabolism, investigating mitochondria-related genes may provide novel therapeutic insights. In this study, we integrated bulk RNA sequencing data from CVB3 viral myocarditis (VMC) model with mitochondrial gene sets from MitoCarta3.0 and human myocarditis-related genes from GeneCards. Through comprehensive bioinformatics analyses, including weighted gene coexpression network analysis (WGCNA), random forest (RF), and SHapley Additive exPlanations (SHAP), we identified mitochondrial metabolism-related genes associated with myocarditis. Single-cell RNA sequencing (scRNA-seq) analysis further revealed that macrophages were the predominant infiltrating immune population, with Tspo expressed in myocarditis macrophages. Tspo knockdown enhanced inflammatory responses and disrupted mitochondrial structure and function, whereas treatment with the Tspo ligand Ro5-4864 exerted the opposite effects. Consistently, administration of Ro5-4864 in a VMC mouse model mitigated inflammation and preserved cardiac function. Collectively, our findings identify Tspo as a novel mitochondria-associated protective response factor in myocarditis, providing new insights into its pathophysiological mechanisms and highlighting Tspo as a promising therapeutic target for future intervention.
Protein fragments are increasingly recognized as both biomarkers and therapeutic targets, offering important insights into disease mechanisms and potential intervention strategies. Evidence from in vitro and in vivo studies indicates that these fragments are not merely degradation products but possess distinct biological activities, actively modulating immune signaling and contributing to both acute and chronic inflammatory processes. Here, we provide an overview of proteases and their inhibitors, with a particular focus on peptide fragments generated through proteolytic cleavage. Special emphasis is placed on fragments derived from α1-antitrypsin (AAT), an acute-phase glycoprotein and major inhibitor of neutrophil elastase and other serine proteases. AAT-derived peptides of varying lengths, generated by both target and nontarget proteases, including metalloproteases, have been detected in human biological fluids and tissues. Beyond reflecting proteolytic activity, these peptides provide clinically relevant information on disease-associated inflammation and tissue remodeling. Accordingly, they are emerging as promising diagnostic, monitoring, and predictive biomarkers. Here, we summarize current knowledge on cleaved AAT fragments, their biological functions, and their potential clinical applications.
BACKGROUND:Parkinson's disease (PD) is a neurodegenerative disorder with limited therapeutic options. Shao Di Pa Ning Decoction (SDPND), a traditional Chinese medicine (TCM) compound formula for PD, has demonstrated therapeutic efficacy, but its underlying mechanisms remain unclear. PURPOSE:This research aims to systematically investigate the mechanisms of SDPND, focusing on its anti-inflammatory effects and related pathways in PD. METHODS:The bioactive components of SDPND were first characterized to establish its material basis. Subsequently, A53T mice were administered SDPND to evaluate therapeutic improvements in motor dysfunction and neuroinflammatory responses, followed by transcriptomic profiling to identify potential pathways. Network pharmacology analysis was employed to validate biological pathways associated with these therapeutic effects. Molecular docking was used to study binding interactions between components and inflammatory, thereby offering mechanistic insights, with western blotting ultimately confirming the modulation of PI3K/AKT pathway activity. RESULTS:Chemical composition analysis revealed 91 compounds. SDPND alleviated motor deficits and mitigated neuroinflammatory responses in A53T mice. Transcriptomic profiling revealed significant downregulation of the PI3K/AKT pathway. Network pharmacology analyses independently reaffirmed the enrichment of PI3K/AKT signaling as a pivotal hub. Molecular docking demonstrated robust binding affinities between bioactive components and core targets within the PI3K/AKT pathway, while western blotting analysis confirmed SDPND mediated suppression of PI3K/AKT phosphorylation, further validating pathway inhibition as a key mechanistic driver. CONCLUSION:Our findings first revealed a novel anti-neuroinflammatory mechanism of SDPND via PI3K/AKT pathway suppression, which underlies its efficacy in mitigating PD symptoms. This discovery provides a robust theoretical foundation and pinpoints a strategic target for refining clinical PD therapeutics.
BACKGROUND:At present, there is no epidemiological study available to confirm the efficacy of neutrophil to high-density lipoprotein cholesterol ratio (NHR) in assessing the prognosis of the asthma population. This study aims to investigate the value of NHR in assessing the prognosis of asthma patients by utilizing data from National Health and Nutrition Examination Survey (NHANES) and constructing the predictive models. METHODS:This study used Cox regression models, cumulative risk curves, and survival 3D interaction plots to check how NHR related to the outcomes for asthma patients. This study also used the least absolute shrinkage and selection operator (LASSO) regression screening to construct key variables for the prediction model, followed by the use of time-dependent receiver operating characteristic (ROC) curves and Shapley additive explanations (SHAP) models to evaluate the performance and practical value of the prediction model. RESULTS:The Cox regression models (HR: 1.12, 95% CI: 1.03-1.22), cumulative risk curves, and survival 3D interaction plots all confirmed that, after accounting for other factors, a higher NHR is linked to a lower survival rate and a higher risk of death for asthma patients. According to the LASSO regression and SHAP model, the five most important significant indicators predicting mortality in individuals with asthma were age, cholesterol, NHR, cardiovascular disease (CVD), and hypertension. The combination of these significant indicators produced superior performance when predicting the 1-year (AUC: 0.874), 5-year (AUC: 0.853), and 9-year (AUC: 0.877) all-cause mortality of asthma populations. CONCLUSIONS:In this nationally representative cohort of participants with asthma, elevated NHR was independently associated with higher all-cause mortality risk. NHR may serve as a readily available marker reflecting systemic inflammatory-metabolic status, but its clinical utility for asthma risk stratification requires further validation in independent cohorts.
We report a case of refractory coccidioidal meningitis presenting with bilateral upper-extremity weakness in a man-in-a-barrel distribution caused by cervical arachnoiditis, adhesive bands, and spinal cord compression. The patient was treated sequentially with fluconazole, other azole therapy, liposomal amphotericin B, intrathecal amphotericin B, and olorofim, with only partial disease control. Neuroimaging demonstrated progressive cervical leptomeningeal inflammation, cord tethering, and CT myelography illustrated adhesive arachnoiditis. Surgical lysis of adhesions and placement of a spinal Ommaya reservoir for intrathecal amphotericin delivery above and below the obstructed segment resulted in partial neurologic improvement. This case broadens the differential diagnosis of man-in-a-barrel syndrome to include active fungal meningitis with compressive cervical myelopathy and highlights the role of combined surgical-medical management in complicated fungal arachnoiditis.
A 41-year-old woman developed chronic unilateral granulomatous conjunctivitis, ipsilateral lymphadenopathy, fever and malaise, diagnostic of Parinaud oculoglandular syndrome, after contact with a sick pet cat. Tear cultures identified Sporothrix schenckii, confirmed by 18S ribosomal RNA PCR, with co-infection by Moraxella osloensis. Biopsy showed suppurative necrotising granulomatous inflammation. Oral itraconazole, topical amphotericin B and amikacin achieved remission. Although Bartonella henselae is the commonest cause of POGS, Sporothrix schenckii warrants consideration in cat-exposed patients, alongside bacterial co-infection.
Liver cirrhosis represents the irreversible end-stage of various chronic liver diseases, whereas hepatic fibrosis, characterized by hepatic stellate cell (HSC) activation, constitutes the critical pathological intermediate in this progression. In this study, we investigated the antifibrotic effects of loganin, a natural iridoid glycoside, and elucidated its underlying mechanisms in bile duct ligation (BDL)-induced cholestatic liver injury and hepatic fibrosis and in TGF-β1-stimulated HSCs. Sprague-Dawley rats subjected to BDL surgery received loganin for 14 days, resulting in marked amelioration of hepatomegaly, inflammatory infiltration, hepatocyte necrosis, and collagen deposition, alongside restoration of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (T-BIL) levels and suppression of fibrogenic gene expression (collagen type I alpha 1 chain [COL1α1], alpha-smooth muscle actin [α-SMA], and fibronectin). Moreover, loganin attenuated hepatic autophagy, as evidenced by reduced Beclin-1 expression and LC3B-II/I ratio, with decreased colocalization of α-SMA and LC3B. Bioinformatics analysis and molecular docking indicated that epidermal growth factor receptor (EGFR) may be the target protein through which loganin exerts its antifibrotic effect. Experimental validation demonstrated that loganin suppressed BDL-induced EGFR phosphorylation in vivo. In TGF-β1-activated HSC-T6 cells, loganin inhibited cell activation, downregulated fibrosis markers, impaired autophagic flux, and suppressed TGF-β1-induced upregulation of Beclin-1 and LC3B-II/I. Critically, cotreatment with the EGFR agonist EGF reversed the autophagy-inhibitory and antifibrotic effects of loganin, whereas the EGFR inhibitor AG-1478 mimicked loganin's actions, confirming EGFR signaling as the functional mediator. Overall, these results indicated that loganin could alleviate liver injury and hepatic fibrosis in BDL rats by inhibiting autophagy and activation of HSCs, and this protective effect is mediated by the EGFR pathway.
Alcohol use is a major coexposure in patients taking acetaminophen (APAP), yet how subchronic alcohol exposure reshapes hepatic vulnerability to APAP remains incompletely defined. In this study, we examined the effects of chronic alcohol intake on APAP-induced liver injury in mice. Our results indicated that subchronic alcohol exposure significantly increased the mortality rate in APAP-overdosed mice. Alcohol pretreatment also exacerbated APAP-induced hepatic damage, as evidenced by elevated serum ALT and AST levels, enhanced inflammatory responses, and aggravated oxidative stress. Quantitative polymerase chain reaction (qPCR) analysis revealed that alcohol consumption suppressed mitochondrial biogenesis (MB)-related genes, including Pgc-1α and transcription factor A, mitochondrial (TFAM). Notably, macrophage depletion via clodronate liposomes not only attenuated hepatocyte injury and inflammation induction but also restored the expression of MB/function-related genes, including Pgc-1α, TFAM, and Opa1. These findings suggest macrophage-involved inflammatory amplification may aggravate APAP-induced liver injury, at least in part, by impairing mitochondrial adaptive repair responses.
OBJECTIVE:To investigate the expression levels of community-acquired respiratory distress syndrome toxin (CARDS TX), myeloid differentiation factor 88 (MyD88), and interleukin-8 (IL-8) in the bronchoalveolar lavage fluid (BALF) of children with severe Mycoplasma pneumoniae pneumonia (SMPP) and explore their clinical significance in the pathogenesis of SMPP. METHODS:This was a retrospective analysis of clinical data from 29 patients with SMPP and 12 patients with general Mycoplasma pneumoniae pneumonia (GMPP). Moreover, the expression levels of CARDS TX, MyD88, and IL-8 in the BALF of the two groups were detected and compared. RESULTS:The expression levels of CARDS TX, MyD88, and IL-8 were positively correlated with SMPP (p < 0.05). Univariate logistic regression analysis indicated that CARDS TX, MyD88, and IL-8 are potential risk factors for SMPP (p < 0.05). The areas under the curve for the CARDS TX, MyD88, and IL-8 assays were 0.857, 0.730, and 0.799, respectively. The optimal cutoff values were 10.91 ng/mL, 2.21 ng/mL, and 120.52 pg/mL, respectively. CONCLUSIONS:Elevated levels of CARDS TX, MyD88, and IL-8 in BALF all demonstrate diagnostic utility for children with SMPP, with CARDS TX exhibiting the highest diagnostic sensitivity. A CARDS TX concentration >10.91 ng/mL, a MyD88 concentration >2.21 ng/mL, and an IL-8 concentration >120.52 pg/mL are potential risk factors for SMPP.
COVID-19-associated pulmonary aspergillosis (CAPA) is typically described in critically ill patients with severe pneumonia. We report a 68-year-old man, 16 weeks post autologous hematopoietic stem cell transplant for AL amyloidosis, who developed invasive pulmonary aspergillosis (IPA) following mild COVID-19 upper respiratory tract infection not requiring oxygen supplementation or ICU admission. Diagnosis was established by positive broncho-alveolar lavage galactomannan with compatible CT chest findings, and he was treated with oral voriconazole. This case highlights that IPA may complicate mild COVID-19 in patients not traditionally considered at highest risk, supporting the concept that cumulative risk factors may precipitate IPA.
Background Rhinocladiella mackenziei is a rare neurotropic dematiaceous fungus that causes cerebral phaeohyphomycosis, predominantly in immunocompetent adults with a geographical predilection to the Middle East. Pediatric infection is exceptionally rare, and to our knowledge, no cases of combined osseous and central nervous system involvement following hematopoietic stem cell transplantation (HSCT) have been reported. Case We report a male child with autosomal recessive chronic granulomatous disease (CGD) who developed traumatic forearm osteomyelitis due to R. mackenziei several months after haploidentical HSCT. Subsequent neuroimaging demonstrated intracerebral abscesses despite immune reconstitution. The infection persisted despite prolonged combination antifungal therapy with voriconazole and amphotericin B and ultimately required neurosurgical excision. The patient recovered without neurological sequelae and continues on long-term posaconazole therapy. Conclusion This case highlights R. mackenziei as a cause of severe, invasive, disseminated fungal disease in pediatric post-bone marrow transplant patients and demonstrates extracerebral inoculation with subsequent CNS dissemination. It also underscores the importance of early recognition and a combined medical-surgical approach in management of refractory disease.
Activation of the NLRP3 inflammasome and its downstream cytokines IL-1β and IL-18 has been increasingly associated with the inflammatory mechanisms underlying diabetic nephropathy (DN), the leading cause of chronic kidney disease and end-stage renal disease worldwide. This study investigated the expression of these inflammatory mediators in renal tissue from patients with DN. Eighty renal biopsies from adult patients (≥18 years) with a histopathological diagnosis of DN and 22 control samples obtained from autopsies were analyzed. NLRP3, IL-1β, and IL-18 expression was assessed by immunohistochemistry, and semi-quantitative analysis was performed to determine the proportion of immunostained cells in the glomerular and interstitial compartments. A significant increase in immunostaining for all three mediators was observed in mesangial cells, podocytes, endothelial cells, and the interstitium of DN samples compared with controls (p < 0.05). Positive and significant correlations were found between NLRP3 and IL-1β in endothelial cells (p < 0.0001; rS = 0.4720) and in the interstitium (p = 0.0230; rS = 0.2540), as well as between NLRP3 and IL-18 in podocytes (p = 0.0055; rS = 0.3074). Moreover, interstitial expression of NLRP3 and IL-1β correlated positively with serum creatinine levels (p = 0.0015; rS = 0.3708; and p = 0.0029; rS = 0.3480, respectively), suggesting an association between inflammasome-mediated inflammation and renal dysfunction. Collectively, these findings indicate that the NLRP3/IL-1β/IL-18 axis plays a central role in glomerular and interstitial injury in DN, supporting its potential as a prognostic biomarker and a promising therapeutic target for disease modulation.
PURPOSE:Diabetic retinopathy (DR) is a leading vision-threatening disease and a common complication of diabetes. However, the understanding of how metabolic dysfunction correlates with ocular inflammation in DR remains poorly understood. Therefore, in this study, we investigated the association between these two factors in DR. METHODS:Using untargeted metabolomics analysis and mass spectrometry detection, the plasma metabolic characteristics of 27 DR patients (15 with nonproliferative diabetic retinopathy [NPDR] and 12 with proliferative diabetic retinopathy [PDR]) and 8 healthy controls (HCs) were examined. Additionally, the concentrations of inflammatory factors and vascular endothelial growth factor (VEGF) in their aqueous humor were measured. Further analysis was conducted to evaluate the correlation between metabolic disorders and abnormalities in inflammatory factors and VEGF in the aqueous humor. RESULTS:Metabolomic analysis revealed significant metabolic dysregulation in DR, with PDR exhibiting particularly pronounced alterations compared to NPDR and HC. ROC analysis identified creatinine, glutamine, indoleacetic acid, and methionine as reliable biomarkers for distinguishing PDR. Elevated cytokines, such as IL-6, IL-8, and VEGF, were significantly correlated with specific metabolism pathways. CONCLUSION:Our study highlights potential biomarkers for DR stratification and provide novel insights into the link between metabolic dysfunction and ocular inflammation/ischemia in PDR.
Qingxin Tongmai Yin (QXTMY), a classic traditional Chinese medicine (TCM) formula widely used for cardiovascular and cerebrovascular diseases, has unclear multitarget mechanisms against atherosclerosis (AS). This study integrated network pharmacology with experimental validation to investigate these mechanisms. Network pharmacology identified 128 bioactive compounds and 135 potential targets of QXTMY, highlighting key anti-AS targets such as TNF, IL6, insulin (INS), IL1B, MMP9, CCL2, and ALB, with the AGE-RAGE signaling pathway as a central mechanism; principal active ingredients included quercetin, kaempferol, luteolin, and cryptotanshinone. In vitro experiments using THP-1-derived macrophages induced with phorbol-12-myristate-13-acetate (PMA) and oxidized low-density lipoprotein (ox-LDL) showed that QXTMY significantly suppressed inflammatory responses, inhibited foam cell formation, and downregulated the AGE-RAGE signaling pathway, as measured by Western blot, ELISA, cholesterol quantification, and Nile Red staining. These findings suggest that QXTMY may exert protective effects against AS, potentially via suppression of the AGE-RAGE-mediated inflammatory axis. However, in vivo validation is still required to support these preliminary conclusions.
Prolonged air leak (PAL) remains one of the most frequent and clinically consequential complications after lung resection, prolonging chest tube duration, delaying recovery, increasing postoperative morbidity, and expanding healthcare resource utilization. Although traditionally approached as a mechanical failure of alveolar-pleural sealing or surgical technique, PAL is increasingly understood as a heterogeneous postoperative syndrome in which persistent air leak dynamics intersect with impaired inflammatory and reparative biology. Surgical manipulation, one-lung ventilation, parenchymal injury, and patient-specific vulnerability may activate cytokine signaling, epithelial barrier disruption, oxidative stress, extracellular matrix remodeling, glycocalyx degradation, and delayed wound repair. This narrative review synthesizes clinical, translational, and experimental evidence on the pathogenesis of PAL, with particular emphasis on inflammatory mediators and biomarker-defined mechanisms relevant to failed closure of alveolar-pleural fistulas (APFs). Candidate biomarkers are discussed according to the biological domains they reflect, including systemic inflammatory burden and poor healing reserve (C-reactive protein [CRP], IL-6, and serum albumin), epithelial injury and damage-associated signaling (high-mobility group box 1 [HMGB1]/receptor for advanced glycation end products [RAGE] and sRAGE), oxidative epithelial stress (4-hydroxynonenal [4-HNE] and malondialdehyde [MDA]), protease-mediated matrix and junctional remodeling (matrix metalloproteinase [MMP]-9), glycocalyx and barrier disruption (syndecan [SDC]-1), and upstream inflammatory regulation (histone deacetylase 6 [HDAC6]-related pathways). The review also considers how quantitative digital chest drainage parameters may complement molecular biomarkers by capturing the physiologic expression of persistent air leak. By integrating these mechanistic and technological signals, this review proposes a conceptual framework for biomarker-informed perioperative risk stratification, PAL phenotyping, and individualized prevention and management. Because most biomarker-driven strategies remain investigational, prospective validation is required before routine clinical implementation.
The current management of acute pancreatitis (AP) primarily relies on supportive measures, such as fluid resuscitation, nutritional support, and infection control. However, these approaches do not adequately address the core drivers of the disease. This limitation arises from an incomplete understanding of the progression from local injury to systemic inflammation and repair, which is a dynamic process with underlying immunoregulatory mechanisms that remain insufficiently characterized. Macrophages are the key effector cells involved throughout the disease course and exhibit pronounced spatiotemporal heterogeneity during this progression. Therefore, they are central to decoding the evolution of the disease and facilitating precise interventions. In terms of spatial dynamics, tissue-resident macrophages (TRMs), which are derived from embryonic sources, and monocyte-derived macrophages (MDMs) recruited from the bone marrow serve functionally complementary roles. Their relative dominance shifts in conjunction with disease progression rather than remaining static. Temporally, the macrophage phenotype undergoes a programmed evolution, beginning with an early phase dominated by M1 proinflammatory responses, transitioning through an intermediate phase where injury and repair coexist, and culminating in a late phase characterized by M2-dominated reparative coordination. This evolution is accompanied by corresponding metabolic reprogramming. Recent single-cell and spatial multiomics studies have unveiled a functional continuum that goes beyond the traditional M1/M2 dichotomy, revealing a rich diversity of cellular subsets and their spatial niches. This insight shifts targeting strategies from broad anti-inflammatory interventions toward more precise modulation aimed at specific phases, subsets, and regions. This review systematically examines the design principles, strengths, and limitations of three classes of intervention—molecular targeting, bioactive natural products, and nanoscale delivery—and identifies the obstacles that continue to impede their clinical translation. Building on this analysis, we propose a dual-dimensional (spatiotemporal) strategy of precise modulation, integrating single-cell and spatial omics, chronobiological principles, and the traditional Chinese medical concept of yin shi zhi yi (adapting treatment to timing), with the aim of shifting AP therapy from symptomatic support toward cause-directed repair.
This report describes a molecularly confirmed case of canine dermatophytosis caused by Arthroderma uncinatum in an 11-month-old English Setter from Southern Italy. The dog presented with two alopecic, erythematous, scaling lesions on the metacarpal and metatarsal regions. While routine microscopic examinations were inconclusive, dermatophyte culture yielded a fungal isolate identified as A. uncinatum by ITS sequencing. Topical 1% clotrimazole administered for three weeks resulted in complete clinical and mycological cure. This case documents an uncommon infection by a geophilic dermatophyte and expands veterinary knowledge of A. uncinatum-associated canine disease.
BACKGROUND:Lichen planus (LP) is a chronic, immune-mediated inflammatory disorder affecting the skin, mucous membranes, hair, and nails. Conventional therapies such as corticosteroids and systemic immunosuppressants often demonstrate limited efficacy and are associated with undesirable side effects. The underlying inflammatory process is largely dominated by Th1/IFN-ɣ cytokines and the activation of the Janus kinase (JAK)-STAT pathway, highlighting JAK inhibitors as a novel, targeted therapeutic approach for recalcitrant forms of LP. AIM:The aim of the study was to systematically analyze the current scientific evidence regarding the efficacy and safety of JAK inhibitors in the treatment of various LP variants. MATERIAL AND METHODS:A comprehensive literature search was performed in accordance with PRISMA guidelines using PubMed, Scopus, and Cochrane databases from inception up to May 2026. Eighty-four relevant studies were enrolled into the final analysis. The risk of bias and quality of evidence were assessed using the JBI critical appraisal tools. RESULTS:The final analysis consisted predominantly of case reports, case series, and limited controlled trials. Both systemic agents (e.g., tofacitinib, upadacitinib, and baricitinib) and topical formulations (e.g., ruxolitinib) demonstrated rapid reductions in pruritus and pain, followed by clinical resolution of inflammatory lesions. High rates of complete and partial clinical responses were observed across diverse variants. Short-term adverse effects were generally mild and manageable, although the overall certainty of the evidence was low. CONCLUSIONS:JAK inhibitors demonstrate a promising preliminary clinical response and acceptable short-term safety for managing refractory LP variants. While these agents present a valuable alternative to conventional therapies, the current evidence relies heavily on observational data. Large, randomized controlled trials with long-term follow-up are needed to establish optimal dosing, confirm safety, and evaluate sustained efficacy in clinical practice.
The circadian clock plays a crucial role in the pathogenesis of various inflammatory and autoimmune diseases, including ulcerative colitis (UC). Deletion of the core transcription factor BMAL1 exacerbated the severity of colitis. However, the underlying molecular mechanisms of BMAL1 in UC remain unclear. We found that BMAL1 was downregulated in UC tissues and in LPS-induced MODE-K cells, whereas CXCL1 was highly expressed. Overexpression of BMAL1 reduced LPS-induced pyroptosis in MODE-K cells and restoring the expression of ZO-1, Claudin-1, and Occludin, thereby improving intestinal epithelial barrier function. Mechanistically, BMAL1 can negatively regulate the CXCL1 expression by inhibiting the activity of its promoter. Additionally, proteomics analysis identified MEF2A as a downstream protein of BMAL1. The protective effect of BMAL1 on MODE-K cells was achieved through direct negative regulation of CXCL1 or indirect negative regulation of MEF2A expression. Thus, BMAL1 plays a protective role in maintaining the integrity of the intestinal epithelial barrier and represents a potential therapeutic target for UC treatment.
