Unveiling correlations between aristolochic acids and liver cancer: spatiotemporal heterogeneity phenomenon.

Aristolochic acids are a class of naturally occurring compounds in Aristolochiaceae that have similar structural skeletons and chemical properties. Exposure to aristolochic acids is a risk factor for severe kidney disease and urinary system cancer. However, the carcinogenicity of aristolochic acids to the liver, which is the main site of aristolochic acid metabolism, is unclear. Although the characteristic fingerprint of aristolochic acid-induced mutations has been detected in the liver and aristolochic acids are known to be hepatotoxic, whether aristolochic acids can directly cause liver cancer is yet to be verified. This review summarizes the findings of long-term carcinogenicity studies of aristolochic acids in experimental animals. We propose that spatiotemporal heterogeneity in the carcinogenicity of these phytochemicals could explain why direct evidence of aristolochic acids causing liver cancer has never been found in adult individuals. We also summarized the reported approaches to mitigate aristolochic acid-induced hepatotoxicity to better address the associated global safety issue and provide directions and recommendations for future investigation.

Networks of human milk microbiota are associated with host genomics, childhood asthma, and allergic sensitization.

The human milk microbiota (HMM) is thought to influence the long-term health of offspring. However, its role in asthma and atopy and the impact of host genomics on HMM composition remain unclear. Through the CHILD Cohort Study, we followed 885 pregnant mothers and their offspring from birth to 5 years and determined that HMM was associated with maternal genomics and prevalence of childhood asthma and allergic sensitization (atopy) among human milk-fed infants. Network analysis identified modules of correlated microbes in human milk that were associated with subsequent asthma and atopy in preschool-aged children. Moreover, reduced alpha-diversity and increased Lawsonella abundance in HMM were associated with increased prevalence of childhood atopy. Genome-wide association studies (GWASs) identified maternal genetic loci (e.g., ADAMTS8, NPR1, and COTL1) associated with HMM implicated with asthma and atopy, notably Lawsonella and alpha-diversity. Thus, our study elucidates the role of host genomics on the HMM and its potential impact on childhood asthma and atopy.

Human milk oligosaccharides are associated with maternal genetics and respiratory health of human milk-fed children.

Breastfeeding provides many health benefits, but its impact on respiratory health remains unclear. This study addresses the complex and dynamic nature of the mother-milk-infant triad by investigating maternal genomic factors regulating human milk oligosaccharides (HMOs), and their associations with respiratory health among human milk-fed infants. Nineteen HMOs are quantified from 980 mothers of the CHILD Cohort Study. Genome-wide association studies identify HMO-associated loci on chromosome 19p13.3 and 19q13.33 (lowest P = 2.4e-118), spanning several fucosyltransferase (FUT) genes. We identify novel associations on chromosome 3q27.3 for 6'-sialyllactose (P = 2.2e-9) in the sialyltransferase (ST6GAL1) gene. These, plus additional associations on chromosomes 7q21.32, 7q31.32 and 13q33.3, are replicated in the independent INSPIRE Cohort. Moreover, gene-environment interaction analyses suggest that fucosylated HMOs may modulate overall risk of recurrent wheeze among preschoolers with variable genetic risk scores (P < 0.01). Thus, we report novel genetic factors associated with HMOs, some of which may protect the respiratory health of children.

Na(C2H10N2)2[Zn3(PO4)2(H0.5PO4)]2: A Short-Wave Ultraviolet Open-Framework Zincophosphate Exhibiting Substantial Optical Dispersion Ability.

The exploration of short-wave ultraviolet (SUV; λ < 280 nm) transparent phosphates with substantial birefringence is crucial for the advancement of SUV laser industry. Despite their SUV transparency and potential for constructing materials with large birefringence, open-framework (OF) phosphates have rarely been explored for their birefringent properties. Herein, through a systematic exploration in this field, a new ethylenediamine-based OF zincophosphate, Na(C2H10N2)2[Zn3(PO4)2(H0.5PO4)]2 (NEZPO), has been developed. NEZPO exhibits remarkable SUV transparency and significant birefringence (Δn = 0.060 at 546 nm), highlighting the potential for the development of benign SUV crystals within the OF phosphates family.

[Anti-myocardial ischemic injury effects and mechanisms of cryptotanshinone in regulating macrophage polarisation through Dectin-1 signalling pathway].

The aim of this study was to investigate the potential mechanism by which cryptotanshinone(CTS) may exert its anti-myo-cardial ischemic effect through the regulation of macrophage polarization via the dendritic cell-associated C-type lectin 1(Dectin-1) signaling pathway. Male C57BL/6 mice, aged six weeks, were utilized to establish myocardial ischemia models and were subsequently divided into five groups: sham, model, CTS low-dose(21 mg·kg~(-1)·d~(-1)), CTS high-dose(84 mg·kg~(-1)·d~(-1)), and dapagliflozin(0.14 mg·kg~(-1)·d~(-1)). The cardiac function, serum enzyme levels, Dectin-1 expression, macrophage polarization, and neutrophil infiltration in the myocardial infarction area were assessed in each group. An in vitro model of M1-type macrophages was constructed using lipopolysaccharide/interfe-ron-γ(LPS/IFN-γ) stimulated RAW264.7 cells to investigate the impact of CTS on macrophage polarization and to examine alterations in key proteins within the Dectin-1 signaling pathway. In the CTS group, compared to the model group mice, there was a significant improvement in the cardiac function and myocardial injury, along with a notable increase in the ratio of M2/M1-type macrophages in the myocardial infarcted area and a decrease in neutrophil infiltration. Additionally, Dectin-1 exhibited low expression. The results of in vitro experiments demonstrated that CTS can decrease the expression of M1-type marker genes and increase the expression of M2-type marker genes. Besides, it can decrease the levels of Dectin-1 and the phosphorylation of its associated proteins, including spleen tyrosine kinase(Syk), protein kinase B(Akt), nuclear factor-kappaB p65(NF-κB p65), and extracellular signal-regulated protein kinases(ERK1/2). Additionally, CTS was found to enhance the phosphorylation of signal transducer and activator of transcription-6(STAT6). The above results suggest that CTS exerts its anti-myocardial ischemic injury effect by regulating macrophage polarization through the Dectin-1 signaling pathway.

[Study on fatigue resistance of mechanical nickel-titanium files by phase-locked infrared flaw detection method].

PURPOSE: The movement trend of the posterior teeth and the distribution of the periodontal membrane stress were studied by using three-dimensional digital technology. METHODS: CBCT data of 88 patients admitted to our hospital from June 2017 to June 2022 were selected, and input into Mimics20.0 software for preliminary extraction of all parts and stored with STL files; then the data were repaired and optimized through Geomagic Studio 2014 software. With the help of normal phase extension, the invisible appliance and periodontal membrane were constructed. Finally, the six FEM models were simulated and observed by the current teeth in different groups. Statistical analysis was performed with SPSS 21.0 software package. RESULTS: The effect force of the largest periodontal membrane was distributed in the neck of the tooth, followed by the apical area, with the maximum effect force value in the NA group. In all accessory groups, the periodontal membrane maximum paradigm isoeffect force values of all patients in the accessory vertical rectangular group were significantly smaller than the values obtained in the horizontal rectangular group. CONCLUSIONS: The design of orthodontic tooth accessories has a strong inhibition effect on the position movement of anterior teeth during recovery, which improves the accuracy of tooth three-dimensional movement to a certain extent. Meanwhile, the normal equivalent stress of the periodontal membrane of patients in the initial application of the invisible appliance without brackets is large.

Six-Membered Ring Directed Assembly of a Zirconium Zeolitic Metal-Organic Framework for Efficient Separation of Hexane Isomers.

The synthesis of zirconium MOFs with zeolite net is quite challenging due to the high connectivity of Zr6 clusters, which is far from tetrahedral connection, a requisite for zeolite net. In this work, we demonstrate a six-membered ring (6MR) strategy through mimicking of mineral zeolites with mixed ditopic and tritopic carboxylate linkers. With this strategy, the ditopic linker cross-links Zr6 clusters to form 4-connected zeolite-like nets, while the tritopic one is used to direct the formation of 6MR and simultaneously consumes extra coordination sites on the cluster. The feasibility of this strategy is shown by one zeolitic metal-organic framework (NNM-5) and this strategy has also led to the synthesis of the other dia-type zirconium MOF (NNM-6). Interestingly, as the tritopic linker not only directs the formation of 6-MR but also partitions 6-MR into small segments, NNM-5 with SOD topology shows a structural feature of small aperture and big cage, which has led to efficient separation of hexane isomers. With both exceptionally high n-hexane uptake (65.9 cm3·g-1) and size-exclusion selectivity, an exceptional separation capability is verified by breakthrough experiments. Calculation results demonstrate that the large difference of diffusion energy barrier due to the small aperture accounts for the underlying separation mechanism.

Long-Range π-π Stacking Brings High Electron Delocalization for Enhanced Photocatalytic Activity in Hydrogen-Bonded Organic Framework.

Unlike many studies that regulate transport and separation behaviour of photogenerated charge carriers through controlling the chemical composite, our work demonstrates this goal can be achieved through simply tuning the molecular π-π packing from short-range to long-range within hydrogen-bonded organic frameworks (HOFs) without altering the building blocks or network topology. Further investigations reveal that the long-range π-π stacking significantly promotes electron delocalization and enhances electron density, thereby effectively suppressing electron-hole recombination and augmenting the charge transfer rate. Simultaneously, acting as a porous substrate, it boosts electron density of Pd nanoparticle loaded on its surfaces, resulting in remarkable CO2 photoreduction catalytic activity (CO generation rate: 48.1 µmol/g/h) without the need for hole scavengers. Our study provide insight into regulating the charge carrier behaviours in molecular assemblies based on hydrogen bonds, offering a new clue for efficient photocatalyst design.

Analysis of status and influencing factors of mental health in patients with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder with varied clinical courses and prognoses, not only did the patients suffer from physical impairment, but also various physical and psychiatric comorbidities. Growing evidence have suggested that mental disorders in SLE patients, can lead to various adverse consequences. AIM: To explored the features and influencing factors of mental health in patients with SLE and clarifying the correlations between mental health and personality characteristics and perceived social support. The results would provide a basis for psychological intervention in patients with SLE. METHODS: The clinical data of 168 patients with SLE admitted at the First Affiliated Hospital of Hainan Medical University between June 2020 and June 2022 were collected. Psychological assessment and correlation analysis were conducted using the Symptom Checklist-90 (SCL-90) and Perceived Social Support Scale, and the collected data were compared with the national norms in China. The relevant factors influencing mental health were identified by statistical analysis. A general information questionnaire, the Revised Life Orientation Test, and Short-Form 36-Item Health Survey were employed to assess optimism level and quality of life (QoL), respectively. RESULTS: Patients with SLE obtained higher scores for the somatization, depression, anxiety, and phobic anxiety subscales than national norms (P < 0.05). A correlation was identified between total social support and total SCL-90 score or each subscale (P < 0.05). The factors significantly affecting patients' mental health were hormone dosage and disease activity index (DAI) (P < 0.05). The average optimism score of patients with SLE was 14.36 ± 4.42, and 30 cases were in the middle and lower levels. A positive correlation was found between optimism level and QoL scores. CONCLUSION: Patients with SLE develop psychological disorders at varying degrees, which are significantly influenced by hormone dosage and DAI. Patients' mental health should be closely monitored during clinical diagnosis and treatment and provided adequate support in establishing positive, healthy thinking and behavior patterns and improving their optimism level and QoL.

Endoplasmic reticulum stress response modulator OsbZIP39 regulates cadmium accumulation via activating the expression of defensin-like gene OsCAL2 in rice.

Accumulation of cadmium (Cd) in rice is not only harmful to the growth of plants but also poses a threat to human health. Exposure to Cd triggers unfolded protein response (UPR) within cells, a process that is still not completely understood. The study demonstrated that the lack of OsbZIP39, an essential endoplasmic reticulum (ER)-resident regulator of the UPR, resulted in decreased Cd intake and reduced Cd levels in the roots, stems, and grains of rice. Upon exposure to Cd stress, GFP-OsbZIP39 translocated from ER to nucleus, initiating UPR. Further investigation revealed that Cd treatment caused changes in sphingolipid levels in the membrane, influencing the localization and activation of OsbZIP39. Yeast one-hybrid and dual-LUC assays were conducted to validate the interaction between activated OsbZIP39 and the promoter of the defensin-like gene OsCAL2, resulting in an increase in its expression. Different variations were identified in the coding region of OsbZIP39, which may explain the varying levels of Cd accumulation observed in the indica and japonica subspecies. Under Cd treatment, OsbZIP39ind exhibited a more significant enhancement in the transcription of OsCAL2 compared to OsbZIP39jap. Our data suggest that OsbZIP39 positively regulates Cd uptake in rice, offering an encouraging objective for the cultivation of low-Cd rice.

Association of systemic inflammation response index with mortality risk in older patients with hip fracture: a 10-year retrospective cohort study.

Objective: With a rapidly aging global population, the assessment of mortality risk following hip fracture in older adults has received increasing attention. Recently, the system inflammation response index (SIRI) has been identified as a novel prognostic marker to reflect both systemic inflammation and immune status. However, it is not yet known whether SIRI is a potential predictor of subsequent death in hip fracture patients. Therefore, this study aimed to investigate the association between SIRI and mortality in older patients with hip fracture. Methods: A total of 1,206 older hip fracture patients undergoing surgery between January 2013 and December 2022 were consecutively derived from our longitudinal database. Patients were divided into three groups according to SIRI tertiles, calculated as neutrophil × monocyte / lymphocyte. Survival status was obtained from medical records or telephone interviews, and the study outcome was all-cause mortality after hip fracture at the longest follow-up. Multivariate Cox proportional hazard model and restricted cubic spline (RCS) regression model were used to evaluate the association between SIRI and mortality. Moreover, a series of sensitivity analyses were conducted to further validate the robustness of the association. Results: During a median follow-up of 43.85 months, 337 patients (27.94%) died. After full adjustment, each unit increase in SIRI was significantly associated with a 2.2% increase in overall mortality (95% confidence interval [CI]: 1.001-1.042, p = 0.029). Similarly, compared with the first tertile of SIRI, the second and third tertile showed a 1.335-fold (95% CI: 1.011-1.762, p = 0.042) and 1.447-fold (95% CI, 1.093-1.917, p = 0.010) higher risk of death. Sensitivity analyses confirmed the stability of the association. Moreover, RCS analysis revealed a positive non-linear relationship between SIRI and mortality (P for nonlinearity = 0.021). Conclusion: High SIRI level at admission was significantly and positively associated with an increased risk of death, suggesting that SIRI may be an independent predictor of mortality in older patients with hip fracture.

Prevalence and genetic diversity of Anaplasma and Ehrlichia in ticks and domesticated animals in Suizhou County, Hubei Province, China.

Anaplasma and Ehrlichia are tick-borne bacterial pathogens that cause anaplasmoses and ehrlichioses in humans and animals. In this study, we examined the prevalence of Anaplasma and Ehrlichia species in ticks and domesticated animals in Suizhou County, Hubei Province in the central China. We used PCR amplification and DNA sequencing of the 16S rRNA, groEL, and gltA genes to analyze. We collected 1900 ticks, including 1981 Haemaphysalis longicornis and 9 Rhipicephalus microplus, 159 blood samples of goats (n = 152), cattle (n = 4), and dogs (n = 3) from May to August of 2023. PCR products demonstrated that Anaplasma bovis, Anaplasma capra, and an Ehrlichia species were detected in the H. longicornis with the minimum infection rates (MIR) of 1.11%, 1.32%, and 0.05%, respectively; A. bovis, A. capra, and unnamed Anaplasma sp. were detected in goats with an infection rate of 26.31%, 1.31% and 1.97%, respectively. Anaplasma and Ehrlichia species were not detected from cattle, dogs and R. microplus ticks. The genetic differences in the groEL gene sequences of the Anaplasma in the current study were large, whereas the 16S rRNA and gltA gene sequences were less disparate. This study shows that ticks and goats in Suizhou County, Hubei Province carry multiple Anaplasma species and an Ehrlichia species, with relatively higher infection rate of A. bovis in goats. Our study indicates that multiple Anaplasma and Ehrlichia species exist in ticks and goats in the central China with potential to cause human infection.

Solvent-free synthesis of defective Zr-based metal-organic framework from waste plastic bottles for highly efficient lomefloxacin removal.

Large amount of polyethylene terephthalate (PET) plastics waster and emerging contaminants in water, including fluoroquinolone antibiotics, pose challenges to human survival. In this work, a green synthesis scheme is proposed in which the defective UiO-66 (d-UiO-66) is fabricated via a solvent-free routine by using PET plastics waster as raw materials for lomefloxacin (LOM) removal. In comparison with defect-free UiO-66, the created defect imparts d-UiO-66 with higher porosity and abundant defective Zr sites, which are beneficial to boost LOM adsorption. As expected, d-UiO-66 exhibited excellent LOM adsorption performances, showcasing a saturation adsorption capacity of 588 mg g-1 and a kinetic rate constant of 0.204 g mg-1 h-1, which are 3.5 and 2.0 times higher than those of the pristine UiO-66, respectively. Remarkably, the LOM saturation adsorption capacity of d-UiO-66 surpasses that of all reported adsorbents. Mechanism study reveals that this outstanding adsorption performance of d-UiO-66 is mainly ascribed to the abundant defective sites, high porosity, together with the strong hydrogen bonding interaction and π-π stacking interaction between d-UiO-66 and LOM. Therefore, the d-UiO-66 obtained by the solvent-free method can not only effectively upcycle PET plastic waster, but also efficiently remove LOM, demonstrating a potential routine to simultaneous address the solid PET waster and wastewater.

Current evidence of synaptic dysfunction after stroke: Cellular and molecular mechanisms.

BACKGROUND: Stroke is an acute cerebrovascular disease in which brain tissue is damaged due to sudden obstruction of blood flow to the brain or the rupture of blood vessels in the brain, which can prompt ischemic or hemorrhagic stroke. After stroke onset, ischemia, hypoxia, infiltration of blood components into the brain parenchyma, and lysed cell fragments, among other factors, invariably increase blood-brain barrier (BBB) permeability, the inflammatory response, and brain edema. These changes lead to neuronal cell death and synaptic dysfunction, the latter of which poses a significant challenge to stroke treatment. RESULTS: Synaptic dysfunction occurs in various ways after stroke and includes the following: damage to neuronal structures, accumulation of pathologic proteins in the cell body, decreased fluidity and release of synaptic vesicles, disruption of mitochondrial transport in synapses, activation of synaptic phagocytosis by microglia/macrophages and astrocytes, and a reduction in synapse formation. CONCLUSIONS: This review summarizes the cellular and molecular mechanisms related to synapses and the protective effects of drugs or compounds and rehabilitation therapy on synapses in stroke according to recent research. Such an exploration will help to elucidate the relationship between stroke and synaptic damage and provide new insights into protecting synapses and restoring neurologic function.

Anchoring Single-Atomic Metal Sites in Metalloporphyrin-Based Covalent Organic Frameworks for Enhanced Photocatalytic Hydrogen Evolution.

A photoactive covalent organic framework (COF) was built from metalloporphyrin and bipyridine monomers and single-atomic Pt sites were subsequently installed. Integrating photosensitizing metalloporphyrin and substrate-activating Pt(bpy) moieties in a single solid facilitates multielectron transfer and accelerates photocatalytic hydrogen evolution with a maximum production rate of 80.4 mmol h-1 gPt -1 and turnover frequency (TOF) of 15.7 h-1 observed. This work demonstrates that incorporation of single-atomic metal sites with photoactive COFs greatly enhances photocatalytic activity and provides an effective strategy for the design and construction of novel photocatalysts.

Cerebrospinal fluid CXCL13 concentration for diagnosis of neurosyphilis: a systematic review and meta-analysis.

OBJECTIVE: To systematically assess the diagnostic accuracy of CXCL13 testing of cerebrospinal fluid (CSF) for neurosyphilis diagnosing. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, Cochrane Library and Web of Science databases from their inception until 1 May 2023. ELIGIBILITY CRITERIA: Both cross-sectional and case-control diagnostic test studies evaluating the diagnostic value of CSF CXCL13 in diagnosing neurosyphilis were included, with no language restrictions. DATA EXTRACTION AND SYNTHESIS: Two researchers extracted data independently from all finally included articles. The updated Quality Assessment of Diagnostic Accuracy Studies tool was used to assess the quality of the included studies. Quantitative synthesis was done using a bivariate random-effects model. RESULTS: This meta-analysis included seven eligible studies involving a total of 1152 patients with syphilis and 430 patients with neurosyphilis. The pooled sensitivity, specificity and summary area under the curve (AUC) of CSF CXCL13 testing for the diagnosis of neurosyphilis were 0.76 (95% CI 0.64 to 0.85; I2=82%), 0.83 (95% CI 0.80 to 0.85; I2=32.29%) and 0.84 (95% CI 0.81 to 0.87), respectively. Sensitivity analysis confirmed the stability of the combined results. Meta-regression analysis revealed that the heterogeneity of pooled sensitivity was related to different study regions; subgroup analysis indicated that the diagnostic value of CSF CXCL13 testing reported in studies from China was superior to that reported in non-Chinese studies (pooled sensitivity, specificity and summary AUC values were 0.84 (I2=0) vs 0.64 (I2=79.53%), 0.83 (I2=42.03%) vs 0.83 (I2=32.87%) and 0.87 vs 0.83, respectively). The diagnostic value reported in studies with a sample size ≥200, unclassified neurosyphilis and HIV-negative subgroups was superior to the total combined value. CONCLUSIONS: This meta-analysis has demonstrated a reasonable level of accuracy for diagnosis of neurosyphilis with CSF CXCL13 testing. Further multicentre, prospective diagnostic studies, especially in asymptomatic neurosyphilis and HIV-infected patients, are needed to provide more evidence for evaluation before clinical application. PROSPERO REGISTRATION NUMBER: CRD42023414212.

Magnetic recyclable visible light-driven Bi2WO6/Fe3O4/RGO for photocatalytic degradation of Microcystin-LR: Mechanism, pathway, and influencing factors.

Photocatalysis was an attractive strategy that had potential to tackle the Microcystin-LR (MC-LR) contamination of aquatic ecosystems. Herein, magnetic photocatalyst Fe3O4/Bi2WO6/Reduced graphene oxide composites (Bi2WO6/Fe3O4/RGO) were employed to degrade MC-LR. The removal efficiency and kinetic constant of the optimized Bi2WO6/Fe3O4/RGO (Bi2WO6/Fe3O4-40%/RGO) was 1.8 and 2.3 times stronger than the pure Bi2WO6. The improved activity of Bi2WO6/Fe3O4-40%/RGO was corresponded to the expanded visible light adsorption ability and reduction of photogenerated carrier recombination efficiency through the integration of Bi2WO6 and Fe3O4-40%/RGO. The MC-LR removal efficiency exhibited a positive tendency to the initial density of algae cells, fulvic acid, and the concentration of MC-LR decreased. The existed anions (Cl-, CO3-2, NO3-, H2PO4-) reduced MC-LR removal efficiency of Bi2WO6/Fe3O4-40%/RGO. The Bi2WO6/Fe3O4-40%/RGO could degrade 79.3% of MC-LR at pH = 7 after 180 min reaction process. The trapping experiments and ESR tests confirmed that the h+, ∙OH, and ∙O2- played a significant role in MC-LR degradation. The LC-MS/MS result revealed the intermediates and possible degradation pathways.

BGP-15 alleviates LPS-induced depression-like behavior by promoting mitophagy.

The high prevalence of major depressive disorder (MDD) frequently imposes severe constraints on psychosocial functioning and detrimentally impacts overall well-being. Despite the growing interest in the hypothesis of mitochondrial dysfunction, the precise mechanistic underpinnings and therapeutic strategies remain unclear and require further investigation. In this study, an MDD model was established in mice using lipopolysaccharide (LPS). Our research findings demonstrated that LPS exposure induced depressive-like behaviors and disrupted mitophagy by diminishing the mitochondrial levels of PINK1/Parkin in the brains of mice. Furthermore, LPS exposure evoked the activation of the NLRP3 inflammasome, accompanied by a notable elevation in the concentrations of pro-inflammatory factors (TNF-α, IL-1ß, and IL-6). Additionally, neuronal apoptosis was stimulated through the JNK/p38 pathway. The administration of BGP-15 effectively nullified the impact of LPS, corresponding to the amelioration of depressive-like phenotypes and restoration of mitophagy, prevention of neuronal injury and inflammation, and suppression of reactive oxygen species (ROS)-mediated NLRP3 inflammasome activation. Furthermore, we elucidated the involvement of mitophagy in BGP-15-attenuated depressive-like behaviors using the inhibitors targeting autophagy (3-MA) and mitophagy (Mdivi-1). Notably, these inhibitors notably counteracted the antidepressant and anti-inflammatory effects exerted by BGP-15. Based on the research findings, it can be inferred that the antidepressant properties of BGP-15 in LPS-induced depressive-like behaviors could potentially be attributed to the involvement of the mitophagy pathway. These findings offer a potential novel therapeutic strategy for managing MDD.

A positive feedback inhibition of isocitrate dehydrogenase 3ß on paired-box gene 6 promotes Alzheimer-like pathology.

Impaired brain glucose metabolism is an early indicator of Alzheimer's disease (AD); however, the fundamental mechanism is unknown. In this study, we found a substantial decline in isocitrate dehydrogenase 3ß (IDH3ß) levels, a critical tricarboxylic acid cycle enzyme, in AD patients and AD-transgenic mice's brains. Further investigations demonstrated that the knockdown of IDH3ß induced oxidation-phosphorylation uncoupling, leading to reduced energy metabolism and lactate accumulation. The resulting increased lactate, a source of lactyl, was found to promote histone lactylation, thereby enhancing the expression of paired-box gene 6 (PAX6). As an inhibitory transcription factor of IDH3ß, the elevated PAX6 in turn inhibited the expression of IDH3ß, leading to tau hyperphosphorylation, synapse impairment, and learning and memory deficits resembling those seen in AD. In AD-transgenic mice, upregulating IDH3ß and downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies. Collectively, our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3ß-lactate-PAX6-IDH3ß. Breaking this loop by upregulating IDH3ß or downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.