Unravelling oncosis: morphological and molecular insights into a unique cell death pathway.

Programmed cell death (PCD) is a fundamental biological process for maintaining cellular equilibrium and regulating development, health, and disease across all living organisms. Among the various types of PCD, apoptosis plays a pivotal role in numerous diseases, notably cancer. Cancer cells frequently develop mechanisms to evade apoptosis, increasing resistance to standard chemotherapy treatments. This resistance has prompted extensive research into alternative mechanisms of programmed cell death. One such pathway is oncosis, characterized by significant energy consumption, cell swelling, dilation of the endoplasmic reticulum, mitochondrial swelling, and nuclear chromatin aggregation. Recent research suggests that oncosis can impact conditions such as chemotherapeutic cardiotoxicity, myocardial ischemic injury, stroke, and cancer, mediated by specific oncosis-related proteins. In this review, we provide a detailed examination of the morphological and molecular features of oncosis and discuss various natural or small molecule compounds that can induce this type of cell death. Additionally, we summarize the current understanding of the molecular mechanisms underlying oncosis and its role in both normal physiology and pathological conditions. These insights aim to illuminate future research directions and propose innovative strategies for leveraging oncosis as a therapeutic tool against human diseases and cancer resistance.

Pathogenic mechanisms of disease in idiopathic inflammatory myopathies: autoantibodies as clues.

Idiopathic inflammatory myopathies (IIMs) encompass a spectrum of autoimmune diseases characterized by muscle inflammation and systemic involvement. This review aimed to synthesize current evidence on the clinical significance and pathogenic mechanisms underlying autoantibodies associated with IIMs. Autoantibodies targeting aminoacyl-tRNA synthetases (ARS) play a pivotal role in antisynthetase syndrome (ASS), highlighting associations with interstitial lung disease (ILD) and distinctive clinical features. Anti-Mi-2 antibodies in dermatomyositis (DM) are hallmarked by characteristic cutaneous manifestations and favorable prognostic outcomes. Conversely, anti-TIF1 antibodies are correlated with DM and a higher risk of malignancies, implicating CD8+ T cells in its pathogenesis. Anti-MDA5 antibodies signify clinically amyopathic DM (CADM) with severe ILD, linked to dysregulated neutrophil extracellular trap (NET) formation. In immune-mediated necrotizing myopathies (IMNMs), anti-SRP and anti-HMGCR antibodies induce complement-mediated myopathy, typically following statin exposure. Additionally, anti-TRIM72 antibodies emerge as potential diagnostic markers in IIMs. Anti-cN1A autoantibodies are linked to inclusion body myositis (IBM) and play a decisive role in muscle protein degradation. Meanwhile, anti-FHL1 autoantibodies are associated with severe disease manifestations and muscle damage, as established in experimental models. Anti-eIF3 autoantibodies, recently identified in polymyositis (PM) patients, are rarely detected (<1%) and associated with a favorable prognosis. Elucidating these autoantibodies is anticipated to not only assist in early diagnosis and disease stratification but also inform targeted therapeutic interventions, emphasizing the intricate interplay between autoimmunity, cellular dysfunction, and clinical outcomes in IIMs.

ALK-positive histiocytosis: Report of a rare case with exclusive involvement of the central nervous system in an adult woman.

ALK-positive histiocytosis is a rare histiocytic disease characterized by ALK positivity. It was first described in 2008 as a systemic disease in infants. The disease often shows positivity for CD68 and CD163 on immunohistochemistry, and genomic analysis frequently reveals KIF5B::ALK fusions. ALK-positive histiocytosis typically follows an indolent course and has a promising prognosis, with conventional treatments usually being effective. Here, we report a rare case of ALK-positive histiocytosis with exclusive involvement of the central nervous system in a 33-year-old Asian adult woman. Although cranial MRI suggested a meningioma, immunohistochemical workup showed that the ALK-positive tumor cells expressed macrophage/histiocyte markers such as CD163 and CD68. Additionally, second-generation sequencing revealed a KIF5B::ALK fusion. Our case highlights the importance of the differential diagnosis in adult central nervous system tumors, emphasizing the combination of morphology, immunophenotype, and molecular approach with ALK status evaluation to confirm a diagnosis of ALK-positive histiocytosis. This case also expands the clinicopathologic spectrum of ALK-positive histiocytosis.

piR-27222 mediates PM2.5-induced lung cancer by resisting cell PANoptosis through the WTAP/m6A axis.

PM2.5 pollution has been associated with the incidence of lung cancer, but the underlying mechanism is still unclear. PIWI-interacting RNAs (piRNAs), initially identified in germline cells, have emerged as a novel class of small non-coding RNAs (26 - 32 nucleotides) with diverse functions in various diseases, including cancer. However, the role and mechanism of piRNAs in the development of PM2.5-induced lung cancer remain to be clarified. In the presented study, we used a PM2.5-induced malignant transformation cell model to analyze the change of piRNA profiles. Among the disturbed piRNAs, piR-27222 was identified as an oncogene that inhibited cell death in a m6A-dependent manner. Mechanistically, we found that piR-27222 could deubiquitinate and stabilize eIF4B by directly binding to eIF4B and reducing its interaction with PARK2. The enhanced expression of eIF4B, in turn, promoted the expression of WTAP, leading to increased m6A modification in the Casp8 transcript. Consequently, the stability of Casp8 transcripts was reduced, rendering lung cancer cells resistant to PANoptosis. Collectively, our findings reveal that PM2.5 exposure up-regulated piR-27222 expression, which could affect EIF4B/WTAP/m6A axis, thereby inhibiting PANoptosis of cells and promoting lung cancer. Our study provides new insights into understanding the epigenetic mechanisms underlining PM2.5-induced lung cancer.

Dynamically visualizing profibrotic maladaptive repair after acute kidney injury by fibroblast activation protein imaging.

A major challenge in prevention and early treatment of organ fibrosis is the lack of valuable tools to assess the evolving profibrotic maladaptive repair after injury in vivo in a non-invasive way. Here, using acute kidney injury (AKI) as an example, we tested the utility of fibroblast activation protein (FAP) imaging for dynamic assessment of maladaptive repair after injury. The temporospatial pattern of kidney FAP expression after injury was first characterized. Single-cell RNA sequencing and immunostaining analysis of patient biopsies were combined to show that FAP was specifically upregulated in kidney fibroblasts after AKI and was associated with fibroblast activation and chronic kidney disease (CKD) progression. This was corroborated in AKI mouse models, where a sustained and exaggerated kidney FAP upregulation was coupled to persistent fibroblast activation and a fibrotic outcome, linking kidney FAP level to post-insult maladaptive repair. Furthermore, using positron emission tomography (PET)/CT scanning with FAP-inhibitor tracers ([18F]FAPI-42, [18F]FAPT) targeting FAP, we demonstrated the feasibility of non-invasively tracking of maladaptive repair evolution toward kidney fibrosis. Importantly, a sustained increase in kidney [18F]FAPT (less hepatobiliary metabolized than [18F]FAPI-42) uptake reflected persistent kidney upregulation of FAP and characterized maladaptive repair after AKI. Kidney [18F]FAPT uptake at hour 2-day 7 correlated with kidney fibrosis 14 days after AKI. Similar changes in [18F]FAPI-42 PET/CT imaging were observed in patients with AKI and CKD progression. Thus, persistent kidney FAP upregulation after AKI was associated with maladaptive repair and a fibrotic outcome. Hence, FAP-specific PET/CT imaging enables dynamic visualization of maladaptive repair after AKI and prediction of kidney fibrosis within a clinically actionable window.

New insights into the function and mechanisms of piRNA PMLCPIR in promoting PM2.5-induced lung cancer.

INTRODUCTION: Extensive studies have established the correlation between long-term PM2.5 exposure and lung cancer, yet the mechanisms underlying this association remain poorly understood. PIWI-interacting RNAs (piRNAs), a novel category of small non-coding RNAs, serve important roles in various diseases. However, their biological function and mechanism in PM2.5-induced lung cancer have not been thoroughly investigated. OBJECTIVES: We aimed to explore the oncogenic role of piRNA in lung cancer induced by PM2.5 exposure, as well as the underlying mechanisms. METHODS: We conducted a PM2.5-induced human lung epithelial cell malignant transformation model. Human samples were used to further verify the finding. In vitro proliferation, migration, and invasion assays were performed to study the function of piRNA. RNA-sequencing was used to elucidate the the mechanisms of how piRNA mediates cell functions. PiRNA pull-down and computational docking analysis were conducted to identify proteins that binding to piRNA. In vivo experiments were used to explore whether inhibition of PMLCPIR could have a therapeutic effect on lung cancer. RESULTS: We identified a new up-regulated piRNA, termed PM2.5-induced lung cancer up-regulation piRNA (PMLCPIR), which promotes the proliferation of PM2.5-transformed cells and lung cancer cells. RNA sequencing revealed ITGB1 as a downstream target of PMLCPIR. Importantly, PMLCPIR binds to nucleolin (NCL) and increases the expression of its target gene, ITGB1, thereby activating PI3K/AKT signaling. The inhibition of PMLCPIR could promote apoptosis in lung cancer cells and enhance their chemosensitivity to anti-tumor drugs. CONCLUSION: We systematically identified the alterations of piRNA expression profiles in the PM2.5-induced malignant transformation model. Then, PMLCPIR was recognized as a novel oncogenic piRNA in PM2.5-induced lung cancer. Mechanically, PMLCPIR binds to NCL, enhancing ITGB1 expression and activating the ontogenetic PI3K/AKT signaling, potentially contributing to lung cancer progression. This study provides novel insights into the revelation of a new epigenetic regulator in PM2.5-induced lung cancer.

Inflammation-Derived and Clinical Indicator-Based Predictive Model for Ischemic Stroke Recovery.

BACKGROUND: Neuroinflammatory responses are closely associated with poststroke prognosis severity. This study aimed to develop a predictive model, combining inflammation-derived markers and clinical indicators, for distinguishing functional outcomes in patients with subacute ischemic stroke. METHODS AND RESULTS: Based on activities of daily living assessments, ischemic stroke participants were categorized into groups with little effective (LE) recovery and obvious effective (OE) recovery. Initial biocandidates were identified by overlapping differentially expressed proteins from proteomics of clinical serum samples (5 LE, 5 OE, and 6 healthy controls) and differentially expressed genes from an RNA sequence of the ischemic cortex in middle cerebral artery occlusion mice (n=3). Multidimensional validations were conducted in ischemia-reperfusion models and a clinical cohort (15 LE, 11 OE, and 18 healthy controls). Models of robust biocandidates combined with clinical indicators were developed with machine learning in the training data set and prediction in another test data set (15 LE and 11 OE). We identified 194 differentially expressed proteins (LE versus healthy controls) and 174 differentially expressed proteins (OE versus healthy controls) in human serum, and 5121 differentially expressed genes (day 3) and 5906 differentially expressed genes (day 7) in middle cerebral artery occlusion mice cortex. Inflammation-derived biomarkers TIMP1 (tissue inhibitor metalloproteinase-1) and galactosidase-binding protein LGLAS3 (galectin-3) exhibited robust increases under ischemic injury in mice and humans. TIMP1 and LGALS3 coupled with clinical indicators (hemoglobin, low-density lipoprotein cholesterol, and uric acid) were developed into a combined model for differentiating functional outcome with high accuracy (area under the curve, 0.8). CONCLUSIONS: The combined model is a valuable tool for evaluating prognostic outcomes, and the predictive factors can facilitate development of better treatment strategies.

Association between excessive alcohol consumption and incident diabetes mellitus among Japanese based on propensity score matching.

The available evidence on the connection between excessive alcohol consumption and diabetes is controversial. Therefore, the primary objective of this investigation was to examine the connection between excessive alcohol consumption and incident diabetes in a Japanese population through the utilization of propensity score matching (PSM) analysis. Our retrospective cohort study encompassed a sample of 15,464 Japanese individuals who were initially free of diabetes between the years 2004 and 2015. The study utilized comprehensive medical records of individuals who underwent a physical examination. Employing a one:one PSM analysis, the current research included 2298 individuals with and without excessive alcohol consumption. Furthermore, a doubly robust estimation method was employed to ascertain the connection between excessive alcohol consumption and diabetes. The findings revealed that individuals with excessive alcohol consumption exhibited a 73% higher likelihood of developing diabetes (HR = 1.73, 95% CI 1.08-2.77). Furthermore, upon adjusting for variables, the PSM cohort demonstrated that individuals with excessive alcohol consumption had a 78% increased risk of developing diabetes in comparison to those with non-excessive alcohol consumption (HR = 1.78, 95% CI 1.08-2.93). Individuals with excessive alcohol consumption were found to have a 73% higher risk of developing diabetes compared to those with non-excessive alcohol consumption, even after controlling for propensity score (HR = 1.73, 95% CI 1.08-2.78). Participants in the PSM cohort with excessive alcohol consumption had a 73% higher risk of developing diabetes than those with non-excessive alcohol consumption after controlling for confounding factors. These findings underscore the importance of alcohol consumption guidelines aimed at reducing excessive drinking. Clinicians should be vigilant in screening for alcohol use in patients, particularly those at risk for diabetes, and provide appropriate counseling and resources to support alcohol reduction.

Selenium Status Associates with Thyroid Hormone and Thyroid Dysfunction in Older Chinese Adults.

Selenium (Se) is physiologically essential for thyroid function. However, epidemiological studies on the association between Se status and thyroid function are limited and the results are inconsistent. Therefore, we explored this association in an elderly Chinese population sample. Participants in the cross-sectional study were people aged 65 years or older who provided fingernail and whole blood samples. Hyperthyroidism and hypothyroidism were defined by serum thyroid hormones concentrations, including thyroid stimulating hormone (TSH), total triiodothyronine (TT3), total thyroxine (TT4), free thyroxine (FT3), and free thyrotropin (FT4). Significant positive association was observed between whole blood and fingernail Se concentrations (r = 0.672, P < 0.001). Compared with the lowest Se quartile (Q1), the other fingernail Se quartile groups had lower TSH, higher FT3 and FT4 levels, and Q2 had higher TT3 levels after adjusting for covariates; the other whole blood Se quartile groups had lower TSH levels, Q2 had higher FT3, FT4 and TT3 levels, Q3 had higher FT3 levels, and Q4 had higher FT4 levels after adjusting for covariates. Compared with Q1, the adjusted odds ratios (OR) and 95% confidence intervals (95%CIs) of hypothyroidism for Q4 of whole blood Se was 0.141 (0.029,0.675), and the adjusted OR (95%CIs) of hyperthyroidism for Q2 and Q3 of fingernail Se were 4.121 (1.233,13.733) and 3.614 (1.095,11.926). Higher Se levels were significantly associated with lower TSH levels and higher levels of TT3, FT3 and FT4. Meanwhile, higher Se levels were associated with lower risk of hypothyroidism and higher risk of hyperthyroidism.

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents.

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.

[Box: see text].

Cadmium Exposure was Associated with Sex-Specific Thyroid Dysfunction: Consistent Evidence from Two Independent Cross-Sectional Studies Based on Urinary and Blood Cadmium Measurements.

Population-based studies on the association between cadmium (Cd) exposure and thyroid function are limited and have shown conflicting results. Two independent cross-sectional studies using different Cd biomarkers were carried out in six rural areas with different soil Cd levels in China. Thyroid dysfunction was defined based on levels of thyroid stimulating hormone (TSH) and free thyroxine (FT4). Multivariable linear regression, multiple logistic regression, and restrictive cubic splines models were used to estimate the association between Cd and thyroid dysfunction. For both of the two independent studies, higher Cd levels were observed to be associated with lower TSH levels and higher risk of thyroid dysfunction. The negative relationship between urinary Cd and TSH was found in both total participants (ß = - 0.072, p = 0.008) and males (ß = - 0.119, p = 0.020) but not in females; however, the negative relationship between blood Cd and TSH was only found in females (ß = - 0.104, p = 0.024). Higher urinary Cd was associated with higher risk of thyroid dysfunction (OR = 1.77, p = 0.031), while higher blood Cd was associated with higher risk of thyroid dysfunction (OR = 1.95, p = 0.011). Results from the two independent cross-sectional studies consistently suggested that higher Cd levels were associated with sex-specific thyroid dysfunction.

Non-linear relationship between pulse pressure and the risk of pre-diabetes: a secondary retrospective Chinese cohort study.

OBJECTIVE: Previous research has shown that pulse pressure (PP) has a significant role in the start and development of type 2 diabetes mellitus. However, there is little proof that PP and pre-diabetes mellitus (Pre-DM) are related. Our study aimed to investigate the relationship between PP and incident pre-DM in a substantial cohort of Chinese participants. DESIGN: The 'DATADRYAD' database (www.Datadryad.org) was used to retrieve the data for this secondary retrospective cohort analysis. PARTICIPANTS: Data from 182 672 Chinese individuals who participated in the medical examination programme were recorded in this retrospective cohort study between 2010 and 2016 across 32 sites and 11 cities in China. SETTING: PP assessed at baseline and incident pre-DM during follow-up were the target-independent and dependent variables. The association between PP and pre-DM was investigated using Cox proportional hazards regression. PRIMARY OUTCOME MEASURES: The outcome was incident pre-DM. Impaired fasting glucose levels (fasting blood glucose between 5.6 and 6.9 mmol/L) were used to define pre-DM. RESULTS: After controlling for confounding variables, PP was positively correlated with incident pre-DM among Chinese adults (HR 1.009, 95% CI 1.007 to 1.010). Additionally, at a PP inflection point of 29 mm Hg, a non-linear connection between the PP and incident pre-DM was discovered. Increased PP was an independent risk factor for developing pre-DM when PP was greater than 29 mm Hg. However, their association was not significant when PP was less than 29 mm Hg. According to subgroup analyses, females, never-smokers and non-obesity correlated more significantly with PP and pre-DM. CONCLUSION: We discovered that higher PP independently correlated with pre-DM risk in this study of Chinese participants. The connection between PP and incident pre-DM was also non-linear. High PP levels were related to a higher risk of pre-DM when PP was above 29 mm Hg. ARTICLE FOCUS: Our study investigated the relationship between PP and incident pre-DM in a secondary retrospective cohort of Chinese participants.

Association between alanine aminotransferase to high-density lipoprotein cholesterol ratio and nonalcoholic fatty liver disease: a retrospective cohort study in lean Chinese individuals.

There is limited research on the association between the alanine aminotransferase to high-density lipoprotein cholesterol ratio (ALT/HDL-C) ratio and nonalcoholic fatty liver disease (NAFLD). The purpose of the current research was to look into the connection between the ALT/HDL-C ratio and the risk of NAFLD in lean Chinese individuals. Between January 2010 and December 2014, 11,975 non-obese people participated in this prospective cohort research. The relationship between the ALT/HDL-C ratio and the risk of developing NAFLD was assessed using the Cox proportional-hazards regression model, Cox proportional hazards regression with cubic spline functions and smooth curve fitting, sensitivity analysis, and subgroup analyses. The ALT/HDL-C ratio's potential value as a NAFLD prognostic marker was to be evaluated using the receiver operating characteristic curve analysis. A total of 5419 (45.253%) women comprised the research's participant population, and the research participants' average age was 43.278 ± 14.941 years. The ALT/HDL-C ratio was 11.607 (7.973-17.422) at the median (interquartile ranges). 2087 (17.428%) patients had NAFLD diagnoses throughout a median follow-up of 24.967 months. The study's findings demonstrated a positive connection between the ALT/AHDL-C ratio and the incident NAFLD (HR = 1.037, 95% CI: 1.031-1.042) when adjusting for relevant factors. The ALT/HDL-C ratio and NAFLD risk had a nonlinear connection, with 12.963 as the ratio's inflection point. Effect sizes (HR) were 1.023 (95% CI: 1.017-1.029) and 1.204 (95% CI: 1.171-1.237), respectively, on the right and left sides of the inflection point. The sensitivity analysis also showed how reliable our findings were. According to subgroup analysis, those with BMI < 24 kg/m2 and DBP < 90 mmHg had a stronger correlation between the ALT/HDL-C ratio and NAFLD risk. The current study shows a positive and non-linear connection between the ALT/HDL-C ratio and NAFLD risk in lean Chinese individuals. When the ALT/HDL-C ratio is less than 12.963, it is significantly linked to NAFLD. Therefore, from a therapy standpoint, it is advised to keep the ALT/HDL-C ratio less than the inflection point.

A non-linear connection between the total cholesterol to high-density lipoprotein cholesterol ratio and stroke risk: a retrospective cohort study from the China Health and Retirement Longitudinal Study.

OBJECTIVE: The connection between total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio and stroke risk is controversial. This study aims to examine the connection between the TC/HDL-C ratio and stroke in middle-aged and older individuals who are part of the China Health and Retirement Longitudinal Study (CHARLS). METHODS: This study conducted a retrospective cohort analysis, enrolling a total of 10,184 participants who met the designated criteria from CHARLS between 2011 and 2012. We then used the Cox proportional-hazards regression model to analyze the relationship between the TC/HDL-C ratio and stroke risk. Using a Cox proportional hazards regression model with cubic spline functions and smooth curve fitting, we were able to identify the non-linear relationship between the TC/HDL-C ratio and stroke occurrence. The sensitivity and subgroup analyses were also performed to investigate the connection between TC/HDL-C ratio and stroke. RESULTS: This study revealed a statistically significant association between the TC/HDL-C ratio and stroke risk in subjects aged 45 years or older after adjusting for risk factors (HR: 1.05, 95%CI 1.00-1.10, P = 0.0410). Furthermore, a non-linear connection between the TC/HDL-C ratio and stroke risk was detected, with a TC/HDL-C ratio inflection point of 3.71. We identified a significant positive connection between the TC/HDL-C ratio and stroke risk, when the TC/HDL-C ratio was less than 3.71 (HR: 1.25, 95%CI 1.07-1.45, P = 0.0039). However, their connection was not significant when the TC/HDL-C ratio exceeded 3.71 (HR: 1.00, 95%CI 0.94-1.06, P = 0.9232). The sensitivity analysis and subgroup analyses revealed that our findings were well-robust. CONCLUSION: Our study demonstrated a positive, non-linear connection between the TC/HDL-C ratio and stroke risk in middle-aged and older individuals. There was a significant positive connection between the TC/HDL-C ratio and stroke risk, when the TC/HDL-C ratio was less than 3.71. The current research can be used as a guideline to support clinician consultation and optimize stroke prevention measures for middle-aged and older adults.

LncRNA ZNF674-AS1 drives cell growth and inhibits cisplatin-induced pyroptosis via up-regulating CA9 in neuroblastoma.

Neuroblastoma (NB) is a challenging pediatric extracranial solid tumor characterized by a poor prognosis and resistance to chemotherapy. Identifying targets to enhance chemotherapy sensitivity in NB is of utmost importance. Increasing evidence implicates long noncoding RNAs (lncRNAs) play important roles in cancer, but their functional roles remain largely unexplored. Here, we analyzed our RNA sequencing data and identified the upregulated lncRNA ZNF674-AS1 in chemotherapy non-responsive NB patients. Elevated ZNF674-AS1 expression is associated with poor prognosis and high-risk NB. Importantly, targeting ZNF674-AS1 expression in NB cells suppressed tumor growth in vivo. Further functional studies have revealed that ZNF674-AS1 constrains cisplatin sensitivity by suppressing pyroptosis and promoting cell proliferation. Moreover, ZNF674-AS1 primarily relies on CA9 to fulfill its functions on cisplatin resistance. High CA9 levels were associated with high-risk NB and predicted poor patient outcomes. Mechanistically, ZNF674-AS1 directly interacted with the RNA binding protein IGF2BP3 to enhance the stability of CA9 mRNA by binding with CA9 transcript, leading to elevated CA9 expression. As a novel regulator of CA9, IGF2BP3 positively upregulated CA9 expression. Together, these results expand our understanding of the cancer-associated function of lncRNAs, highlighting the ZNF674-AS1/IGF2BP3/CA9 axis as a constituting regulatory mode in NB tumor growth and cisplatin resistance. These insights reveal the pivotal role of ZNF674-AS1 inhibition in recovering cisplatin sensitivity, thus providing potential therapeutic targets for NB treatment.

[Mercury species analysis and tissue distribution in rats after continuous administration of Cinnabaris].

Cinnabaris is a traditional Chinese medicine(TCM) commonly used for sedation and tranquilization in clinics, and its safety has always been a concern. This study intends to investigate the species and tissue distribution of mercury in rats after continuous administration of Cinnabaris. In the experiment, 30 rats were randomly divided into the control group(equivalent to 0.5% carboxy-methyl cellulose sodium), low-dose Cinnabaris group(0.2 g·kg~(-1)), high-dose Cinnabaris group(2 g·kg~(-1)), pseudogerm-free control group(equivalent to 0.5% sodium carboxymethyl cellulose), and pseudogerm-free Cinnabaris group(2 g·kg~(-1)). They were orally administered for 30 consecutive days. Ultrasound-assisted acid extraction method combined with high performance liquid chromatography and inductively coupled plasma-mass spectrometry(HPLC-ICP-MS) was adopted to determine inorganic mercury [Hg(Ⅱ)], methylmercury(MeHg), and ethylmercury(EtHg) in different tissue, plasma, urine, and feces of rats. The optimal detection conditions and extraction methods were optimized, and the linearity(R~2>0.999 3), precision(RSD<7.0%), and accuracy(spike recoveries ranged from 73.05% to 109.5%) of all the mercury species were satisfied, meeting the requirements of analysis. The results of mercury species detection showed that Hg(Ⅱ) was detected in all the tissue of the five experimental groups, and the main accumulating organs were the intestinal tract, stomach, and kidney. MeHg existed at a low concentration in most tissue, and EtHg was not detected in all groups. In addition, pathological examination results showed that hepatocyte vacuolar degeneration, loose cytoplasm, light staining, and mononuclear cell infiltration were observed in the high-dose Cinnabaris group, low-dose Cinnabaris group, and pseudogerm-free Cinnabaris group, with slightly milder lesions in the low-dose Cinnabaris group. Hydrous degeneration of renal tubular epithelium could be seen in the high-dose Cinnabaris group and pseudogerm-free Cinnabaris group, but there was no significant difference between the other groups and the control group. No abnormal changes were found in the brain tissue of rats in each group. This paper studied the different mercury species and tissue distribution in normal and pseudogerm-free rats after continuous administration of Cinnabaris for 30 days and clarified its effects on the tissue structure of the liver, kidney, and brain, which provided supporting evidence for the safety evaluation of Cinnabaris.

Palladium-catalyzed synthesis and anti-AD biological activity evaluation of N-aryl-debenzeyldonepezil analogues.

A series of novel N-aryl-debenzeyldonepezil derivatives (1-26) were designed and synthesized as cholinesterase inhibitors by the modification of anti-Alzheimer's disease drug donepezil, using Palladium catalyzed Buchwald-Hartwig cross-coupling reaction as a key chemical synthesis strategy. In vitro cholinesterase inhibition studies demonstrated that the majority of synthesized compounds exhibited high selective inhibition of AChE. Among them, analogue 13 possessing a quinoline functional group showed the most potent AChE inhibition effect and significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Furthermore, Compound 13 did not show significant cytotoxicity on SH-SY5Y. These results suggest that 13 is a potential multifunctional active molecule for treating Alzheimer's disease.

Lysine ß-hydroxybutyrylation promotes lipid accumulation in alcoholic liver disease.

Continuous (chronic or sub-chronic) alcohol consumption induces a metabolic byproduct known as ketone bodies, and the accumulation of ketones leads to a life-threatening syndrome called alcoholic ketoacidosis. However, the mechanism underlining the physiological effects of ketone accumulation in alcoholic liver disease (ALD) is still in its infancy. Here, we discovered that mitochondrial acetyl-CoA accumulation was diverted into the ketogenesis pathway in ethanol-fed mice and ethanol-exposed hepatocytes. Unexpectedly, global protein lysine ß-hydroxybutyrylation (Kbhb) was induced in response to increased ketogenesis-derived ß-hydroxybutyrate (BHB) levels both in hepatocytes and in livers of mice. Focusing on the solute carrier family (SLCs), we found that SLC25A5 presented obvious Kbhb at lysine residues 147 and 166. Kbhb modifications at these two lysine residues stabilized SLC25A5 expression by blocking ubiquitin-proteasome pathway. Subsequent mutation analysis revealed that Kbhb of SLC25A5 at K147 and K166 had site-specific regulatory roles by increasing peroxisome proliferator activated receptor gamma (PPARγ) expression, which further promoting lipogenesis. Additionally, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2), a rate-limiting enzyme for BHB production, was profoundly induced by ethanol exposure, and knockout of Hmgcs2 with CRISPR/Cas9 attenuated SLC25A5 Kbhb. Together, our study demonstrated a widespread Kbhb landscape under ethanol exposure and clarified a physiological effect of Kbhb modification on liver lipid accumulation.

Neutrophil counts and cardiovascular disease.

BACKGROUND AND AIMS: Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated with atherosclerosis in experimental studies. This study aimed to investigate the associations between neutrophil counts and risk of nine cardiovascular endpoints using observational and genetic approaches. METHODS: Observational studies were conducted in the Copenhagen General Population Study (n = 101 730). Genetic studies were firstly performed using one-sample Mendelian randomization (MR) with individual-level data from the UK Biobank (n = 365 913); secondly, two-sample MR analyses were performed using summary-level data from the Blood Cell Consortium (n = 563 085). Outcomes included ischaemic heart disease, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, ischaemic stroke, vascular-related dementia, vascular dementia, heart failure, and atrial fibrillation. RESULTS: Observational analyses showed associations between high neutrophil counts with high risks of all outcomes. In the UK Biobank, odds ratios (95% confidence intervals) per 1-SD higher genetically predicted neutrophil counts were 1.15 (1.08, 1.21) for ischaemic heart disease, 1.22 (1.12, 1.34) for myocardial infarction, and 1.19 (1.04, 1.36) for peripheral arterial disease; similar results were observed in men and women separately. In two-sample MR, corresponding estimates were 1.14 (1.05, 1.23) for ischaemic heart disease and 1.11 (1.02, 1.20) for myocardial infarction; multiple sensitivity analyses showed consistent results. No robust associations in two-sample MR analyses were found for other types of leucocytes. CONCLUSIONS: Observational and genetically determined high neutrophil counts were associated with atherosclerotic cardiovascular disease, supporting that high blood neutrophil counts is a causal risk factor for atherosclerotic cardiovascular disease.

Emerging Human Fascioliasis: A Retrospective Study of Epidemiological Findings in Dali, Yunnan Province, China (2012-2021).

BACKGROUND Human fascioliasis is an emerging zoonotic disease caused by the trematodes, or flatworms, Fasciola hepatica and Fasciola gigantica, also known as liver flukes. This retrospective study aimed to report the epidemiological findings in 95 cases of human fascioliasis in Dali, Yunnan Province, southwestern China, diagnosed between 2012 and 2021. MATERIAL AND METHODS The epidemiologic and clinical data of 95 patients diagnosed with human fascioliasis in Dali area from January 2012 to December 2021 were collected and retrospectively analyzed. The diagnosis of fascioliasis was based on the Chinese National Standard of Diagnosis of Fascioliasis (WS/T566-2017). RESULTS The mean age of patients was 38.54±15.68 years, and there were more female patients than male (61.05% vs 38.95%). The high-incidence seasons were identified as summer and autumn. The patients with human fascioliasis lived in pastoral areas or were infected F. gigantica by consuming contaminated vegetables or water containing metacercaria. Meanwhile, human fascioliasis was diagnosed by positive serologic tests (1: 640), and Fasciola eggs (144-180×73-96 µm) were detected in stool samples of 6 patients. The most common clinical features were abdominal pain (70.53%), accompanied by elevated eosinophils in 89.5% of these patients. Antiparasitic treatment with triclabendazole at 10 mg/kg/day for 2 days led to symptom relief in all patients. CONCLUSIONS The findings from this observational epidemiological study have highlighted the importance of recognizing, diagnosing, and managing fascioliasis, which is an emerging zoonosis associated with increased human proximity to plant-eating domestic and farmed animals.