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Doxorubicin (DOX) is one of the most effective and widely used chemotherapeutic drugs. However, DOX resistance is a critical risk problem for breast cancer treatment. Previous studies have demonstrated that metadherin (MTDH) involves in DOX resistance in breast cancer, but the exact mechanism remains unclear. In this study, we found that glutaminyl-peptide cyclotransferase (QPCT) was a MTDH DOX resistance-related downstream gene in breast cancer. Elevated expression of QPCT was found in the GEPIA database, breast cancer tissue, and breast cancer cells. Clinical data showed that QPCT expression was positively associated with poor prognosis in DOX-treated patients. Overexpression of QPCT could promote the proliferation, invasion and migration, and reduce DOX sensitivity in MCF-7 and MDA-MB-231 cells. Mechanistically, MTDH positively regulates the expressions of NF-κB (p65) and QPCT, and NF-κB (p65) directly regulates the expression of QPCT. Therefore, MTDH/NF-κB (p65)/QPCT signal axis was proposed. Collectively, our findings delineate the mechanism by which the MTDH/NF-κB (p65) axis regulate QPCT signaling and suggest that this complex may play an essential role in breast cancer progression and affect DOX sensitivity.

The type 2 scavenger receptor CD36 functions not only as a long chain fatty acid transporter, but also as a pro-inflammatory mediator. Ceramide is the simple N-acylated form of sphingosine and exerts distinct biological activity depending on its acyl chain length. Six ceramide synthases (CerS) in mammals determine the chain length of ceramide species, and CerS6 mainly produces C16-ceramide. Endotoxin-induced septic shock shows high mortality, but the pathophysiologic role of sphingolipids involved in this process has been hardly investigated. This paper aims to highlight the different role of CerS isoforms in endotoxin-induced inflammatory responses and the regulatory role of CD36 in CerS6 protein degradation with an emphasis as the potential therapeutic candidates in humans. Lipopolysaccharide (LPS), the endotoxin of the Gram-negative bacterial cell wall, was treated to induce endotoxin-induced inflammation both in vitro and in vivo. CerS6-derived C16-ceramide propagated LPS-induced inflammatory responses activating various intracellular signaling pathways, such as mitogen-activated protein kinase and nuclear factor-κB, resulting in the formation of inflammasome complex and pro-inflammatory cytokines. Mechanistically, CerS6-derived C16-ceramide augmented inflammatory responses via endoplasmic reticulum stress, and CerS6 protein stability was regulated by CD36. Finally, CerS6 protein expression and LPS-induced lethality were strikingly reduced in CD36 knockout mice. Collectively, our findings show that CerS6-derived C16-ceramide plays a pivotal role in endotoxin-induced inflammation and suggest CerS6 and its regulator CD36 as possible targets for therapy under life-threatening inflammation such as septic shock., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Yes-associated protein 1 (YAP1) is a crucial downstream effector of the Hippo pathway that plays a role in regulating inflammation and mitochondrial function. However, whether YAP1 regulates pyroptosis in nucleus pulposus (NP) cells caused by inflammation via mitophagy remains unclear. This study aimed to investigate the effects of YAP1 on the pyroptosis of NP cells induced by LPS. Here, we demonstrated that the protein expression of YAP1 in the NP tissue of degenerative discs was significantly reduced. Next, we found that NLRP3 inflammasome activation in YAP1-overexpressing (YAP1-ov) NP cells was further enhanced in the LPS-induced inflammatory microenvironment. YAP1-ov strongly aggravated inflammation-induced pyroptosis and senescence, but these effects were reversed by the inhibition of BNIP3-mediated mitophagy. However, comparative analysis of the overexpression of YAP1 in normal discs and discs after annulus fibrosus puncture revealed that YAP1-ov accelerated the degeneration of normal discs and attenuated the degeneration of annulus fibrosus punctured discs in vivo. Additionally, YAP1-ov upregulated the expression of TNFAIP3, an anti-inflammatory protective protein, and CLPP, a vital protein in the mitochondrial unfolded protein response, in NP cells. Collectively, the above results revealed that YAP1 exacerbates LPS-induced pyroptosis and senescence of NP cells by promoting BNIP3-mediated mitophagy, which causes disc degeneration. Notably, YAP1-ov mitigated the degeneration of the disc caused by annular needle puncture in vivo, suggesting its potential as a therapeutic candidate foracute IDD injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The role of B-cell lymphoma 2 (BCL2)-associated X (BAX) macropores in the leakage of mitochondrial DNA (mtDNA) and their impact on acute kidney injury (AKI) has recently been brought to the focus of researchers. This study aimed to explore the relationship between mtDNA leakage and BAX macropores during wasp sting-induced AKI. BAX mitochondrial translocation and macropores opening increased in both in vivo and in vitro models of wasp sting-induced AKI. In a mouse model, BAX inhibition dramatically attenuated mitochondrial impairment, cytoplasmic release of mtDNA, and suppressed activation of the mtDNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. This attenuation improved kidney function, reduced inflammatory response, and decreased apoptosis in mouse models. Furthermore, in cultured human proximal tubular epithelial cells (HK-2) treated with myoglobin and subjected to BAX knockdown, quantitative real-time polymerase chain reaction (PCR) directly demonstrated decreased mtDNA release into the cytoplasm. Consistent with in vivo results, downregulation of BAX expression in vitro ameliorated mitochondrial damage and attenuated subsequent inflammation and apoptosis caused by the activation of the mtDNA-cGAS-STING signaling pathway. Our findings revealed that mtDNA is released into the cytoplasm through BAX macropores in wasp sting-induced AKI, which provided an important novel perspective for understanding wasp sting-induced AKI and is conducive for identifying novel therapeutic targets and strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Butyrate can strengthen the intestinal epithelial barrier. However, the mechanisms by which butyrate affects intestinal epithelial cells (IECs) pyroptosis in Crohn's disease (CD) remain unclear. In this study, we collected colonic biopsy samples from CD patients and healthy controls to assess pyroptosis levels. Our findings indicated elevated expression of pyroptosis markers in CD patients, alongside distinct morphological evidence of pyroptosis in IECs. We further investigated the effects of tributyrin on pyroptosis and the cGAS-STING pathway in a trinitrobenzene sulfonic acid-induced colitis rat model. Tributyrin significantly mitigated intestinal inflammation, reduced pathological progression, and inhibited pyroptosis and cGAS-STING pathway activation in the colitis rat model. Similarly, in an in vitro model of IECs pyroptosis, sodium butyrate inhibited pyroptosis and cGAS-STING pathway activation in HT-29 cells. Co-treatment with a cGAS-STING pathway activator and butyrate demonstrated that the activator reversed the inhibitory effects of butyrate on pyroptosis and cGAS-STING pathway activation in both the colitis rat model and HT-29 cells. Mechanistically, the cGAS-STING pathway was found to interact with NLRP3. Taken together, butyrate may mitigate intestinal inflammation in CD by suppressing cGAS-STING-NLRP3 axis-mediated IECs pyroptosis. These findings offer new insights into potential therapeutic strategies for managing CD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: The existence of human cytomegalovirus (HCMV) is extremely widespread, causing serious diseases in patients with low immune function. The purpose of this study is to explore the efficacy and mechanism of Corilagin in the control of CMV infection, in order to provide scientific basis for the control of CMV infection., Methods: Our study employed an animal model in Balb/c mice, infected with MCMV, alongside cellular models in HFF cells and THP-1 cells, stimulated with HCMV. The expression of cGAS-STING signaling pathway molecules was detected in liver tissue, lung tissue, serum, cells and cell supernatant. The liver function and histopathological changes of mice were evaluated., Results: In vivo and in vitro experiments showed that Corilagin significantly inhibits CMV levels and attenuates pathological damage in liver and lung tissues in vivo, and similarly inhibits viral load in cells in vitro. Corilagin promotes the expression levels of STING and its downstream molecules in vivo and in vitro. Inhibition/down-regulation of STING significantly promotes CMV replication, on the contrary, activation/up-regulation of STING inhibits CMV replication, and Corilagin also promotes the expression levels of molecules related to the cGAS-STING signaling pathway in the above cases., Conclusion: Corilagin could effectively inhibit the infection and replication of CMV in vitro and in vivo, which may be through the activation of cGAS-STING signaling pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Peptidyl arginine deiminase 4 (PAD4)-mediated neutrophil extracellular traps (NETs) play a crucial role in the pathogenesis of ulcerative colitis (UC). The cGAS-STING intracellular DNA-sensing pathway has been recognized as a pivotal mediator of inflammation. This study aimed to explore how NETs contribute to intestinal inflammation and barrier dysfunction in UC, focusing on the cGAS-STING pathway. We observed a significant increase of STING expression in UC mouse colons, which was mitigated by blocking NET formation through PAD4 genetic knockout. Moreover, NETs were discovered to activate the cGAS-STING pathway in MC38 cells in a dose and time-dependent manner, leading to the secretion of inflammatory cytokines and impaired barrier function. Additionally, STING deficiency ameliorated the clinical colitis index, intestinal inflammation, and barrier dysfunction. These findings underscore the involvement of cGAS-STING in regulating NET-mediated intestinal inflammation, suggesting its potential as a novel therapeutic target for UC., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Benzothiazole-urea hybrid 8l was found to be a potent anti-bacterial agent against methicillin-resistant Staphylococcus aureus (MRSA2858) (MIC = 0.78 μM, Eur J Med Chem. 2022,236:114333). Herein, 8l was further evaluated to remedy the MRSA-infected scald with bacterial infection and severe inflammation. In scalded skin model with MRSA infection, 8l not only effectively reduced bacterial load, but also decreased pro-inflammatory cytokines secretion and promoted collagen deposition to effectively reverse the progression of wound infection and inflammation by blocking cGAS/STING/NF-κB/IRF3 signaling pathway. In vitro model of RAW264.7 cells verified that 8l can inhibit MRSA-induced inflammation via regulating this pathway. All in all, dual anti-bacterial and anti-inflammatory agent 8l could heal MRSA-infected refractory scald by regulating cGAS/STING/NF-κB/IRF3 pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

TMEM97, also known as the sigma-2 receptor, plays a crucial role as an endoplasmic reticular protein involved in various physiological processes such as wound healing, and cholesterol metabolism. Moreover, TMEM97 has been implicated in multiple human diseases including neurodegenerative disorders and cancers. Histatin peptides are endogenous peptides with diverse biological effects, including antimicrobial, immunomodulatory, and wound healing functions. Recent studies have revealed that histatin-1 (Hst1) acts as an endogenous ligand for TMEM97 and is essential for Hst1-induced corneal epithelial migration. In this study, we sought to establish the crucial Hst1 residues that facilitate binding to TMEM97. The purified full-length (FL)-TMEM97 expressed from Escherichia coli exhibited comparable binding affinity, as indicated by the dissociation equilibrium constant (K D ) determined by Surface plasmon resonance (SPR), to commercially sourced TMEM97 expressed in mammalian cells. SPR analysis revealed that TMEM97 bound to FL-Hst1 and selected deletion mutants of Hst1. Truncation experiments pinpointed the central region of Hst1 as crucial for its binding to TMEM97, with the loss of residues 15-19 either significantly weakening or completely abolishing the binding interaction. Furthermore, alanine substitution mutant experiments highlighted residues 9-19 as critical for the interaction between TMEM97 and Hst1. Functional assays including migration and signaling were also compared for Hst1 and mutant Hst1. Collectively, these findings underscore the specific binding of Hst1 to TMEM97 and elucidate the critical regions within Hst1 necessary for this interaction which is critically important for the epithelial migration and signaling changes in the ERK and Akt pathways., Competing Interests: Declaration of competing interest Vinay Kumar Aakalu, Kyung No Son and Stephanie Cologna are inventors on patents owned by the Board of Trustees of the University of Illinois at Chicago and the University of Michigan. Vinay Kumar Aakalu is an equity owner of ViSo Therapeutics Inc. These financial interests do not directly relate to the presented information., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Cell surface enzymes are important proteins that play essential roles in controlling a wide variety of biological processes, such as cell-cell adhesion, recognition and communication. Dysregulation of enzyme-catalyzed processes is known to contribute to numerous diseases, including cancer, cardiovascular diseases and neurodegenerative disease. From the perspective of drug discovery and development, there is a growing interest in detecting the cell surface enzyme activity, propelled by the arising need for innovative diagnostic and therapeutic approaches to address various health conditions., Results: In this review, we focus on advances in chemical strategies for the detection of cell surface enzyme activity. Firstly, this comprehensive review delves into the diverse landscape of cell surface enzymes, detailing their structural features and diverse biological functions. Various enzyme families on the cell surface are examined in depth, elucidating their roles in cellular homeostasis and signaling cascades. Subsequently, various biosensors, including electrochemical biosensors, optical biosensors and dual-mode biosensors, used for detecting the cell surface enzyme activity are described. Exemplars are provided to illustrate the mechanisms, limit of detection and prospective applications of these different biosensors. Furthermore, this review unravels the intricate interplay between cell surface enzymes and cellular physiology, contributing to the development of novel diagnostic and therapeutic strategies for various diseases. In the end, the review provides insights into the ongoing challenges and future prospects associated with the detection of cell surface enzyme activity., Significance: Detecting cell surface enzyme activity holds pivotal significance in biomedical research, offering valuable insights into cellular physiology and disease pathology. Understanding enzyme activity aids in elucidating signaling pathways, drug interactions and disease mechanisms. This knowledge informs the development of diagnostic tools and therapeutic interventions targeting various ailments, from cancer to neurodegenerative disease. Additionally, it contributes to the advancement of drug screening and personalized medicine approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fibroblast activation protein (FAP) has been extensively studied as a cancer biomarker for decades. Recently, small-molecule FAP inhibitors have been widely adopted as a targeting moiety of experimental theranostic radiotracers. Here we present a fast qPCR-based analytical method allowing FAP inhibition screening in a high-throughput regime. To identify clinically relevant compounds that might interfere with FAP-targeted approaches, we focused on a library of FDA-approved drugs. Using the DNA-linked Inhibitor Antibody Assay (DIANA), we tested a library of 2667 compounds within just a few hours and identified numerous FDA-approved drugs as novel FAP inhibitors. Among these, prodrugs of cephalosporin antibiotics and reverse transcriptase inhibitors, along with one elastase inhibitor, were the most potent FAP inhibitors in our dataset. In addition, by employing FAP DIANA in the quantification mode, we were able to determine FAP concentrations in human plasma samples. Together, our work expands the repertoire of FAP inhibitors, analyzes the potential interference of co-administered drugs with FAP-targeting strategies, and presents a sensitive and low-consumption ELISA alternative for FAP quantification with a detection limit of 50 pg/ml., Competing Interests: Declaration of competing interest DIANA technology is protected by patents US10718772 (B2) and US10718772 (B2) and ketoamide inhibitors are protected by patent US20230192647 (A1). The authors declare that they have no other conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Sepsis-induced acute kidney injury (SI-AKI) has become a focal point in nephrology research field due to its high mortality and potential progression to chronic kidney disease (CKD). The increase of M1 macrophages within renal tissue and their associated inflammatory responses are key contributors to renal inflammation and subsequent damage. Additionally, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway is abnormally activated during the onset of acute kidney injury (AKI). However, the relationship between the activation of this pathway and the increase in M1 macrophages has not been fully elucidated. This study investigated the protective effects and underlying mechanisms of the STING pathway-specific inhibitor C-176 on LPS-induced AKI, using an LPS and IFN-γ induced M1 macrophage model and an LPS-induced sepsis AKI mouse model. The in vivo results demonstrate that C-176 intervention can alleviate acute kidney injury and improve renal function by reducing macrophage infiltration in renal tissue, decreasing the proportion of M1 macrophages, and mitigating the inflammatory response. Additionally, in vitro results indicate that C-176 intervention inhibits the polarization of M0 macrophages to M1 macrophages, promotes their polarization to M2 macrophages, and reduces the amounts of pro-inflammatory cytokines such as IL-6 and TNF-α at both the protein and gene expression levels. The biological effects of C-176 are associated with the inhibition of STING-IRF3 signaling pathway activation. In summary, the findings of this study have certain scientific significance and application value for exploring the pathogenesis and treatment methods of SI-AKI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests that might be perceived to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fibroblast activation protein-α (FAPα) is highly expressed in tumor-associated cells and has become one of the most attractive targeting sites in cancer diagnosis and therapy. To ameliorate the rapid metabolism of FAPα inhibitor (FAPI), here, a multifunctional binding agent was introduced to simultaneously achieve 211 At radiolabeling and tumor retention prolongation of corresponding radiolabeled drug. 211 At-APBA-FAPI was successfully synthesized by conjugating 211 At with the designed FAPI carrier in satisfactory radiochemical yield (>60 %). 211 At-APBA-FAPI exhibited excellent in vitro stability, significant tumor affinity and specific killing effect on FAPα-positive U87MG cells. Molecular docking reveals that FAPI decorated with albumin binder can bind with FAPα protein via multiple intermolecular interactions with a considerable binding energy of -9.66 kcal/mol 211 At-APBA-FAPI exhibits good targeting in murine xenograft models, showing obviously longer tumor retention than previously-reported radioastatinated compound. As a result, 211 At-APBA-FAPI presents pronounced therapeutic effect with ignorable normal organs/tissues biotoxicity. All these indicate that introducing a multifunctional binding agent can effectively enhance the availability of FAPI for 211 At conjugation and tumoricidal effect, providing vital hints for the translation of targeted-alpha therapy based on radiolabeled FAPI derivatives., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

By detecting and responding to cytosolic DNA, the cGAS STING pathway regulates the innate immune responses bymediatinginflammatory reactions and antiviral defense. Thederegulation and modification of this system have been linked to variousneurodegenerative diseases like AD, PD and ALS. Accumulation of tau protein and Aβ aggregates to activate the pathway and releases neuroinflammatory cytokines which accelerates neuronal dysfunction and cognitive impairment as the symptom of AD. Similarly, in PD Alpha-synuclein aggregates activate the cGAS STING pathway and regulate the neuroinflammation and oxidative stress. In ALS, mutation of the genes causes the activation of the pathway which leads to motor neuron degeneration. Alteration of the cGAS STING pathway also leads to mitochondrial dysfunction and impaired autophagy. Preclinical investigations of AD, PD, and ALS animal models showed that STING pathway inhibitors reduced inflammation and improved neurological outcomes and modulators of the cGAS STING pathway may treat these neurodegenerative disorders. In this review we focus on the fact thatneuroinflammation, neuronal dysfunction, and various disease progressions can be treated byaltering the cGAS STING pathway. Understanding the processes and creating specific interventions for this route may offer new treatments for these terrible illnesses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, necessitating the discovery of new therapeutic targets. NPLOC4 is known as an endoplasmic reticulum protein involved in protein degradation and cellular stress responses. Herein, NPLOC4 was investigated for its role in HF using a transverse aortic constriction (TAC) mouse model and an Angiotensin II (Ang II)-induced H9c2 cardiomyocyte model. Transcriptomic analysis revealed NPLOC4 upregulation in HF. NPLOC4 knockdown in the TAC model inhibited HF progression, as evidenced by reduced cardiac hypertrophy and fibrosis. Subsequent knockdown experiments showed the relievement in heart failure phenotypes, reduced reactive oxygen species (ROS) levels and enhanced mitochondrial function caused by NPLOC4 depletion in Ang II-induced H9c2 cells. STRING analysis predicted ERO1α as a potential NPLOC4 interactor, with further studies identifying that NPLOC4 knockdown increases ERO1α expression and disrupts mitochondria-associated membranes (MAMs). Additionally, NPLOC4 knockdown modulated the β-catenin/GSK3β pathway, enhancing mitochondrial dynamics and mitophagy. These findings suggest NPLOC4 as a promising therapeutic target for HF., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Parabens are preservatives used in personal care products, cosmetics, and pharmaceuticals. Steroid 5α-reductase 1 (SRD5A1) catalyzes the conversion of testosterone to dihydrotestosterone and is present in the brain, contributing to neurosteroid production. This study aimed to assess the effects of nine paraben preservatives on SRD5A1 in human SF126 glioblastoma cell and rat brain microsomes, particularly focusing on dihydrotestosterone production in SF126 cells. The results showed that methyl, ethyl, propyl, butyl, hexyl, heptyl, nonyl, phenyl, and benzyl paraben inhibited human SRD5A1, with nonylparaben having the strongest effect (7.59 μM). Additionally, kinetic analysis indicated that parabens acted as mixed/noncompetitive inhibitors, leading to a significant decrease in dihydrotestosterone production in SF126 cells. While rat SRD5A1 exhibited lower sensitivity to parabens, docking analysis revealed that parabens bind to the NADPH-binding site of both human and rat SRD5A1. In conclusion, these results highlight the inhibitory effects of paraben preservatives on SRD5A1 and elucidate their binding mechanisms, underscoring their role in hormone production., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pterostilbene (PTS) is a dietary phytochemical that has shown antitumor activity in many types of cancer, but the molecular mechanism remains unclear. It has also not been adequately studied on PTS against esophageal squamous cell carcinoma (ESCC). Thus, this study investigated the effect of PTS on ESCC in vitro and in vivo and explored the underlying molecular mechanism. We found that PTS can inhibit the proliferation, colony formation, and migration of ESCC cells. According to the bioinformatics analysis of proteomics, PTS had a great influence on the metabolic process of ESCC cells. KEGG analysis showed that PTS down-regulated the pyruvate metabolism pathway. Moreover, PTS can inhibit the PK activity, glucose consumption, and lactate production in ESCC cells. By administration of PTS into xenograft mice, experiment results demonstrated that PTS can suppress tumor progress and the PKM2/STAT3/c-MYC signaling pathway. We found that PTS inhibited the PKM2/STAT3/c-MYC signaling pathway by targeting PKM2 in ESCC cells. Collectively, this study revealed that PTS inhibited ESCC growth by suppressing PKM2 mediated aerobic glycolysis and PKM2/STAT3/c-MYC signaling pathway, which enriching the anti-tumor molecular mechanism of PTS and providing a theoretical basis for its clinical application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Programmed cell death ligand 1 (PDL1) has been implicated in immune evasion in various tumor types. The objective of this investigation was to assess the correlation between metastasis-associated interferon-induced transmembrane protein 2 (IFITM2) and PDL1, and explore their impact on tumor immunity in gastric cancer (GC). The expression of IFITM2 and PDL1 in human GC tissues was initially evaluated using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, as well as immunohistochemistry (IHC). Subsequently, the relationship between IFITM2 and PDL1 was analyzed through Real-time quantitative PCR (RT-qPCR) and western blotting after cell transfection and inhibitor treatment in vitro. The role of IFITM2 and PDL1 in immune killing was further elucidated in both in vitro and in vivo settings. Our study revealed frequent overexpression of IFITM2 and PDL1 in GC. Notably, IFITM2 expression was significantly associated with lymphatic metastasis, clinical stage, and poor survival. Moreover, a positive correlation between PDL1 expression and IFITM2 expression in GC was identified. The activation of tumor-derived IFITM2 was found to enhance PDL1 expression via the JAK/STAT3 pathway in human GC cells (MKN28 and MKN45), leading to apoptosis of Jurkat T cells. Furthermore, IFITM2 induced PDL1 expression in a xenograft mouse model of GC. Based on our findings, we propose that IFITM2 modulates PDL1 expression and tumor immunity through the JAK/STAT3 pathway in GC cells, highlighting the potential of IFITM2 as a therapeutic target for GC immunotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Recently studies showed that cow mastitis seriously affected the economic benefit of dairy industry and pathogen infection including S. aureus is the main cause of mastitis. However, there is still a lack of safe and effective treatment for S. aureus-induced mastitis due to its complex pathogenesis. Endogenous retroviruses (ERVs) have long been symbiotic with mammals, and most ERVs still have the ability to produces complementary DNA (cDNA) by reverse transcription, whose induction by commensal or pathogens can regulate host immunity and inflammatory responses through the cGAS-STING pathway. However, whether and how ERVs participate in the pathogenesis of S. aureus-induced mastitis still unclear. In this study, we found that S. aureus treatment increased the levels of ERVs and IFN-β. Inhibition the transcription of ERVs by emtricitabine alleviated S. aureus-induced mammary injury, reduced mammary bacterial burden, and inhibited the production of mammary proinflammatory factors including TNF-α, IL-1β and MPO activity. Moreover, inhibition of ERVs restored the function of blood-milk barrier caused by S. aureus. Next, we showed that S. aureus infection activated mammary cGAS-STING signaling pathway, which was mediated by ERVs, as evidenced by emtricitabine inhibited S. aureus-induced activation of the cGAS-STING pathway. Interestingly, inhibition of cGAS-STING by Ru.521 and H151 respectively, significantly alleviated S. aureus-induced mammary injury and inflammatory responses, which was associated with the inhibition of NF-κB and NLRP3 signaling pathways. In conclusion, our study revealed that ERVs regulate the development of S. aureus-induced mastitis in mice through NF-κB- and NLRP3-mediated inflammatory responses via the activation of cGAS-STING pathway, suggesting that targeting ERVs-cGAS-STING axis may be a potential approach for the treatment of S. aureus-induced mastitis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aberrant activation of the innate immune molecule STING can initiate inflammation and autoimmune diseases. Small molecule inhibitors targeting STING have demonstrated therapeutic efficacy against these conditions. Moreover, employing degradants to target STING represents a novel approach to drug design strategy. Consequently, we have designed and synthesized a series of covalent degradants targeting STING. Among them, compound P8 exhibited the highest degradation capacity, with a 24-h DC 50 of 2.58 μM in THP-1 cells. In THP-1 cells, P8 specifically degraded STING proteins through the lysosomal pathway, acting as dual a degrader and inhibitor to manifest anti-inflammatory effects. Conversely, in RAW264.7 cells, P8 solely acted as an inhibitor without exhibiting degradative capacity towards the STING protein level. Additionally, P8 displayed renal-protective properties in a cisplatin-induced acute kidney injury model. These results highlight the significant potential of further investigating compound P8., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

To investigate the mechanism by which swertiamarin (swertianin, SWE) regulates the polarization of tumor microenvironment-associated macrophages to M1 phenotype, thereby exerting anti-tumor effects.SWE promoted the formation of M1 cells and increased the proportion of CD86 + cells in both RAW264.7 and primary monocyte-derived macrophages, while activating the STING-NF-κB pathway. When STING or P65 was knocked out, the effects of SWE were antagonized, inhibiting the formation of CD86 + M1 cells. At the animal level, SWE inhibited tumor growth, activated STING-NF-κB, and promoted the formation of CD86 + cells. STING-KO inhibited the effects of SWE.SWE can activate the STING-NF-κB signal to promote macrophage M1 polarization, playing an anti-tumor role., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Triphala is renowned for its curative attributes and has been utilized for centuries to address diverse health ailments. Moreover, the active component of Triphala, polyphenols, is widely recognized for its excellent pharmacological activities, such as anti-inflammatory properties, and has been utilized as a potential natural remedy. However, the precise mechanism through which Triphala alleviates cognitive dysfunction and anxiety induced by chronic sleep deprivation (SD) remains restricted. The objective of this investigation is to examine and clarify the potential mechanism of action that underlies the therapeutic benefits of Triphala in addressing cognitive dysfunction and anxiety induced by chronic SD. Our results demonstrated that Triphala significantly alleviates chronic SD-induced behavioral abnormalities. Additionally, Triphala was highly effective at preventing histopathological or morphological damage to neurons located in the hippocampus. The therapeutic effects of Triphala in treating cognitive dysfunction and anxiety induced by chronic SD involve the modulation of several biological pathways, including inflammation and immune responses, oxidative stress, cell growth and differentiation, metabolism, and neurotransmitter communication. Moreover, our study illustrated that Triphala increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and significantly activated the Nrf2/hemeoxygenase-1 (HO-1) axis. Additionally, the neuroprotective properties of Triphala were found to be counteracted by the Nrf2 inhibitor ML385. Our study represented the first to unveil that Triphala exerts therapeutic benefits in alleviating chronic SD-induced cognitive deficits and anxiety by activation of the Nrf2/HO-1 axis. Triphala emerges as a promising nutraceutical ingredient for mitigating cognitive deficits and anxiety linked to chronic SD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS)-dependent pathway is a key DNA-sensing pathway that recognizes cytosolic DNA and plays a crucial role in initiating innate immune responses against pathogenic microbes and cancer. Various molecules have been identified as regulators of the cGAS-dependent pathway that controls innate immune responses. However, despite the important roles of Stimulator-of-interferon genes (STING) in the cGAS-dependent pathway, the regulation of its activation has not been elucidated. Here, we show that the E3 ubiquitin ligase, RING finger protein 39 (RNF39), interacts with STING in macrophages and HERK293T cells. Moreover, RNF39 accelerates DNA-sensing pathways by promoting lysine (K)63-linked ubiquitination of STING, and then facilitating the formation of STING-TBK1 complex. Concordantly, Rnf39 deficiency inhibits innate immune responses triggered by DNA viral infection and accelerates viral replication. Furthermore, herpes simplex virus-1 (HSV-1) infection induces RNF39 expression in an IFN-I-dependent manner. Thus, we outline a novel mechanism for controlling STING activation and a feedback mechanism for controlling antiviral immune responses. RNF39 could be a priming intervention target for the prevention and treatment of viral diseases, especially DNA viral infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Osteoarthritis (OA) is a degenerative disease, its characteristic lies in the inflammation and extracellular matrix (ECM) degradation, can lead to significant personal disability and social burden. Lycopodium japonicum Thunb. (LJT) is a lycopinaceae plant with anti-inflammatory and analgesic effects. In traditional Oriental medicine, LJT is commonly used to treat a variety of conditions, including osteoarthritis and low back pain., Aim of the Study: To investigate the anti-apoptotic, anti-inflammatory and anti-senescence properties of LJT in IL-1β-induced mouse chondrocytes, and to clarify the underlying mechanisms involved. In addition, the study also examined the effects of LJT by establishing a mouse model of osteoarthritis. The ultimate goal is to identify the mechanism of LJT as an anti-osteoarthritis agent., Materials and Methods: In this research, molecular docking and network pharmacology analysis were performed to identify the latent pathways and key targets of LJT action. The CCK-8 kit was used to evaluate LJT's effect on chondrocyte viability. Western blotting, Immunofluorescence, TUNEL staining kit, and SA-β-gal staining were employed to verify LJT's impact on chondrocytes. Additionally, SO, HE, and Immunohistochemical were utilized to assess LJT's effects on osteoarthritis in mice. In vitro and in vivo experiments were performed to verify the potential mechanism of LJT in OA., Results: Network pharmacology analysis revealed that AKT1, PTGS2, and ESR1 were the key candidate targets for the treatment of OA with LJT. The results of molecular docking indicated that AKT1 exhibited a low binding affinity to the principal constituents of LJT. Hence, we have chosen STING, an upstream regulator of PTGS2, as our target for investigation. Molecular docking revealed that sitosterol, formononetin, stigmasterol and alpha-Onocerin, the main components of LJT, have good binding activity with STING. In vitro experiments showed that LJT inhibited IL-1β-mediated secretion of inflammatory mediators, apoptosis and senescence of chondrocytes. The results showed that LJT abolished cartilage degeneration induced by unstable medial meniscus (DMM) in mice. Mechanism research has shown that LJT by inhibiting the STING/NF-κB signaling pathways, down-regulating the NF-κB activation, so as to inhibit the development of OA., Conclusion: LJT reversed the progression of OA by inhibiting inflammation, apoptosis and senescence in animal models and chondrocytes. The effects of LJT are mediated through the STING/NF-κB pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Sanqi oral solution (SQ) is a traditional Chinese patent medicine, widely used to treat chronic kidney diseases (CKD) in the clinic in China. Previous studies have confirmed its anti-renal fibrosis effect, but the specific pharmacological mechanism is still unclear., Aim of the Study: Focusing on energy metabolism in fibroblasts, the renoprotective mechanism of SQ was investigated in vitro and in vivo., Methods: Firstly, the fingerprint of SQ was constructed and its elementary chemical composition was analyzed. In the 5/6Nx rats experiment, the efficacy of SQ on the kidney was evaluated by detecting serum and urine biochemical indexes and pathological staining of renal tissues. Lactic acid and pyruvic acid levels in serum and renal tissues were detected. PCNA protein expression in kidney tissue was detected by immunofluorescence assay and Western blot. Expression levels of HIF-1α, PKM2 and HK2 were determined by immunohistochemistry, Western blot or RT-qPCR assay. In addition, the effect of SQ intervention on cell proliferation and glycolysis was evaluated in TGF-β1-induced NRK-49F cells, and the role of SQ exposure and HIF-1α/PKM2/glycolysis pathway were further investigated by silencing and overexpressing HIF-1α gene in NRK-49F cells., Results: In 5/6 Nx rats, SQ effectively improved renal function and treated renal injury. It reduced the levels of lactic acid and pyruvic acid in kidney homogenates from CKD rats and decreased the expression levels of HIF-1α, PKM2, HK2, α-SMA, vimentin, collagen I and PCNA in kidney tissues. Similar results were observed in vitro. SQ inhibited NRK-49F cell proliferation, glycolysis and the expression levels of HIF-1α, PKM2 induced by TGF-β1. Furthermore, we established NRK-49F cells transfected with siRNA or pDNA to silence or overexpress the HIF-1α gene. Overexpression of HIF-1α promoted cellular secretion of lactic acid and pyruvic acid in TGF-β1-induced NRK-49F cells, however, this change was reversed by intervention with SQ or silencing the HIF-1α gene. Overexpression of HIF-1α can further induce increased PKM2 expression, while SQ intervention can reduce PKM2 expression. Moreover, PKM2 expression was also inhibited after silencing HIF-1α gene, and SQ was not effective even when given., Conclusion: The mechanism of action of SQ was explored from the perspective of energy metabolism, and it was found to regulate PKM2-activated glycolysis, inhibit fibroblast activation, and further ameliorate renal fibrosis in CKD by targeting HIF-1α., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Secretory proteins are critically dependent on the correct processing of their signal sequence by the signal peptidase complex (SPC). This step, which is essential for the proper folding and localization of proteins in eukaryotic cells, is still not fully understood. In eukaryotes, the SPC comprises four evolutionarily conserved membrane subunits (Spc1-3 and Sec11). Here, we investigated the role of Spc2, examining SPC cleavage efficiency on various models and natural signal sequences in yeast cells depleted of or with mutations in Spc2. Our data show that discrimination between substrates and identification of the cleavage site by SPC is compromised when Spc2 is absent or mutated. Molecular dynamics simulation of the yeast SPC AlphaFold2-Multimer model indicates that membrane thinning at the center of SPC is reduced without Spc2, suggesting a molecular explanation for the altered substrate recognition properties of SPC lacking Spc2. These results provide new insights into the molecular mechanisms by which SPC governs protein biogenesis., (© 2024 Chung et al.)

Two recent papers by Szentgyörgyi et al. (http://doi.org/10.1083/jcb.202401167) and Pankiv et al. (http://doi.org/10.1083/jcb.202408173) provide new insights into the roles of BEACH domain proteins in membrane trafficking and cellular homeostasis. They explore which membranes they are recruited to, how they are recruited, and the potential coat-like functions of these proteins., (© 2024 Pereira and Gershlick.)

We identify BEACH domain-containing proteins (BDCPs) as novel membrane coat proteins involved in the sorting of transmembrane proteins (TMPs) on the trans-Golgi network and tubular sorting endosomes. The seven typical mammalian BDCPs share a predicted alpha-solenoid-beta propeller structure, suggesting they have a protocoatomer origin and function. We map the subcellular localization of seven BDCPs based on their dynamic colocalization with RAB and ARF small GTPases and identify five typical BDCPs on subdomains of dynamic tubular-vesicular compartments on the intersection of endocytic recycling and post-Golgi secretory pathways. We demonstrate that BDCPs interact directly with the cytosolic tails of selected TMPs and identify a subset of TMPs, whose trafficking to the plasma membrane is affected in cells lacking BDCP. We propose that the competitive binding of BDCPs and clathrin coat adaptors to the cytosolic tails of TMPs, followed by their clustering to distinct subdomains of secretory/recycling tubules function as a mechanism for sorting of TMPs in pleomorphic tubular-vesicular compartments that lack a clathrin coat., (© 2024 Pankiv et al.)

As a consequence of hypoosmotic shock, yeast cells swell rapidly and increase the surface area by ∼20% in 20 s. Approximately, 35% of this surface increase is mediated by the ER-plasma membrane contact sites, specifically the tricalbins, which are required for the delivery of both lipids and the GPI-anchored protein Crh2 from the cortical ER to the plasma membrane. Therefore, we propose a new function for the tricalbins: mediating the fusion of the ER to the plasma membrane at contact sites. This proposed fusion is triggered by calcium influx via the stretch-gated channel Cch1 and is supported by the anoctamin Ist2., (© 2024 Smith et al.)

Kidney is a classic organ undergoing senescence, and chronic inflammation has an important effect in cellular senescence. Mincle has been shown to be vital for maintaining the M1 phenotype of macrophages, but its role in regulating renal aging has yet to be explored. Young (2 months of age) and old (24 months of age) mice were used to analyze the changes of kidney damage during natural aging. Mice were subcutaneously injected with D-galactose (D-gal) to establish a renal aging model, and miR-6948-3p mimic and Mincle siRNA were administered via the tail vein every 3 days. Aged kidney and experimental aging kidney were characterized by decreased renal function and structural damage, and upregulated expression of senescence-related proteins and SPAP components. The ratio of M1 macrophages was increased in the aged kidney, and Mincle accumulated in the aged kidney macrophages. Administration of miR-6948-3p mimic or Mincle siRNA alleviated D-gal-induced renal senescence. LPS was used to induce M1 polarization of bone marrow-derived macrophages, and a coculture system of M1 macrophages and mouse renal tubular epithelial cells (TCMK-1) was established. Mincle was upregulated in LPS-induced M1 macrophages in vitro, and silencing Mincle in M1 macrophages attenuated M1 macrophage-induced TCMK-1 cell senescence. Mechanistically, Mincle was regulated by miR-6948-3p and maintained the M1 phenotype of macrophages through the Syk/NF-κB pathway. In conclusion, Mincle, posttranscriptionally suppressed by miR-6948-3p, modulated renal senescence by maintaining the phenotype of M1 macrophages through the Syk/NF-κB pathway., (© 2024 Wiley Periodicals LLC.)

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by a high metastatic potential with an overall survival rate of ~5%. The transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed by >50% of tumors, including SCLC, but its role in SCLC development and metastasis is unclear. Here, we show that, while STAT3 deletion restricts primary tumor growth, it paradoxically enhances metastatic spread by promoting immune evasion. This occurs because STAT3 is crucial for maintaining the immune sensor stimulator of interferon (IFN) genes (STING). Without STAT3, the cyclic adenosine monophosphate-guanosine monophosphate synthase-STING pathway is inactive, resulting in decreased type I IFN secretion and an IFN gene signature. Importantly, restoration of IFN signaling through re-expression of endogenous STING, enforced expression of IFN response factor 7 or administration of recombinant type I IFN re-established antitumor immunity, inhibiting metastatic SCLC in vivo. These data show the potential of augmenting the innate immune response to block metastatic SCLC., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes [1] signaling pathway has emerged as a pivotal immune response mechanism, activating immune defenses upon detection of both exogenous and endogenous DNA within cells. Its activation is intricately linked to various diseases and inflammatory processes, spanning autoimmune disorders, infectious ailments, and malignancies. Among pancreatic diseases, encompassing acute pancreatitis, chronic pancreatitis, and pancreatic cancer, current clinical treatment efficacy remains suboptimal. Here, we elucidate the molecular intricacies of the cGAS-STING signaling pathway and delineate its therapeutic potential in acute pancreatitis, chronic pancreatitis, and pancreatic cancer. Additionally, we offer an overview of recent advancements in STING agonists and antagonists, assessing their therapeutic potential in pancreatic-related disorders. In summary, by exploring the multifaceted roles of the cGAS-STING signaling pathway and its implications in pancreatic diseases, we aim to shed light on potential avenues for therapeutic intervention and management in these challenging clinical contexts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Acute lung injury (ALI) is a common complication of sepsis and a leading cause of mortality in septic patients. Studies indicate that STING may play a crucial role in the pathogenesis of sepsis-induced ALI by interacting with the PARP-1/NLRP3 pathway. Therefore, targeting STING inhibition has potential as a novel therapeutic strategy for ALI. However, effective inhibition remains challenging due to the widespread expression of STING across various tissues. In this study, we developed a nanozyme-based drug delivery system, DSPE-TK-mPEG-MnO 2 @siSTING (abbreviated as DTmM@siSTING), using DSPE-TK-mPEG-MnO 2 as the carrier, and characterized it via scanning electron microscopy, dynamic light scattering, nanoparticle size analysis, and gel electrophoresis. To evaluate the therapeutic effects of DTmM@siSTING, an in vitro ALI cell model and an in vivo ALI mouse model were established, assessing the nanozyme's impact on ROS levels, inflammatory responses, and the PARP-1/NLRP3 pathway in sepsis-induced ALI. Results demonstrated that DTmM@siSTING exhibited good physiological stability. In vitro, DTmM@siSTING significantly reduced ROS levels, myeloperoxidase activity, and expression of inflammatory cytokines, while also inhibiting PARP-1/NLRP3 pathway activation. In vivo experiments further revealed that DTmM@siSTING effectively delivered siSTING to the lungs, mitigating sepsis-induced ALI and associated inflammatory responses. Additionally, DTmM@siSTING displayed excellent biocompatibility. In summary, our findings suggest that DTmM@siSTING significantly enhances the therapeutic efficacy of siSTING, alleviating ALI by inhibiting ROS production, inflammatory responses, and activation of the PARP-1/NLRP3 pathway. This novel approach presents a promising therapeutic avenue for sepsis-induced ALI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: The aberrant H-type vessel formation was found to be intimately linked to subchondral bone remodeling during osteoarthritis (OA) development. Herein, we investigated the role and mechanism of osteoblast-secreted slit guidance ligand 3 (Slit3) in H-type vessel formation during OA progression., Methods: Slit3 protein levels in subchondral bone samples of OA patients were detected. The isolated osteoblasts were transfected with Slit3 overexpression or knockdown plasmids, and their conditioned medium was cultured with endothelial progenitor cells (EPCs). The migration, tube formation, VEGF, and H-type vessel marker protein CD31 and endomucin (EMCN) levels in EPCs were accessed. The interactions between Slit3 and roundabout (Robo) family members were validated by Co-IP assay. Besides, whether the Slit3/Robo signaling affects the transforming growth factor β1 (TGF-β1)/SMADs pathway was determined. Additionally, sh-Slit3 was injected into OA mice, followed by the detection of articular cartilage degradation, subchondral bone remodeling, and H-type vessel formation., Results: Slit3 was upregulated in subchondral bone tissues of OA patients. Slit3 overexpression in osteoblasts intensified the migration and H-type vessel formation of EPCs, while Slit3 knockdown showed the opposite results. Slit3 overexpression enhanced Robo1 protein level. Robo1 knockdown abrogated Slit3-mediated migration and H-type vessel formation in EPCs. Slit3 activated the TGF-β1/SMADs pathway in EPCs, which might be associated with H-type vessel formation in EPCs. Additionally, Slit3 silencing restrained articular cartilage degradation, aberrant subchondral bone formation, and H-type vessel formation in OA mice., Conclusion: Inhibition of Slit3/Robo1 signaling alleviates osteoarthritis in mice by reducing abnormal H-type vessel formation in the subchondral bone.

Background: The kidneys are the primary excretory organs for platinum drugs, making them susceptible to damage from these drugs. Cisplatin-induced acute kidney injury (CIAKI) is the most common side effect observed in patients undergoing clinical cisplatin treatment. A traditional Chinese medicinal preparation, the Yi-Qi-Jian-Pi-Xiao-Yu formula (YQJPXY), which is a modified formulation of the classical Chinese medicine formula Buyang Huanwu Decoction, has long been used in the treatment of clinical kidney diseases. It is expected to be used to ameliorate cisplatin-induced acute kidney injury. However, the mechanism of this YQJPXY for the treatment of cisplatin-induced acute kidney injury remains unclear., Purpose: The objective of this study is to examine the impact of the YQJPXY on the inhibition of ferroptosis in cisplatin-induced acute kidney injury and to elucidate the underlying mechanisms., Methods: The active components of YQJPXY were analysed using UPLC-MS/MS. A comprehensive investigation was conducted to elucidate the effects and regulatory mechanisms of YQJPXY on CIAKI and ferroptosis in mice subjected to acute cisplatin treatment and in mice receiving cisplatin treatment after STING expression was inhibited using the STING inhibitor C176. The renoprotective effect of YQJPXY on cisplatin-treated mice was evaluated by measuring tissue damage, inflammation and pro-fibrosis. In addition, we employed network pharmacology and molecular docking methodologies to analyse the principal regulatory targets of YQJPXY. Furthermore, the expression of key proteins and markers of ferroptosis and iron metabolism, as well as the levels of key indicators related to STING-associated ferritinophagy, were examined by immunoblotting, immunohistochemistry, immunoprecipitation, quantitative real-time PCR (qPCR) and specific probes., Results: The results demonstrated that YQJPXY reduced the levels of indicators of injury, inflammation and pro-fibrosis in CIAKI mice, with renoprotective effects. Network pharmacological analyses revealed that ferroptosis might be the main biological process regulated by YQJPXY. Furthermore, molecular docking results indicated that STING might be a potential regulatory target of YQJPXY. Furthermore, YQJPXY treatment resulted in a significant reduction in MDA and 4-HNE levels, as well as the inhibition of ferroptosis and improvement in iron metabolic processes. Concomitantly, YQJPXY exhibited a robust protective effect on ferroptosis and iron metabolism homeostasis, as evidenced by its inhibitory action on ferritinophagy. Validation experiments utilising the cisplatin inhibitor C176 demonstrated that YQJPXY inhibits cisplatin-induced ferroptosis in kidney via STING-mediated ferritinophagy., Conclusion: These suggest that YQJPXY alleviates cisplatin-induced acute kidney injury through suppressing ferroptosis via STING-NCOA4-mediated Ferritinophagy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background and Aims: The small intestine plays a central role in lipid metabolism, most notably the uptake of dietary fats that are packaged into chylomicrons and secreted into the circulation for utilisation by peripheral tissues. While microsomal triglyceride transfer protein (MTP) is known to play a key role in this pathway, the intracellular assembly, trafficking, and secretion of chylomicrons is incompletely understood., Methods and Results: Using human transcriptome datasets to find genes co-regulated with MTTP, we identified ERICH4 as a top hit. The gene encodes for glutamate-rich protein 4, a protein of unknown function. REACTOME gene-function prediction tools indicated that ERICH4 is involved in intestinal lipid metabolism. In addition, GWAS data point to a strong relationship between ERICH4 and plasma lipids. To validate ERICH4 as a lipid gene, we generated whole-body Erich4 knockout (Erich4 -/- ) mice. ERICH4 deficiency, however, did not result in changes in body weight and composition, food intake, circulating plasma lipids, energy absorption and excretion, and tissue weights compared to controls. Additionally, there were no morphological abnormalities seen in the small intestine. Challenging mice with a high-fat diet did not give rise to a phenotype either., Conclusions: Despite prediction tools indicating ERICH4 as a strong candidate gene in intestinal lipid metabolism, we here show that ERICH4 does not play a role in intestinal lipid metabolism in mice. It remains to be established whether ERICH4 plays a role in human lipid metabolism., Competing Interests: Declaration of competing interest The other authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Listeria monocytogenes ( L. monocytogenes ) is a foodborne intracellular pathogen that causes serious disease in both humans and animals. InlB is the major internalin protein of L. monocytogenes , which anchors to the bacterial surface and mediates its invasion into various host cells. Recent studies have shown that galactosylation of the cell wall polymer wall teichoic acid (WTA) is essential for InlB anchoring on the cell surface of L. monocytogenes serotype 4b strains. Galactosylation of WTA is exerted by the coordinated action of several glycosyltransferases, including GalU, GalE, GtcA, GttA, and GttB. Among these glycosyltransferases, GttA and GttB are specific to serotype 4b strains, whereas GalE, GalU, and GtcA are conserved across all serotypes. The role of GalE in InlB anchoring and L. monocytogenes pathogenicity remains unclear. In this study, we deleted the galE gene, which is involved in galactosylation, from L. monocytogenes strain ScottA. We found that galE deletion reduced InlB anchoring, weakened bacterial adhesion and invasion of Caco-2 cells (human colorectal adenocarcinoma cells) and MGC803 cells (human gastric carcinoma cells), increased phagocytosis but decreased proliferation in RAW264.7 cells (mouse mononuclear macrophage leukaemia cells), and decreased bacteria load, mortality, and tissue damage in infected mice. Taken together, galE deletion significantly reduced the anchoring of InlB and weakened the pathogenicity of L. monocytogenes . This finding provides new insights into the correlation between cell wall modification and pathogenicity of L. monocytogenes .

Membrane proteins remain challenging targets for conventional structural biology techniques because they need to reside within complex hydrophobic lipid environments to maintain proper structure and function. Magnetic resonance combined with site-directed spin labeling is an alternative method that provides atomic-level structural and dynamical information from effects introduced by an electron- or nuclear-based spin label. With the advent of bioorthogonal click chemistries and genetically engineered non-canonical amino acids (ncAAs), options for linking spin probes to biomolecules have substantially broadened outside the conventional cysteine-based labeling scheme. Here, we highlight current strategies to spin-label membrane proteins through ncAAs for nuclear and electron paramagnetic resonance applications. Such advances are critical for developing bioorthogonal spin labeling schemes to achieve in-cell labeling and in-cell measurements of membrane protein conformational dynamics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Gut microbiome dysbiosis is involved in non-alcoholic fatty liver disease (NAFLD) development. Hepatic transmembrane 4 L six family member 5 (TM4SF5) overexpression promotes NAFLD. However, how gut microbiota are associated with TM4SF5-mediated NAFLD remains unexplored. We analyzed the gut microbiome using feces from hepatocyte-specific TM4SF5-overexpressing transgenic (Alb-TG Tm4sf5 -Flag , TG) or Tm4sf5 -/- knock-out (KO) mice fed a normal chow diet (NCD), high-fat diet (HFD) for 2 weeks (HFD 2W ), or methionine-choline-deficient diet (MCD) for 4 weeks to investigate associations among Tm4sf5 expression, diet, and the gut microbiome. TG-NCD mice showed a higher Firmicutes-to-Bacteroidetes (F/B) ratio, with less enrichment of Akkermansia muciniphila and Lactobacillus reuteri. NASH-related microbiomes in feces were more abundant in TG-HFD 2w mice than in KO-HFD 2w mice. Further, TG-MCD showed a higher F/B ratio than TG-NCD or KO mice, with decreases or increases in microbiomes beneficial or detrimental to the liver, respectively. Such effects in TG-MCD animals were correlated with functional pathways producing short-chain fatty acids (SCFAs). Furthermore, potential functional pathways of the gut microbiome were metabolically parallel to NAFLD features in TG-MCD mice. These results suggest that hepatocyte Tm4sf5 supports gut microbiome dysbiosis and metabolic activity, leading to SCFA production and hepatic inflammation during NAFLD development., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Autophagy is an important cellular process for maintaining physiological homeostasis and is known to protect against cardiovascular diseases including ischemia reperfusion (I/R) injury. The underlying mechanisms behind its protection require further characterization., Materials and Methods: Atg7 knock out (AKO) mice were generated and subjected to I/R injury, complemented by Atg7 KO in a H9c2 cardiomyoblast cellular model ± hypoxia-reoxygenation. Subsequently, in both models, inflammation and cell death were studied., Key Findings: We confirmed that Atg7 KO led to autophagy, including mitophagy, deficiency. Upon H/R, Atg7 KO cells exhibited increased cell death compared to WT cells. Notably, we found that autophagy deficiency increased stress-induced mitochondrial fission, release of mitochondrial DNA, and sterile inflammation, namely activation of a STING/IRF3 axis leading to elevated interferon-α. Following I/R injury, AKO mice showed elevated cell death which correlated with a gene expression profile indicative of decreased anti-inflammatory responses., Significance: Autophagy deficiency in the cardiomyocyte setting results in detrimental effects during I/R injury in mice or H/R injury in cells, mediated in part via mtDNA/IRF3/STING pathway. As such, modulation of this pathway may yield novel and promising therapeutics to treat or prevent I/R injury., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gary Sweeney reports financial support was provided by the Heart & Stroke Foundation of Canada. Gary Sweeney reports a relationship with Allysta Pharmaceuticals Inc. that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Transmembrane protein 151A (TMEM151A) has been identified as a causative gene for paroxysmal kinesigenic dyskinesia, though its molecular function remains almost completely unknown. Understanding the membrane topology of transmembrane proteins is crucial for elucidating their functions and possible interacting partners. In this study, we utilized molecular dynamics simulations, immunocytochemistry, and electron microscopy to define the topology of TMEM151A. Our results validate a starting AlphaFold model of TMEM151A and reveal that it comprises a transmembrane domain with two membrane-spanning alpha helices connected by a short extracellular loop and an intramembrane helix-hinge-helix structure. Notably, most of the protein is oriented towards the intracellular side of the membranes with a large cytosolic domain featuring a combination of alpha-helix and beta-sheet structures, as well as the protein N- and C-termini. These insights into TMEM151A's topology and orientation of its domains with respect of the cell membranes provide essential information for future functional studies and represent a first fundamental step for understanding its role in the pathogenesis of paroxysmal kinesigenic dyskinesia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Small cell transformation (SCT) is a typical mechanism of adaptive resistance to third generation epidermal growth factor receptor inhibitors (EGFRi) which have become the standard of care for EGFR-driven non-small cell lung cancer (EGFR+ NSCLC). Little is known about the optimal management of SCT patients. This study aimed to compare outcomes under platinum/etoposide chemotherapy alone (chemo) or in combination with EGFR inhibitors (EGFRi+chemo) or immune checkpoint inhibitors (ICI+chemo). In addition, DLL3 expression was explored as potential novel therapeutic target., Methods: We conducted a retrospective study on patients with EGFR+ NSCLC and SCT treated at 19 centers in Europe and the United States. A total of 47 patients were included of whom 17 received chemo, 20 ICI+chemo, and 10 EGFRi+chemo. We analyzed DLL3 expression by immunohistochemistry., Results: In the entire cohort, median overall survival (OS) from start of first SCT therapy was 11 months (95 % confidence interval [95 %CI] 9.1-12.9) and median progression-free survival (PFS) was 5 months (95 %CI 4.2-5.8). Median PFS was similar in all three groups (chemo and ICI+chemo 4 months, EGFRi+chemo 6 months), and 12-months PFS was 12 % (95 %CI 2 %-31 %), 13 % (95 %CI 0 %-43 %), and 0 % for ICI+chemo, EGFRi+chemo, and chemo, respectively. Median OS in the ICI+chemo group was 13 months (95 %CI 5.5-20.5) compared to 10 months (95 %CI 7.6-12.4) with chemo and EGFRi+chemo (95 %CI 8.1-11.9), respectively. Before and after SCT, 0 % and 93 % of tumors were DLL3-positive., Conclusions: Our results suggest that ICI+chemo and DLL3-targeting agents are worth further exploration in EGFR+ NSCLC undergoing SCT., Presented Elsewhere: Part of this work has been presented at ESMO annual meeting in Madrid, Spain in October 2023 (Poster 1336 P)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Allgäuer, M received speaker fees from Boehringer Ingelheim. Alt, J received speaker fees and/or honoraria for advisory boards by Astra Zeneca, Pfizer, Daichii Sankyo, Roche, Amgen, MSD, Novartis, Janssen, Boehringer Ingelheim, Merck, BMS. Aust, DEA received honoraria from Roche, Astra Zeneca, MSD, Pfizer, Novartis. Christopoulos. P received research funding from Roche, Amgen, Boehringer Ingelheim, Takeda, Merck, AstraZeneca, and Novartis, honoraria from Roche, Takeda, Gilead, AstraZeneca, Merck, Thermo Fisher, Janssen, Pfizer, and Novartis, travel support from AstraZeneca, Pfizer, Janssen, Merck, Gilead, Daiichi Sankyo, Takeda, Novartis, Eli Lilly and compensation for advisory roles for Pfizer, Chugai, Boehringer Ingelheim, Takeda, Janssen, Novartis, astraZeneca, MSD, Roche. Griesinger, F received speaker fees and/or honoraria for advisory boards from AstraZeneca, Boehringer, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Tesaro/GSK, Siemens, Tesaro, Amgen, Sanofi, Daiichi-Sankyo, Beigene. Grohé, C received honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche, and has had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. Hochmair, M received honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche, and has had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. Illini, O received speaker fees and/or honoraria for advisory boards from Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Menarini, Merck Sharp & Dohme, Pfizer, and Roche and received research grants from Amgen and AstraZeneca outside of the submitted study. Jöhrens, K received compensation for advisory roles for BMS, GSK, Merck Sharp & Dohme, honoraria from AstraZeneca, Agilent, Boehringer Ingelheim, and DSO, and serves as medical advisor for QuIP. Kauffmann-Guerrero received speaker fees and/or honoraria for advisory boards from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Novartis, Pfizer, Roche, Takeda. Kirfel, J received speaker fees and/or honoraria for advisory boards, from AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer and Roche. König, D received a personal grant from Geistlich-Stucki-Stiftung, consulting fees from AstraZeneca, Merck, MSD, Novartis, PharmaMar, honoraria for presentations from Amgen, BMS, Mirati, Sanofi, Swiss Oncology in Motion, support for attending meetings from Amgen, Roche, Sanofi, honoraria for advisory boards from AstraZeneca, BMS, Merck, MSD, PharmaMar, Roche. Michels, S received research grants from Novartis and Pfizer, personal fees from Eli Lilly, Janssen, and Astra Zeneca as well as support for attending meetings and/or travel from Eli Lilly, and Janssen. Overbeck, T received speaker fees and/or honoraria for advisory boards by AstraZeneca, BMS, Boehringer-Ingelheim, Eli Lilly, Janssen-Cilag, Merck, MSD, Novartis, Roche, Takeda, Tesaro/GSK, Lilly, Roche, travel reimbursement by AstraZeneca, Boehringer-Ingelheim, Janssen-Cilag, Lilly, and Roche. Rohde, G received personal fees from Astra Zeneca, Atriva, Boehringer Ingelheim, GSK, Insmed, MSD, Sanofi, Novartis and Pfizer for consultancy during advisory board meetings and personal fees from Astra Zeneca, Berlin Chemie, BMS, Boehringer Ingelheim, Chiesi, Essex Pharma, Grifols, GSK, Insmed, MSD, Roche, Sanofi, Solvay, Takeda, Novartis, Pfizer and Vertex for lectures. Rothschild, S received honoraria (institutional) from, Roche, AstraZeneca, BMS, Boheringer Ingelheim, MSD Oncology, Novartis, Amgen, Lilly, Eisai, Merck serono, Pfizer, Takeda, Bayer, Janssen Oncology, Otsuka, PharmaMar, and Sanofi, compensation for advisory roles for AstraZeneca, Boerhinger Ingelheim, BMS, Pfizer, Eisai, Eli Lilly, Merck Serono, MSD Oncology, Novartis, Roche Pharma AG, Takeda, Amgen, Otsuka, PharmaMar, serves for the speakers bureau of Roche Pharma AG, Sanodi/Aventis, Amgen, AstraZeneca, Takeda, received research funding from Abbvie, BMS, AstraZeneca, Boerhinger Ingelheim, Merck Serono, Roche Pharma AG, and travel support, accomodation, expenses from Sanofi, Roche Pharma AG, BMS, MSD Oncology, AstraZeneca, Takeda, Boehringer Ingelheim, Amgen. He serves at the Federal Drug Comission of the Federal Office of Public Health and the Swiss Group for Clinical Cancer Research (SAKK). Saalfeld, F received research funding from Roche, consultancy fees from Boehringer Ingelheim, honoraria for lectures from AstraZeneca, Janssen, Takeda, Pfizer, Novartis, Thieme, and GWT-TUD, travel support from Janssen and Eli Lilly, and compensation for advisory meetings with BMS, Pfizer, AstraZeneca, Janssen, MSD, and Roche. Stenzinger, A received research grants from Bayer, BMS, Chugai, Incyte, and MSD, and compensation for advisory boards/speaker’s bureau: Agilent, Aignostics, Amgen, Astellas, Astra Zeneca, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Qlucore, QuiP, Roche, Sanofi, Seagen, Servier, Takeda, Thermo Fisher. Syrigos, K received honoraria for advisory boards from Merck Sharp & Dohme, AstraZeneca, BMS Amgen. Thomas, M received research funding (institution) from AstraZeneca, BMS, Merck, Roche, Takeda, speaker fees and/or honoraria for advisory boards by Amgen, AstraZeneca, Beigene, BMS, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Takeda. Veluswamy, R served on advisory boards for Bristol-Myers Squibb, Astrazeneca, Merck, Boehringer Ingelheim, Merus, Novocure, Regeneron, BerGenBio, and Serna Bio, on unbranded speaker’s bureau of Astrazeneca and EMD Serono, received consulting honorarium from Beigene, received research funding from Bristol-Myers Squibb, Onconova, Astrazeneca, Boehringer Ingelheim, Lung Cancer Research Foundation, Stand Up 2 Cancer. Wenzel, C received speaker fees from Astra Zeneca. Wermke, M received honorary from Lilly, Boehringer-Ingelheim, SYNLAB, Janssen, Merck Serono, GWT, Amgen, Novartis, Pfizer, BMS and has/had paid consulting or advisory positions for BMS, Novartis, Lilly, Boehringer-Ingelheim, ISA Pharmaceuticals, Amgen, Immatics, Bayer, ImCheck, AstraZeneca, Tacalyx, Regeneron, Daiichi, Zymeworks, PharmaMar. He receive research funding (instution) from Roche and travel support from Pfizer, BMS, AstraZeneca, Amgen, Gemoab, Sanofi-Aventis, Merck Serono, Immatics, Janssen, Iovance, Daiichi-Sankyo. Wesseler, C received speaker fees and/or honoraria for advisory boards from Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, MSD, Novartis, Takeda, AstraZeneca, Chugai, BMS. Wiesweg, M received honoraria and Advisory Role: Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Takeda, and travel costs from Amgen, Janssen, Daiichi Sankyo, and research funding from Bristol-Myers Squibb, Takeda. Klimova, A, Kulhvay, J, Möller, J, Pelusi, N, Rasokat, A, Schubart, C, Schütz, M, Wang, A, and Vathiotis, J have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cisplatin resistance is common in non‑small cell lung cancer (NSCLC); however, the molecular mechanisms remain unclear. The present study aimed to identify a new function of Golgi phosphoprotein 3 (GOLPH3) in NSCLC‑associated cisplatin resistance. Using A549 human NSCLC cells and the cisplatin‑resistant variant, stable cell lines with GOLPH3 knockdown or overexpression were established using lentiviral vectors. Through Cell Counting Kit‑8 and EdU assays, it was revealed that knockdown of GOLPH3 significantly enhanced cisplatin sensitivity in NSCLC cells. Specifically, flow cytometric analysis showed that GOLPH3 knockdown promoted apoptosis and G 2 ‑phase cell cycle arrest in A549 cells. Mechanistically, intracellular reactive oxygen species (ROS) and glutathione (GSH) levels were measured using assay kits, and it was demonstrated that GOLPH3 knockdown decreased intracellular GSH levels, and further attenuated intracellular cisplatin efflux and GSH/ROS imbalance. In addition, tumor‑sphere formation assays verified that GOLPH3 knockdown mitigated the stem cell‑like phenotype of NSCLC cells. In conclusion, the present findings indicated the relevance of GOLPH3 in NSCLC‑associated cisplatin resistance, and thus targeting GOLPH3 may be developed into a combination therapy to overcome cisplatin resistance.

Objective: This study aimed to investigate the therapeutic effects of sulforaphane and the role of the Nrf2-Keap1/HO-1/ROS pathway in AngII-induced oxidative stress in podocyte injury., Methods: Mouse mpc5 podocytes were divided into four groups: control (Con), AngII, AngII + sulforaphane (AngII + SFN), and control + sulforaphane (Con + SFN). Western blotting was used to detect protein expression of Nrf2-Keap1, antioxidant enzyme HO-1, and apoptosis-related proteins. ROS levels were measured using a ROS assay kit, and cell survival and viability were assayed using the CCK-8 kit. Molecular interactions between Nrf2 and sulforaphane were analyzed computationally., Results: Compared with the Con group, podocytes treated with AngII alone exhibited inhibited proliferation, reduced cell viability, lower Bcl-2 expression, and higher cleaved caspase 3 expression. In the presence of sulforaphane, AngII group showed a mild inhibition on podocyte proliferation but did not induce the aforementioned changes in Bcl-2 and cleaved caspase 3 expression. Similarly, compared to the Con group, AngII treatment alone had lower Nrf2 expression and higher Keap1 expression in podocytes, accompanied by a significant decrease in ROS content. However, in the presence of sulforaphane, AngII failed to induce increases in Nrf2 and a decrease in Keap1 expression, as well as ROS levels. Furthermore, cells treated with sulforaphane exhibited higher HO-1 levels than control cells, and co-incubation with AngII did not alter HO-1 levels. Computational modeling revealed hydrophobic interactions between sulforaphane and the amino acid LYS-462 of Nrf2, as well as hydrogen bonding with amino acid HIS-465. The binding score between sulforaphane and Nrf2 was -4.7., Conclusion: Sulforaphane alleviated AngII-induced podocyte oxidative stress injury via the Nrf2-Keap1/HO-1/ROS pathway, providing new insights into therapeutic compounds for mitigating chronic kidney disease.

Aims: Cisplatin (CDDP) is still one of the most commonly used first-line treatments for advanced and recurrent oral squamous cell carcinoma (OSCC) patients in clinical practice. However, the decrease in tumor sensitivity to CDDP weakens its therapeutic effect. There is still limited research on the effect of METTL3-mediated methylation of m6A on CDDP sensitivity in OSCC. TMEM30A widely exists in biomembranes and regulates the lipid asymmetry of the membrane, but there is no report on its function in OSCC. This study aims to explore the specific mechanism by which METTL3 regulates m6A methylation of TMEM30A and affects the occurrence and development of OSCC, and further investigate the effects of METTL3 and TMEM30A on the anti-tumor activity of CDDP., Key Findings: In OSCC, METTL3 plays a pro-cancer role and weakens the anti-tumor efficacy of CDDP; METTL3 positively regulates the expression of TMEM30A by m6A methylation modification and binding to TMEM30A; The abnormally high expression of TMEM30A in OSCC not only weakens CDDP sensitivity, but also enhances the malignant evolution of cancer cells, regulates the metabolic balance of ATP and lactate in cells, and is a potential oncogenic gene., Significance: TMEM30A promotes malignant progression of tumors through METTL3 mediated m6A methylation modification, participates in maintaining the balance of tumor ATP and lactate metabolism, and reduces the anti-tumor activity of CDDP. TMEM30A is a potential gene target for CDDP anti-tumor activity in OSCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The study focuses on lung adenocarcinoma (LUAD), a predominant type of lung cancer. Despite advancements in diagnostics and molecular therapies, treatment remains challenging due to its low five-year survival rate. This study aims to investigate the role of the transmembrane protein TMEM164 in ferroptosis and anti-tumor immunity in LUAD, and to evaluate its potential as a therapeutic target. Through cellular experiments (such as QPCR, WB, CCK-8, EdU, Transwell, flow cytometry, CO-IP) and animal model experiments (including HE staining and IHC analysis), the relationship between TMEM164 expression and LUAD progression was explored, with particular attention to its mechanisms in ferroptosis and autophagy. The results show that TMEM164 expression is downregulated in LUAD and is associated with poor prognosis. Increasing TMEM164 expression significantly inhibits cell proliferation, migration, and invasion, while promoting an autophagy process dependent on ATG5 for autophagosome formation, thus facilitating ferroptosis. In mouse models, high TMEM164 expression combined with anti-PD-1 antibodies demonstrated synergistic anti-tumor effects. These findings highlight the critical role of TMEM164 in LUAD, suggesting that modulating TMEM164 expression could open new avenues for LUAD treatment.

As a constituent of the Per- and Polyfluoroalkyl Substances (PFAS) family, perfluorodecanoic acid (PFDA) is ubiquitous in the environment and enters the human body through environmental exposure, the food chain, and other pathways, resulting in various toxic effects. Previous population-based studies have suggested a correlation between PFDA exposure and inflammation. However, the evidence is still limited, and the potential mechanisms underlying this correlation remain to be further elucidated. In our study, we observed that exposure to internal doses of PFDA significantly promoted macrophage inflammation through in vitro assays. Utilizing RNA-seq screening and molecular experiments, we identified that environmentally relevant concentration of PFDA promote inflammation mainly by activating non-canonical cGAS/STING/NF-κB pathways in vitro. Finally, we confirmed in the typical mouse inflammatory bowel disease (IBD) model that PFDA could exacerbate intestinal inflammation in a cGAS dependent manner. In conclusion, our research firstly demonstrated that even at environmentally relevant concentrations, PFDA could promote the progression of intestinal inflammation primarily through the cGAS/STING/NF-κB pathway, revealing the potential risk associated with PFDA exposure and providing theoretical evidence for its management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cisplatin plays a pivotal role in the chemotherapy treatment of various cancers, but its use is often limited due to its nephrotoxic side effects. Identifying compounds that can mitigate cisplatin-induced nephrotoxicity is therefore of great importance. This study focused on evaluating the protective effects of reserpine against cisplatin-induced acute kidney injury. Reserpine was found to significantly safeguard against kidney damage caused by cisplatin, as indicated by the decreased levels of serum creatinine, blood urea nitrogen, and lactate dehydrogenase induced by cisplatin. Moreover, reserpine improved kidney histology damage caused by cisplatin treatment, with hematoxylin-eosin and periodic acid-Schiff staining revealing notable recovery from renal injury. Mechanistically, reserpine mitigated oxidative stress triggered by cisplatin and exhibits the ability to inhibit ferroptosis both in vivo and in vitro . Additionally, reserpine blocked the activation of the cGAS/STING signaling pathway and the subsequent expression of inflammatory genes, thus reducing inflammation-driven kidney damage. In summary, the findings suggest that reserpine offers a promising new strategy for preventing nephrotoxicity induced by cisplatin.

Neuroinflammation is a central player in postoperative cognitive dysfunction (POCD), an intractable and highly confounding neurological complication with finite therapeutic options. Celastrol, a quinone methide triterpenoid, is a bioactive ingredient extracted from Tripterygium wilfordii with talented anti-inflammatory capacity. However, it is unclear whether celastrol can prevent anesthesia/surgery-evoked cognitive deficits in an inflammation-specific manner. The STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was used to determine whether celastrol possesses neuroprotection dependent on the STING pathway in vivo and in vitro. Isoflurane and laparotomy triggered cGAS-STING activation, caspase-3/GSDME-dependent pyroptosis, and enhanced Iba-1 immunoreactivity. Celastrol improved cognitive performance and decreased the levels of cGAS, 2'3'-cGAMP, STING, NF-κB phosphorylation, Iba-1, TNF-α, IL-6, and IFN-β. Downregulation of cleaved caspase-3 and N-GSDME was observed in the hippocampus of POCD mice and HT22 cells after celastrol administration, accompanied by limited secretion of pyroptosis-pertinent pro-inflammatory cytokines IL-1β and IL-18. DMXAA neutralized the favorable influences of celastrol on cognitive function, as confirmed by the activation of the STING/caspase-3/GSDME axis. These findings implicate celastrol as a therapeutic agent for POCD through anti-inflammation and anti-pyroptosis., Competing Interests: Declaration of competing interest The authors have no relevant financial or nonfinancial interests to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system that regulates multiple different forms of synaptic plasticity, including learning and memory. Glutamate transduces its signal by activating ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs). Group I mGluRs belong to the G protein-coupled receptor (GPCR) family. Regulation of cell surface expression and trafficking of the glutamate receptors represents an important mechanism that assures proper transmission of information at the synapses. There is growing evidence implicating dysregulated glutamate receptor trafficking in the pathophysiology of several neuropsychiatric disorders. The postsynaptic density (PSD) region consists of many specialized proteins which are assembled beneath the postsynaptic membrane of dendritic spines. Many of these proteins interact with group I mGluRs and have essential roles in group I mGluR-mediated synaptic function and plasticity. This review provides up-to-date information on the molecular determinants regulating cell surface expression and trafficking of group I mGluRs and discusses the role of few of these PSD proteins in these processes. As substantial evidences link mGluR dysfunction and maladaptive functioning of many PSD proteins to the pathophysiology of various neuropsychiatric disorders, understanding the role of the PSD proteins in group I mGluR trafficking may provide opportunities for the development of novel therapeutics in multiple neuropsychiatric disorders., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)