Acute kidney injury (AKI) is a severe clinical condition with high morbidity and mortality. Caveolin-1 (Cav-1), a main structural protein of caveolae, orchestrates key cellular processes including endocytosis, lipid transport, and signal transduction by serving as a platform. However, its specific role in AKI remains unclear. Here, we report that Cav-1 is upregulated in distal tubule epithelial cells (TECs) in both AKI patients and mouse models induced by ischemia/reperfusion injury (IRI) and lipopolysaccharide (LPS). Global and distal TEC-specific Cav1 knockout exacerbates IRI and LPS-induced AKI. RNA-seq reveals that Cav-1 deficiency exacerbates intracellular calcium ion (Ca2+) homeostasis imbalance and endoplasmic reticulum (ER) stress in injured kidney tissues. Mechanistically, Cav-1 interacts with sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2), a key regulator of intracellular Ca2+ homeostasis, through its scaffolding domain, promoting SERCA2 deubiquitination and stability in the ER, thereby maintaining intracellular Ca2+ homeostasis and suppressing ER stress in distal TECs. Furthermore, supplementation with a cell-permeable Cav-1 scaffolding domain peptide (CSP) or activation of SERCA2 with a small-molecule agonist CDN1163 alleviates IRI- and LPS-induced AKI, while distal TEC-specific SERCA2 knockdown abrogates CSP's therapeutic effect. Together, these findings reveal a novel Cav-1-mediated pathway and highlight its potential as a therapeutic target for AKI.

INTRODUCTION:Cellular calcium homeostasis is essential for maintaining kidney function. Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), the primary calcium pump responsible for transporting cytosolic calcium ions back into the endoplasmic reticulum, is a key regulator of endoplasmic reticulum stress and intracellular calcium balance. However, its specific role in acute kidney injury (AKI) and the underlying regulatory mechanisms remain poorly understood. METHODS:SERCA2 expression was measured in biopsies of patients with AKI, animal models, and cellular assays. AKI models were established using SERCA2 conditional knockdown and overexpression mice, HK-2 cells and primary kidney tubular epithelial cells in vitro. To investigate the underlying mechanisms, we integrated approaches including RNA-sequencing, transmission electron microscopy, immunofluorescence, and Seahorse analyses. RESULTS:Transcriptomic and histopathological analyses revealed reduced SERCA2 expression in proximal tubules of both patient AKI biopsies and murine models. Proximal tubule-specific SERCA2 knockdown exacerbated kidney dysfunction and tubular injury in murine AKI, while SERCA2 allosteric activation with CDN1163 or its overexpression attenuated these injuries. Mechanistically, SERCA2 deficiency disrupted endoplasmic reticulum calcium homeostasis, leading to endoplasmic reticulum stress and promoting voltage dependent anion channel 1 (VDAC1) oligomerization through impaired mitochondria-associated endoplasmic reticulum membranes. These changes led to mitochondrial permeability transition pore opening, mitochondrial calcium overload, oxidative stress, and ferroptosis. Importantly, stopping VDAC1 oligomerization with small molecule inhibitor VBIT-4 or blocking ferroptosis with ferrostatin-1 restored mitochondrial function and mitigated ferroptosis in SERCA2-deficient models. CONCLUSIONS:Our study identifies the SERCA2-VDAC1 axis as a critical regulator of endoplasmic reticulum-mitochondrial calcium homeostasis in AKI. Both SERCA2 activation and inhibition of VDAC1 oligomerization conferred substantial renoprotection, highlighting this pathway as a promising therapeutic target for attenuating tubular damage in AKI.

Inflammatory bowel disease (IBD) is closely related to changes in the gut microbiota, with proton pump inhibitors (PPIs) possibly playing a role. PPIs use is associated with altering gut microbiota and potentially influencing IBD onset and progression. This review explores the mechanisms by which PPIs affect gut microbiota and IBD, suggests strategies to mitigate dysbiosis, outlook on the causal relationship validation between PPIs use and IBD risk, emphasizing the broader impact of acid suppressants on gut health.

Damage-associated molecular patterns (DAMPs) are a cause of Crohn’s disease (CD). Peroxiredoxin 1 (Prdx1), a newly identified DAMP, plays a critical role in organ injury with its potent proinflammatory properties. However, its specific role in CD remains unclear. Here, we identify serum Prdx1 as a DAMP involved in CD. Serum Prdx1 levels were significantly increased and positively correlated with the severity of intestinal inflammation in both CD patients and mice with experimental colitis. Genetic knockout of Prdx1 or administration of a Prdx1-neutralizing antibody attenuated colitis in mice, as evidenced by restoration of the colonic epithelium, improved disease activity, and reduced colonic inflammation. These protective effects were impaired by introduction of recombinant Prdx1 (rPrdx1). Mechanistically, Prdx1 exacerbated intestinal inflammation by promoting macrophage infiltration and subsequent cytokine production. Depletion of macrophages abolished the rPrdx1-mediated exacerbation of colitis. Further, rPrdx1 was internalized by macrophages, leading to lysosomal disruption and subsequent activation of the NLRP3 inflammasome. Pharmacological inhibition of NLRP3 effectively abrogated rPrdx1-induced exacerbation of colitis. In conclusion, serum Prdx1 promotes intestinal inflammation in CD at least in part by activating the NLRP3 inflammasome through lysosomal disruption in macrophages. These findings highlight the pathogenic role of Prdx1 in CD and reveal therapeutic potential of managing CD via neutralization of circulating Prdx1.

Abstract Background Dysbiosis of the gut microbiota is pivotal in Crohn’s disease (CD) and modulated by host physiological conditions. Hyperbaric oxygen therapy (HBOT) is a promising treatment for CD that can regulate gut microbiota. The relationship between HBOT and the gut microbiota in CD remains unknown. Methods CD patients were divided into an HBOT group (n = 10) and a control group (n = 10) in this open-label prospective interventional study. The fecal samples before and after HBOT were used for 16 S rRNA gene sequencing and fecal microbiota transplantation (FMT). A colitis mouse model was constructed using dextran sulfate sodium, and intestinal and systematic inflammation was evaluated. The safety and long-term effect of HBOT were observed. Results HBOT significantly reduced the level of C-reactive protein (CRP) (80.79 ± 42.05 mg/L vs. 33.32 ± 18.31 mg/L, P = 0.004) and the Crohn’s Disease Activity Index (CDAI) (274.87 ± 65.54 vs. 221.54 ± 41.89, P = 0.044). HBOT elevated the declined microbial diversity and ameliorated the altered composition of gut microbiota in patients with CD. The relative abundance of Escherichia decreased, and that of Bifidobacterium and Clostridium XIVa increased after HBOT. Mice receiving FMT from donors after HBOT had significantly less intestinal inflammation and serum CRP than the group before HBOT. HBOT was safe and well-tolerated by patients with CD. Combined with ustekinumab, more patients treated with HBOT achieved clinical response (30%vs.70%, P = 0.089) and remission (20%vs.50%, P = 0.160) at week 4. Conclusions HBOT modulates the dysbiosis of gut microbiota in CD and ameliorates intestinal and systematic inflammation. HBOT is a safe option for CD and exhibits a promising auxiliary effect to ustekinumab. Trial registration Chinese Clinical Trial Registry, ChiCTR2200061193. Registered 15 June 2022, https://www.chictr.org.cn/showproj.html?proj=171605 .

Acute liver failure (ALF) is a critical condition that can lead to substantial liver dysfunction. It is characterized by complex clinical manifestations and rapid progression, presenting significant challenges in diagnosis and treatment. We investigated the protective effect of mefunidone (MFD), a novel antifibrosis pyridone agent, on ALF in mice, and explored its potential mechanism of action. MFD pretreatment can alleviate lipopolysaccharide (LPS) and d-galactosamine (D-GalN)-induced ALF, reduce hepatocyte apoptosis, and reduce inflammation and oxidative stress. Additionally, MFD alleviated LPS/D-GalN-stimulated reactive oxygen species (ROS) production and cell death in AML12 cells. RNA sequencing enrichment analysis showed that MFD significantly affected the Mitogen-Activated Protein Kinase (MAPK) pathway. In vivo and in vitro experiments showed that MFD inhibited MKK4 and JNK phosphorylation. JNK activation caused by MKK4 and JNK activators could eliminate the therapeutic effect of MFD on AML12. In addition, MFD pretreatment alleviated ConA-induced ALF, reduced inflammation and oxidative stress in mice, and reduced mouse mortality. These results suggest that MFD can potentially protect against ALF, partially by inhibiting the MKK4-JNK pathway, and is a promising new therapeutic drug for ALF

Learning points for cliniciansTo date, only three TTC37 mutation cases have been recorded associated with inflammatory bowel disease (IBD).In this study, we identified two novel heterozygous TTC37 variants (NM_014639.3:c.4348G>T;p.Ala1450Ser and NM_014639.3:c.4508G>T;p.Arg1503Leu) in two Chinese Crohn's disease (CD) patients.Our findings present the first two Asian cases of CD associated with TTC37 mutations, which contribute to the genetic counseling and diagnosis of patients with IBD and CD.

Learning point for cliniciansAt present, only five mutations of ANKZF1 have been identified in patients with inflammatory bowel disease (IBD).This study identified a novel variant of ANKZF1 (NM_018089.2:c.1243T>G; p.Leu415Val) in a young patient with IBD.Our findings demonstrate the first case of IBD attributed to ANKZF1 heterozygous mutation in Asia, which broadens the variant spectrum of ANKZF1 and contributes to a more quickly genetic counseling.

Aims: Acute liver failure (ALF) is a life-threatening disease characterized by abrupt and extensive hepatic necrosis and apoptosis, resulting in high mortality. The approved drug, N-acetylcysteine (NAC), is only effective for acetaminophen (APAP)-associated ALF at the early stage. Thus, we investigate whether fluorofenidone (AKF-PD), a novel antifibrosis pyridone agent, protects against ALF in mice and explore its underlying mechanisms. Methods: ALF mouse models were established using APAP or lipopolysaccharide/D-galactosamine (LPS/D-Gal). Anisomycin and SP600125 were used as JNK activator and inhibitor, respectively, and NAC served as a positive control. Mouse hepatic cell line AML12 and primary mouse hepatocytes were used for in vitro studies.Results: AKF-PD pretreatment alleviated APAP-induced ALF with decreased necrosis, apoptosis, reactive oxygen species (ROS) markers, and mitochondrial permeability transition in liver. Additionally, AKF-PD alleviated mitochondrial ROS stimulated by APAP in AML12 cells. RNA-sequencing in the liver and subsequent gene set enrichment analysis showed that AKF-PD significantly impacted MAPK and IL-17 pathway. In vitro and in vivo studies demonstrated that AKF-PD inhibited APAP-induced phosphorylation of MKK4/JNK, while SP600125 only inhibited JNK phosphorylation. The protective effect of AKF-PD was abolished by anisomycin. Similarly, AKF-PD pretreatment abolished hepatotoxicity caused by LPS/D-Gal, decreased ROS levels, and diminished inflammation. Furthermore, unlike NAC, AKF-PD, inhibited the phosphorylation of MKK4 and JNK upon pretreatment, and improved survival in cases of LPS/D-Gal-induced mortality with delayed dosing.Conclusions: In summary, AKF-PD can protect against ALF caused by APAP or LPS/D-Gal, in part, via regulating MKK4/JNK pathway. AKF-PD might be a novel candidate drug for ALF.

Objectives:Liver fibrosis is a key stage in the progression of various chronic liver diseases to cirrhosis and liver cancer, but at present, there is no effective treatment. This study investigated the therapeutic effect of the new antifibrotic drug fluorofenidone (AKF-PD) on liver fibrosis and its related mechanism, providing implications for liver cancer.Materials and Methods:The effects of AKF-PD on hepatic stellate cell (HSC) autophagy and extracellular matrix (ECM) expression were assessed in a carbon tetrachloride (CCl4)-induced rat liver fibrosis model. In vitro, HSC-T6 cells were transfected with Smad2 and Smad3 overexpression plasmids and treated with AKF-PD. The viability and number of autophagosomes in HSC-T6 cells were examined. The protein expression levels of Beclin-1, LC3 and P62 were examined by Western blotting. The Cancer Genome Atlas (TCGA) database was used for comprehensively analyzing the prognostic values of SMAD2 and SMAD3 in liver cancer. The correlation between SMAD2, SMAD3, and autophagy-related scores in liver cancer was explored. The drug prediction of autophagy-related scores in liver cancer was explored.Results:AKF-PD attenuated liver injury and ECM deposition in the CCl4-induced liver fibrosis model. In vitro, the viability and number of autophagosomes in HSCs were reduced significantly by AKF-PD treatment. Meanwhile, the protein expression of FN, α-SMA, collagen III, Beclin-1 and LC3 was increased, and P62 was reduced by the overexpression of Smad2 and Smad3; however, AKF-PD reversed these effects. SMAD2 and SMAD3 were hazardous factors in liver cancer. SMAD2 and SMAD3 correlated with autophagy-related scores in liver cancer. Autophagy-related scores could predict drug response in liver cancer.Conclusions:AKF-PD alleviates liver fibrosis by inhibiting HSC autophagy via the transforming growth factor (TGF)-β1/Smadpathway. Our study provided some implications about how liver fibrosis was connected with liver cancer by SMAD2/SMAD3 and autophagy.

Damage-associated molecular patterns (DAMPs) are a cause of acute kidney injury (AKI). Our knowledge of these DAMPs remains incomplete. Here, we report serum peroxiredoxin 1 (Prdx1) as a novel DAMP for AKI. Lipopolysaccharide (LPS) and kidney ischemia/reperfusion injury instigated AKI with concurrent increases in serum Prdx1 and reductions of Prdx1 expression in kidney tubular epithelial cells. Genetic knockout of Prdx1 or use of a Prdx1-neutralizing antibody protected mice from AKI and this protection was impaired by introduction of recombinant Prdx1 (rPrdx1). Mechanistically, lipopolysaccharide increased serum and kidney proinflammatory cytokines, macrophage infiltration, and the content of M1 macrophages. All these events were suppressed in Prdx1-/-mice and renewed upon introduction of rPrdx1. In primary peritoneal macrophages, rPrdx1 induced M1 polarization, activated macrophage-inducible C-type lectin (Mincle) signaling, and enhanced proinflammatory cytokine production. Prdx1 interacted with Mincle to initiate acute kidney inflammation. Of note, rPrdx1 upregulated Mincle and the spleen tyrosine kinase Syk system in the primary peritoneal macrophages, while knockdown of Mincle abolished the increase in activated Syk. Additionally, rPrdx1 treatment enhanced the downstream events of Syk, including transcription factor NF-KB signaling pathways. Furthermore, serum Prdx1 was found to be increased in patients with AKI; the increase of which was associated with kidney function decline and inflammatory biomarkers in patient serum. Thus, kidney-derived serum Prdx1 contributes to AKI at least in part by activating Mincle signaling and downstream pathways.

To the Editors, Adalimumab is a fully humanized monoclonal antitumor necrosis factor (anti-TNF-α) antibody approved for treating Crohn’s disease (CD). Here, we present 2 patients with CD diagnosed with unilateral painless vulval swelling for the first time. Adalimumab administration was associated with unilateral painless vulval swelling in both patients. The first patient was a 19-year-old woman with ileocolonic CD. She was previously treated with infliximab, which was replaced with adalimumab in August 2020. She experienced swelling without pain and pruritus on the left labia majora for 2 months since July 2021 (Figure 1A). She had no sexual contact. Gynecological examination, gynecologic and vulvar color Doppler ultrasonography, and pelvic magnetic resonance imaging (MRI) showed normal findings (Figure 2A&B). She underwent surgery for an enterovesical fistula formation and discontinued adalimumab therapy. The vulval swelling improved without supplementary treatment. She remained under maintenance therapy with mesalazine. After...

Inflammatory bowel disease (IBD) is a progressive and destructive chronic intestinal inflammatory disease. Fatigue is one of the most common symptoms of IBD patients, which has a negative impact on the quality of life of patients. Its subjectivity and complexity make it difficult for clinicians to evaluate. Fatigue is always overlooked in clinical works. The mechanism of fatigue is unclear and there is no effective therapy to alleviate fatigue in IBD for now. We mainly review the research progress of influencing factors and therapy of fatigue in IBD patients to help clinicians have better awareness of fatigue.

Renal amyloidosis secondary to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is extremely rare. Here, we reported a 77-year-old woman with ANCA-associated vasculitis. Renal biopsy with Masson trichrome staining showed pauci-immune crescentic glomerulonephritis, and electron microscopy showed amyloid deposition in the mesangial area. Immunofluorescence revealed kappa light chain and lambda light chain negative. Bone marrow biopsy revealed no clonal plasma cell. Finally, she was diagnosed as ANCA-associated vasculitis with secondary renal amyloid A amyloidosis.

炎症性肠病(IBD)是一种病因尚未明确的慢性非特异性肠道炎性疾病,包括克罗恩病(CD)和溃疡性结肠炎(UC).贫血是IBD常见的合并症,严重影响患者的生活质量及药物的疗效.IBD合并贫血的病因多种多样,除营养性贫血、慢性病性贫血、药物相关性贫血外,遗传性贫血和免疫相关性贫血常被人忽视,尤其地中海贫血表现为小细胞低色素性贫血,容易被误诊为缺铁性贫血(IDA).该文就IBD合并贫血的研究进展作一综述,以期提高对该病的诊治水平.

一合并结核感染的克罗恩病(Crohn's disease,CD)患者,抗结核治疗后达到了临床缓解及黏膜愈合,但CD仍在进展,现对该病例进行报道,并对CD合并结核感染的致病机制进行文献复习,以增强临床医师对CD合并结核感染的认识.

Autoimmune gastritis(AIG) is a CD4 + T cell-mediated organ specific autoimmune disease of the stomach, characterized by the inherent gland atrophy in the stomach and intestinal metaplasia and/or pseudopyloric gland metaplasia. The diversity and nonspecificity of clinical features make the diagnosis difficult. In the past, AIG was thought to occur in the West, but in recent years, more and more studies have shown that the prevalence rate of AIG in China is not low. However, the disease has not attracted the attention of domestic clinical workers. Therefore, this paper reviews the latest research progress in the etiology, clinical characteristics, relationship with other diseases, diagnosis and treatment of AIG, so as to improve the understanding of clinical workers and improve the treatment rate and prognosis of AIG.

Despite the increasing understanding of the pathophysiology of hepatic fibrosis, the therapies to combat it remain inadequate. Fluorofenidone (AKF-PD) is a novel pyridone agent able to ameliorate hepatic fibrosis in an experimental hepatic fibrosis model induced by dimethylnitrosamine. However, the underlying mechanism remains to be further elucidated. In light of the critical role of the NF-κB pathway in inflammation and hepatic fibrosis, together with the preliminary finding that AKF-PD decreases the release of proinflammatory cytokines in the endotoxemia and unilateral ureteral occlusion model, the aim of this study was to explore whether AKF-PD exerts an antifibrotic effect in hepatic fibrosis by inhibiting inflammation and suppressing the activation of the NF-κB pathway in vivo and in vitro. To test this possibility, the effect of AKF-PD on hepatic fibrosis models induced by both carbon tetrachloride (CCL4 ) and porcine serum (PS) was investigated. Our results showed that AKF-PD treatment ameliorated hepatic injury and fibrosis in both models. Furthermore, the administration of AKF-PD induced a robust anti-inflammatory reaction revealed by the downregulation of the proinflammatory cytokines as well as the suppression of the infiltration of inflammatory cells in the fibrotic liver. The analysis of the mechanism of action demonstrated that the attenuation of the production of proinflammatory cytokines and chemokines mediated by AKF-PD in vivo and in vitro were accompanied by the suppression in the activation of the NF-κB signaling pathway. In conclusion, AKF-PD might be considered as an antifibrotic agent attenuating hepatic inflammation and fibrosis potentially through the suppression of the NF-κB pathway.

In response to microbes and other danger signals, the NLRP3 inflammasome in immune cells triggers the activation of the protease caspase-1, which mediates the maturation of the inflammatory cytokine IL-1β. Here, we investigated how the NLRP3 inflammasome is regulated. We found that its activation in primary mouse macrophages induced the Src family kinase Lyn to phosphorylate NLRP3 at Tyr918, which correlated with a subsequent increase in its ubiquitination that facilitated its proteasome-mediated degradation. NLRP3 tyrosine phosphorylation and ubiquitination was abrogated in Lyn-deficient macrophages, which produced increased amounts of IL-1β. Furthermore, mice lacking Lyn were more susceptible to LPS-induced septic shock in an NLRP3-dependent manner. Our data demonstrate that Lyn-mediated tyrosine phosphorylation is a prerequisite for the ubiquitination that dampens NLRP3 inflammasome activity.