Baicalin inhibits PANoptosis by blocking mitochondrial Z-DNA formation and ZBP1-PANoptosome assembly in macrophages.

PANoptosis is an emerging form of regulated cell death (RCD) characterized by simultaneous activation of pyroptotic, apoptotic, and necroptotic signaling that not only participates in pathologies of inflammatory diseases but also has a critical role against pathogenic infections. Targeting PANoptosis represents a promising therapeutic strategy for related inflammatory diseases, but identification of inhibitors for PANoptosis remains an unmet demand. Baicalin () is an active flavonoid isolated from Scutellaria baicalensis Georgi (Huangqin), a traditional Chinese medicinal herb used for heat-clearing and detoxifying. Numerous studies suggest that baicalin possesses inhibitory activities on various forms of RCD including apoptosis/secondary necrosis, pyroptosis, and necroptosis, thereby mitigating inflammatory responses. In this study we investigated the effects of baicalin on PANoptosis in macrophage cellular models. Primary macrophages (BMDMs) or J774A.1 macrophage cells were treated with 5Z-7-oxozeaenol (OXO, an inhibitor for TAK1) in combination with TNF-α or LPS. We showed that OXO plus TNF-α or LPS induced robust lytic cell death, which was dose-dependently inhibited by baicalin (50-200 µM). We demonstrated that PANoptosis induction was accompanied by overt mitochondrial injury, mitochondrial DNA (mtDNA) release and Z-DNA formation. Z-DNA was formed from cytosolic oxidized mtDNA. Both oxidized mtDNA and mitochondrial Z-DNA puncta were co-localized with the PANoptosome (including ZBP1, RIPK3, ASC, and caspase-8), a platform for mediating PANoptosis. Intriguingly, baicalin not only prevented mitochondrial injury but also blocked mtDNA release, Z-DNA formation and PANoptosome assembly. Knockdown of ZBP1 markedly decreased PANoptotic cell death. In a mouse model of hemophagocytic lymphohistiocytosis (HLH), administration of baicalin (200 mg/kg, i.g., for 4 times) significantly mitigated lung and liver injury and reduced levels of serum TNF-α and IFN-γ, concomitant with decreased levels of PANoptosis hallmarks in these organs. Baicalin also abrogated the hallmarks of PANoptosis in liver-resident macrophages (Kupffer cells) in HLH mice. Collectively, our results demonstrate that baicalin inhibits PANoptosis in macrophages by blocking mitochondrial Z-DNA formation and ZBP1-PANoptosome assembly, thus conferring protection against inflammatory diseases. PANoptosis is a form of regulated cell death displaying simultaneous activation of pyroptotic, apoptotic, and necroptotic signaling. This study shows that induction of PANoptosis is linked to mitochondrial dysfunction and mitochondrial Z-DNA formation. Baicalin inhibits PANoptosis in macrophages in vitro via blocking mitochondrial dysfunction and the mitochondrial Z-DNA formation and thereby impeding the assembly of ZBP1-associated PANoptosome. In a mouse model of hemophagocytic lymphohistiocytosis (HLH), baicalin inhibits the activation of PANoptotic signaling in liver-resident macrophages (Kupffer cells) in vivo, thus mitigating systemic inflammation and multiple organ injury in mice.

An integrated machine learning model enhances delayed graft function prediction in pediatric renal transplantation from deceased donors.

BACKGROUND: Kidney transplantation is the optimal renal replacement therapy for children with end-stage renal disease; however, delayed graft function (DGF), a common post-operative complication, may negatively impact the long-term outcomes of both the graft and the pediatric recipient. However, there is limited research on DGF in pediatric kidney transplant recipients. This study aims to develop a predictive model for the risk of DGF occurrence after pediatric kidney transplantation by integrating donor and recipient characteristics and utilizing machine learning algorithms, ultimately providing guidance for clinical decision-making. METHODS: This single-center retrospective cohort study includes all recipients under 18 years of age who underwent single-donor kidney transplantation at our hospital between 2016 and 2023, along with their corresponding donors. Demographic, clinical, and laboratory examination data were collected from both donors and recipients. Univariate logistic regression models and differential analysis were employed to identify features associated with DGF. Subsequently, a risk score for predicting DGF occurrence (DGF-RS) was constructed based on machine learning combinations. Model performance was evaluated using the receiver operating characteristic curves, decision curve analysis (DCA), and other methods. RESULTS: The study included a total of 140 pediatric kidney transplant recipients, among whom 37 (26.4%) developed DGF. Univariate analysis revealed that high-density lipoprotein cholesterol (HDLC), donor after circulatory death (DCD), warm ischemia time (WIT), cold ischemia time (CIT), gender match, and donor creatinine were significantly associated with DGF (P < 0.05). Based on these six features, the random forest model (mtry = 5, 75%p) exhibited the best predictive performance among 97 machine learning models, with the area under the curve values reaching 0.983, 1, and 0.905 for the entire cohort, training set, and validation set, respectively. This model significantly outperformed single indicators. The DCA curve confirmed the clinical utility of this model. CONCLUSIONS: In this study, we developed a machine learning-based predictive model for DGF following pediatric kidney transplantation, termed DGF-RS, which integrates both donor and recipient characteristics. The model demonstrated excellent predictive accuracy and provides essential guidance for clinical decision-making. These findings contribute to our understanding of the pathogenesis of DGF.

Spin-Orbit-Locking Chiral Bound States in the Continuum.

Bound states in the continuum (BICs), which are confined optical modes exhibiting infinite quality factors and carrying topological polarization configurations in momentum space, have recently sparked significant interest across both fundamental and applied physics. Here, we show that breaking time-reversal symmetry by an external magnetic field enables a new form of chiral BICs with spin-orbit locking. Applying a magnetic field to a magneto-optical photonic crystal slab lifts doubly degenerate BICs into a pair of chiral BICs carrying opposite pseudospins and orbital angular momenta. Multipole analysis verifies the nonzero angular momenta and reveals the spin-orbital-locking behaviors. In momentum space, we observe ultrahigh quality factors and near-circular polarization surrounding chiral BICs, enabling potential applications in spin-selective nanophotonics. Compared to conventional BICs, the magnetically induced chiral BICs revealed here exhibit distinct properties and origins, significantly advancing the topological photonics of BICs by incorporating broken time-reversal symmetry.

Recent progress on triterpenoid derivatives and their anticancer potential.

Cancer poses a significant global public health challenge, with commonly used adjuvant or neoadjuvant chemotherapy often leading to adverse side effects and drug resistance. Therefore, advancing cancer treatment necessitates the ongoing development of novel anticancer agents with diverse structures and mechanisms of action. Natural products remain crucial in the process of drug discovery, serving as a primary source for pharmaceutical leads and therapeutic advancements. Triterpenoids are particularly compelling due to their complex structures and wide array of biological activities. Recent research has demonstrated that naturally occurring triterpenes and their derivatives have the potential to serve as promising candidates for new drug development. This review aims to comprehensively explore the anticancer properties of triterpenoids and their synthetic analogs, with a focus on recent advancements. Various aspects, such as synthesis, phytochemistry, and molecular simulation for structure-activity relationship analyses, are summarized. It is anticipated that triterpenoid derivatives will emerge as notable anticancer agents following further investigation into their mechanisms of action and in vivo studies.

First Report on the Trophic Transfer and Priority List of Liquid Crystal Monomers in the Pearl River Estuary.

Liquid crystal monomers (LCMs) are emerging organic pollutants due to their potential persistence, toxicity, and bioaccumulation. This study first characterized the levels and compositions of 19 LCMs in organisms in the Pearl River Estuary (PRE), estimated their bioaccumulation and trophic transfer potential, and identified priority contaminants. LCMs were generally accumulated in organisms from sediment, and the LCM concentrations in all organisms ranged from 32.35 to 1367 ng/g lipid weight. The main LCMs in organisms were biphenyls and analogues (BAs) (76.6%), followed by cyanobiphenyls and analogues (CBAs) (15.1%), and the least were fluorinated biphenyls and analogues (FBAs) (11.2%). The most abundant LCM monomers of BAs, FBAs, and CBAs in LCMs in organisms were 1-(4-propylcyclohexyl)-4-vinylcyclohexane (15.1%), 1-ethoxy-2,3-difluoro-4-(4-(4-propylcyclohexyl) cyclohexyl) benzene (EDPBB, 10.1%), and 4'-propoxy-4-biphenylcarbonitrile (5.1%), respectively. The niche studies indicated that the PRE food web was composed of terrestrial-based diet and marine food chains. Most LCMs exhibited biodilution in the terrestrial-based diet and marine food chains, except for EDPBB and 4,4'-bis(4-propylcyclohexyl) biphenyl (BPCHB). The hydrophobicity, position of fluorine substitution of LCMs, and biological habits may be important factors affecting the bioaccumulation and trophic transfer of LCMs. BPCHB, 1-(prop-1-enyl)-4-(4-propylcyclohexyl) cyclohexane, and EDPBB were characterized as priority contaminants. This study first reports the trophic transfer processes and mechanisms of LCMs and the biomonitoring in PRE.

Monoclonal antibody based colloidal gold immunochromatographic assay for the visual and rapid screening of profenofos.

Profenofos (PFF) is a commonly used organophosphorus insecticide that requires strict monitoring due to its potential environmental, ecological, and human health risks originating from residues in soil and water systems, as well as accumulation in crops. In this study, a novel monoclonal antibody (mAb) specific to PFF was prepared for the first time and the recognition mechanism was investigated through molecular simulation. Subsequently, a mAb-based colloidal gold immunochromatographic assay (GICA) was developed for the rapid screening of PFF in fruit and vegetable samples. The mAb exhibited an IC50 value of 12.9 ng/mL, and limit of detection (LOD) of 4.6 ng/mL, respectively in indirect competitive immunosorbent enzyme-linked immunosorbent assay (ic-ELISA). After optimization, the developed GICA exhibited a visual limit of detection (vLOD) of 20 ng/mL and a quantitative of detection (qLOD) of 5.2 ng/mL, with a linear range from 10.0 to 83.8 ng/mL. Good correlation was observed between the results of GICA and standard Gas Chromatography-Tandem Mass Spectrometry (GC-MS/MS) in matrix and recovery test. The developed GICA can be used for rapid sample detection within 15 min, which is an excellent tool for screening PFF in foods and environmental samples.

Robust fatigue markers obtained from muscle synergy analysis.

This study aimed to utilize the nonnegative matrix factorization (NNMF) algorithm for muscle synergy analysis, extracting synergy structures and muscle weightings and mining biomarkers reflecting changes in muscle fatigue from these synergy structures. A leg press exercise to induce fatigue was performed by 11 participants. Surface electromyography (sEMG) data from seven muscles, electrocardiography (ECG) data, Borg CR-10 scale scores, and the z-axis acceleration of the weight block were simultaneously collected. Three indices were derived from the synergy structures: activation phase difference, coactivation area, and coactivation time. The indicators were further validated for single-leg landing. Differences in heart rate (HR) and heart rate variability (HRV) were observed across different fatigue levels, with varying degrees of disparity. The median frequency (MDF) exhibited a consistent decline in the primary working muscle groups. Significant differences were noted in activation phase difference, coactivation area, and coactivation time before and after fatigue onset. Moreover, a significant correlation was found between the activation phase difference and the coactivation area with fatigue intensity. The further application of single-leg landing demonstrated the effectiveness of the coactivation area. These indices can serve as biomarkers reflecting simultaneous alterations in the central nervous system and muscle activity post-exertion.

Sleep Deprivation Induces Gut Damage via Ferroptosis.

Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD.

Half-Sandwich Iridium Complexes: A Recyclable and Stable Catalyst for Dehydrogenation of Alcohols to Carboxylic Acids.

A series of acylhydrazone-based N,N-chelate half-sandwich iridium complexes have been synthesized through a facile route in good yields. The dehydrogenation of a series of aromatic and aliphatic primary alcohols to corresponding carboxylic acids has been accomplished catalyzed by the prepared air stable iridium complexes under mild reaction conditions. Carboxylic acids were obtained in high yields under open flask condition with broad substrates and good tolerance to sensitive functional groups. Such a half-sandwich iridium catalyst system exhibited high catalytic activity and stability, and a high TOF of 316.7 h-1 could be achieved with a catalyst loading as low as 0.05 mol %. Furthermore, the sustainable catalyst could be reused at least five times without obviously losing its activity, highlighting its potential application in industry. Molecular structure of iridium complex 1 was confirmed by single-crystal X-ray analysis.

Comparison and phylogenetic analysis of the mitochondrial genomes of Synodontis eupterus and Synodontis polli.

We aimed to distinguish Synodontis eupterus and Synodontis polli. We performed sequencing and bioinformatic analysis of their mitochondrial genomes and constructed a phylogenetic tree of Mochokidae fish using maximum likelihood and Bayesian methods based on protein-coding gene (PCG) sequences of 14 Mochokidae species. The total length of the S. eupterus mitochondrial genome was 16,579 bp, including 13 (PCGs), 22 tRNA genes, two rRNA genes, and one D-loop, with an AT-biased nucleotide composition (56.0%). The total length of the S. polli mitochondrial genome was 16,544 bp, including 13 PCGs, 22 tRNA genes, two rRNA genes, and one D-loop, with an AT-biased nucleotide composition (55.0%). In both species, except for COI, PCGs use ATG as the starting codon, the vast majority use TAG or TAA as the ending codon, and a few use incomplete codons (T - or TA -) as the ending codon. Phylogenetic analysis showed that S. eupterus and Synodontis clarias converged into one branch, S. polli and Synodontis petricola converged into one branch, Mochokiella paynei, Mochokus brevis, and nine species of the genus Synodontis converged into one branch, and M. paynei clustered with the genus Synodontis. This study lays a foundation for rebuilding a clearer Mochokidae fish classification system.

Delocalized Orbitals Over Metal Clusters and Organic Linkers Enable Boosted Charge Transfer in Metal-Organic Framework for Overall CO2 Photoreduction.

The conversion of CO2 to C2 through photocatalysis poses significant challenges, and one of the biggest hurdles stems from the sluggishness of the multi-electron transfer process. Herein, taking metal-organic framework (PFC-98) as a model photocatalyst, we report a new strategy to facilitate charge separation. This strategy involves matching the energy levels of the lowest unoccupied node and linker orbitals of the MOF, thereby creating the lowest unoccupied crystal orbital (LUCO) delocalized over both the node and linker. This feature enables the direct excitation of electrons from photosensitive linker to the catalytic centers, achieving a direct charge transfer (DCT) pathway. For comparison, an isoreticular MOF (PFC-6) based on analogue components but with far apart frontier energy level was synthesized. The delocalized LUCO caused the presence of an internal charge-separated state (ICS), prolonging the excited state lifetime and further inhibiting the electron-hole recombination. The presence of an internal charge-separated state (ICS) prolongs the excited state lifetime and further inhibits the electron-hole recombination. Moreover, it also induced abundant electrons accumulating at the catalytic sites, enabling the multi-electron transfer process. As a result, the material featuring delocalized LUCO exhibits superior overall CO2 photocatalytic performance with high C2 production yield and selectivity.

Core-shell structured alginate-based hydrogel beads modified by starch and protocatechuic acid: Preparation, characterization, phenolic slow release and stable antioxidant potential.

A novel core-shell structured alginate-based hydrogel bead modified by co-gelatinizing with starch and protocatechuic acid (PA), was designed to modulate physical properties of beads, release behavior and antioxidant stability of encapsulated bioactives. Core was fabricated by ionotropic gelation, and its formulation (ratio of sodium alginate/starch) was determined by particle size/starch distribution, texture and bioactive encapsulation capacity of core. Then, coating core with shell-forming solution co-gelatinized with different doses of PA, and subsequently cross-linked with Ca2+ to obtain core-shell structured beads. Surface microstructure, mechanical characteristics, and swelling ratio of beads were affected by concentrations of PA. Besides, core-shell structure containing PA could enhance delivery and sustained release of encapsulated phenolic bioactives during in vitro digestion, and improve their antioxidant potential stability. Furthermore, interaction between PA and polysaccharide components was elucidated by FTIR and TGA. The present information was beneficial for the advancement of functional food materials and bioactive delivery systems.

Integrating Multiple Bacterial Phenotypes and Bayesian Network for Analyzing Health Risks of Pathogens in Plastisphere.

Plastic pollution represents a critical threat to soil ecosystems and even humans, as plastics can serve as a habitat for breeding and refuging pathogenic microorganisms against stresses. However, evaluating the health risk of plastispheres is difficult due to the lack of risk factors and quantification model. Here, DNA sequencing, single-cell Raman-D2O labeling, and transformation assay were used to quantify key risk factors of plastisphere, including pathogen abundance, phenotypic resistance to various stresses (antibiotic and pesticide), and ability to acquire antibiotic resistance genes. A Bayesian network model was newly introduced to integrate these three factors and infer their causal relationships. Using this model, the risk of pathogen in the plastisphere is found to be nearly 3 magnitudes higher than that in free-living state. Furthermore, this model exhibits robustness for risk prediction, even in the absence of one factor. Our framework offers a novel and practical approach to assessing the health risk of plastispheres, contributing to the management of plastic-related threats to human health.

Scutellarin inhibits inflammatory PANoptosis by diminishing mitochondrial ROS generation and blocking PANoptosome formation.

PANoptosis is manifested with simultaneous activation of biomarkers for both pyroptotic, apoptotic and necroptotic signaling via the molecular platform PANoptosome and it is involved in pathologies of various inflammatory diseases including hemophagocytic lymphohistiocytosis (HLH). Scutellarin is a flavonoid isolated from herbal Erigeron breviscapus (Vant.) Hand.-Mazz. and has been shown to possess multiple pharmacological effects, but it is unknown whether scutellarin has any effects on PANoptosis and related inflammatory diseases. In this study, we found that scutellarin inhibited cell death in bone marrow-derived macrophages (BMDMs) and J774A.1 cells treated with TGF-ß-activated kinase 1 (TAK1) inhibitor 5Z-7-oxozeaenol (OXO) plus lipopolysaccharide (LPS), which has been commonly used to induce PANoptosis. Western blotting showed that scutellarin dose-dependently inhibited the activation biomarkers for pyroptotic (Caspase-1p10 and GSDMD-NT), apoptotic (cleaved Casp3/8/9 and GSDME-NT), and necroptotic (phosphorylated MLKL) signaling. The inhibitory effect of scutellarin was unaffected by NLRP3 or Caspase-1 deletion. Interestingly, scutellarin blocked the assembly of PANoptosome that encompasses ASC, RIPK3, Caspase-8 and ZBP1, suggesting its action on upstream signaling. Consistent with this, scutellarin inhibited mitochondrial damage and mitochondrial reactive oxygen species (mtROS) generation in cells treated with OXO+LPS. Further, mito-TEMPO that can scavenge mtROS significantly inhibited OXO+LPS-induced PANoptotic cell death. In line with the in vitro results, scutellarin markedly alleviated systemic inflammation, multiple organ injury, and activation of PANoptotic biomarkers in mice with HLH. Collectively, our data suggest that scutellarin can inhibit PANoptosis by suppressing mitochondrial damage and mtROS generation and thereby mitigating multiple organ injury in mice with inflammatory disorders.

Effect of Si3N4 Additive on Microstructure and Mechanical Properties of Ti(C,N)-Based Cermet Cutting Tools.

Development of high-performance cutting tool materials is one of the critical parameters enhancing the surface finishing of high-speed machined products. Ti(C,N)-based cermets reinforced with and without different contents of silicon nitride were designed and evaluated to satisfy the requirements. In fact, the effect of silicon nitride addition to Ti(C,N)-based cermet remains unclear. The purpose of this study is to investigate the influence of Si3N4 additive on microstructure, mechanical properties, and thermal stability of Ti(C,N)-based cermet cutting tools. In the present work, α-Si3N4 "grade SN-E10" was utilized with various fractions up to 6 wt.% in the designed cermets. A two-step reactive sintering process under vacuum was carried out for the green compact of Ti(C,N)-based cermet samples. The samples with 4 wt.% Si3N4 have an apparent solid density of about 6.75 g/cm3 (relative density of about 98 %); however, the cermet samples with 2 wt.% Si3N4 exhibit a superior fracture toughness of 10.82 MPa.m1/2 and a traverse rupture strength of 1425.8 MPa. With an increase in the contents of Si3N4, the Vickers hardness and fracture toughness of Ti(C,N)-based cermets have an inverse behavior trend. The influence of Si3N4 addition on thermal stability is clarified to better understand the relationship between thermal stability and mechanical properties of Ti(C,N)-based cermets.

Prognostic models for mucinous and non-specific adeno cholangiocarcinoma: a population-based retrospective study.

Background: Clinically, the diagnosis and treatment of cholangiocarcinoma are generally different according to the location of occurrence, and the studies rarely consider the differences between different pathological types. Cholangiocarcinomas in large- and middle-sized intrahepatic bile ducts are mostly mucinous, while in small sized bile duct are not; mucinous extrahepatic cholangiocarcinomas are also more common than mucinous intrahepatic cholangiocarcinoma. However, it is unclear whether these pathological type differences are related to the prognosis. Methods: Data of total 22509 patients was analyzed from Surveillance, Epidemiology, and End Results program database out of which 22299 patients were diagnosed with common adeno cholangiocarcinoma while 210 were diagnosed with mucinous cholangiocarcinoma. Based on the propensity score matching (PSM) analysis, between these two groups' clinical, demographic, and therapeutic features were contrasted. The data were analyzed using Cox and LASSO regression analysis and Kaplan-Meier survival curves. Ultimately, overall survival (OS) and cancer specific survival (CSS) related prognostic models were established and validated in test and external datasets and nomograms were created to forecast these patients' prognosis. Results: There was no difference in prognosis between mucinous cholangiocarcinoma and adeno cholangiocarcinoma. Therefore, we constructed prognostic model and nomogram that can be used for mucinous and adeno cholangiocarcinoma at the same time. By comparing the 9 independent key characteristics i.e. Age, tumor size, the number of primary tumors, AJCC stage, Grade, lymph node status, metastasis, surgery and chemotherapy, risk scores were calculated for each individual. By integrating these two pathological types in OS and CSS prognostic models, effective prognosis prediction results could be achieved in multiple datasets (OS: AUC 0.70-0.87; CSS: AUC 0.74-0.89). Conclusion: Age, tumor size, the number of primary tumors, AJCC stage, Grade, lymph node status, metastasis, surgery and chemotherapy are the independent prognostic factors in OS or CSS of the patients with mucinous and ordinary cholangiocarcinoma. Nomogram that can be used for mucinous and adeno cholangiocarcinoma at the same time is of significance in clinical practice and management of cholangiocarcinoma.

Enhancing safety in conditionally automated driving: Can more takeover request visual information make a difference in hazard scenarios with varied hazard visibility?

Autonomous driving technology has the potential to significantly reduce the number of traffic accidents. However, before achieving full automation, drivers still need to take control of the vehicle in complex and diverse scenarios that the autonomous driving system cannot handle. Therefore, appropriate takeover request (TOR) designs are necessary to enhance takeover performance and driving safety. This study focuses on takeover tasks in hazard scenarios with varied hazard visibility, which can be categorized as overt hazards and covert hazards. Through ergonomic experiments, the impact of TOR interface visual information, including takeover warning, hazard direction, and time to collision, on takeover performance is investigated, and specific analyses are conducted using eye-tracking data. The following conclusions are drawn from the experiments: (1) The visibility of hazards significantly affects takeover performance. (2) Providing more TOR visual information in hazards with different visibility has varying effects on drivers' visual attention allocation but can improve takeover performance. (3) More TOR visual information helps reduce takeover workload and increase human-machine trust. Based on these findings, this paper proposes the following TOR visual interface design strategies: (1) In overt hazard scenarios, only takeover warning is necessary, as additional visual information may distract drivers' attention. (2) In covert hazard scenarios, the TOR visual interface should better assist drivers in understanding the current hazard situation by providing information on hazard direction and time to collision to enhance takeover performance.

Neferine inhibits BMECs pyroptosis and maintains blood-brain barrier integrity in ischemic stroke by triggering a cascade reaction of PGC-1α.

Blood-brain barrier disruption is a critical pathological event in the progression of ischemic stroke (IS). Most studies regarding the therapeutic potential of neferine (Nef) on IS have focused on neuroprotective effect. However, whether Nef attenuates BBB disruption during IS is unclear. We here used mice underwent transient middle cerebral artery occlusion (tMCAO) in vivo and bEnd.3 cells exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro to simulate cerebral ischemia. We showed that Nef reduced neurobehavioral dysfunction and protected brain microvascular endothelial cells and BBB integrity. Molecular docking, short interfering (Si) RNA and plasmid transfection results showed us that PGC-1α was the most binding affinity of biological activity protein for Nef. And verification experiments were showed that Nef upregulated PGC-1α expression to reduce mitochondrial oxidative stress and promote TJ proteins expression, further improves the integrity of BBB in mice. Intriguingly, our study showed that neferine is a natural PGC-1α activator and illustrated the mechanism of specific binding site. Furthermore, we have demonstrated Nef reduced mitochondria oxidative damage and ameliorates endothelial inflammation by inhibiting pyroptosis to improve BBB permeability through triggering a cascade reaction of PGC-1α via regulation of PGC-1α/NLRP3/GSDMD signaling pathway to maintain the integrity of BBB in ischemia/reperfusion injury.

Mechanisms of gastrointestinal toxicity in neuromyelitis optica spectrum disorder patients treated with mycophenolate mofetil: insights from a mouse model and human study.

Mycophenolate mofetil (MMF) is commonly utilized for the treatment of neuromyelitis optica spectrum disorders (NMOSD). However, a subset of patients experience significant gastrointestinal (GI) adverse effects following MMF administration. The present study aims to elucidate the underlying mechanisms of MMF-induced GI toxicity in NMOSD. Utilizing a vancomycin-treated mouse model, we compiled a comprehensive data set to investigate the microbiome and metabolome in the GI tract to elucidate the mechanisms of MMF GI toxicity. Furthermore, we enrolled 17 female NMOSD patients receiving MMF, who were stratified into non-diarrhea NMOSD and diarrhea NMOSD (DNM) groups, in addition to 12 healthy controls. The gut microbiota of stool samples was analyzed using 16S rRNA gene sequencing. Vancomycin administration prevented weight loss and tissue injury caused by MMF, affecting colon metabolomes and microbiomes. Bacterial ß-glucuronidase from Bacteroidetes and Firmicutes was linked to intestinal tissue damage. The DNM group showed higher alpha diversity and increased levels of Firmicutes and Proteobacteria. The ß-glucuronidase produced by Firmicutes may be important in causing gastrointestinal side effects from MMF in NMOSD treatment, providing useful information for future research on MMF. IMPORTANCE: Neuromyelitis optica spectrum disorder (NMOSD) patients frequently endure severe consequences like paralysis and blindness. Mycophenolate mofetil (MMF) effectively addresses these issues, but its usage is hindered by gastrointestinal (GI) complications. Through uncovering the intricate interplay among MMF, gut microbiota, and metabolic pathways, this study identifies specific gut bacteria responsible for metabolizing MMF into a potentially harmful form, thus contributing to GI side effects. These findings not only deepen our comprehension of MMF toxicity but also propose potential strategies, such as inhibiting these bacteria, to mitigate these adverse effects. This insight holds broader implications for minimizing complications in NMOSD patients undergoing MMF therapy.

Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy.

Spinal Muscular Atrophy (SMA) is typically characterized as a motor neuron disease, but extra-neuronal phenotypes are present in almost every organ in severely affected patients and animal models. Extra-neuronal phenotypes were previously underappreciated as patients with severe SMA phenotypes usually died in infancy; however, with current treatments for motor neurons increasing patient lifespan, impaired function of peripheral organs may develop into significant future comorbidities and lead to new treatment-modified phenotypes. Fatty liver is seen in SMA animal models , but generalizability to patients and whether this is due to hepatocyte-intrinsic Survival Motor Neuron (SMN) protein deficiency and/or subsequent to skeletal muscle denervation is unknown. If liver pathology in SMA is SMN-dependent and hepatocyte-intrinsic, this suggests SMN repleting therapies must target extra-neuronal tissues and motor neurons for optimal patient outcome. Here we showed that fatty liver is present in SMA and that SMA patient-specific iHeps were susceptible to steatosis. Using proteomics, functional studies and CRISPR/Cas9 gene editing, we confirmed that fatty liver in SMA is a primary SMN-dependent hepatocyte-intrinsic liver defect associated with mitochondrial and other hepatic metabolism implications. These pathologies require monitoring and indicate need for systematic clinical surveillance and additional and/or combinatorial therapies to ensure continued SMA patient health.