Retinal Explant Culture from Mouse, Human, and Nonhuman Primates and Its Applications in Vision Research.

The retinal explant culture system is a valuable tool for studying the pharmacological, toxicological, and developmental aspects of the retina. It is also used for translational studies such as gene therapy. While no photoreceptor-like cell lines are available for in vitro studies of photoreceptor cell biology, the retinal explant culture maintains the laminated retinal structure ex vivo for as long as a month. Human and nonhuman primate (NHP) postmortem retinal explants cut into small pieces offer the possibility of testing multiple conditions for safety and adeno-associated viral (AAV) vector optimization. In addition, the cone-enriched foveal area can be studied using the retinal explants. Here, we present a detailed working protocol for retinal explant isolation and culture from mouse, human, and NHP for testing drug efficacy and AAV transduction. Future applications of this protocol include combining live imaging and multiwell retinal explant culture for high-throughput drug screening systems in rodent and human retinal explants to identify new drugs against retinal degeneration.

RRFERV stabilizes TEAD1 expression to mediate nasopharyngeal cancer radiation resistance rendering tumor cells vulnerable to ferroptosis.

BACKGROUND: Long noncoding RNAs (lncRNAs) regulate various essential biological processes, including cell proliferation, differentiation, apoptosis, migration, and invasion. However, in nasopharyngeal carcinoma (NPC), the clinical significance and mechanisms of lncRNAs in malignant progression are unknown. METHODS: RNA sequencing and bioinformatic analysis were used to determine the potential function of RRFERV (radiation-resistant but ferroptosis vulnerable), and its biological effects were investigated using in vitro and in vivo experiments. Western blotting, quantitative real-time reverse transcription PCR, RNA immunoprecipitation (RIP) assays, and flow cytometry detected RRFERV expression. Ferroptosis and lipid peroxidation were added to evaluate the relationship between it and radiotherapy resistance. RESULTS: LncRNA-RRFERV was both highly expressed in NPC tissues and radiation-resistant cells. RRFERV is associated with poor clinical outcomes of NPC patients and stabilizes TEAD1 by competitive binding with microRNA-615-5p and microRNA-1293. RRFERV-TEAD1 signaling axis leads to malignant progression and radiotherapy resistance of NPC. Furthermore, we observed that NPC radiotherapy resistance cells exist in a fragile oxidative stress equilibrium, which makes them more sensitive to ferroptosis inducers. Surprisingly, we found that RRFERV-TEAD1 signaling axis also plays a key role in mediating the lipid peroxidation levels of NPC radiotherapy resistance cells through transcriptional activation of ACSL4/TFRC. CONCLUSIONS: RRFERV serves as an independent prognostic factor in NPC. During the malignant progression of NPC caused by high expression of RRFERV, ferroptosis can be induced to effectively kill cancer cells and reverse the radiotherapy resistance of NPC cells, suggesting a potential treatment approach for recurrent and refractory NPC.

Investigating the relationship of co-exposure to multiple metals with chronic kidney disease: An integrated perspective from epidemiology and adverse outcome pathways.

Systematic studies on the associations between co-exposure to multiple metals and chronic kidney disease (CKD), as well as the underlying mechanisms, remain insufficient. This study aimed to provide a comprehensive perspective on the risk of CKD induced by multiple metal co-exposures through the integration of occupational epidemiology and adverse outcome pathway (AOP). The study participants included 401 male mine workers whose blood metal, ß2-microglobulin (ß2-MG), and cystatin C (Cys-C) levels were measured. Generalized linear models (GLMs), quantile g-computation models (qgcomp), least absolute shrinkage and selection operator (LASSO), and bayesian kernel machine regression (BKMR) were utilized to identify critical nephrotoxic metals. The mean concentrations of lead, cadmium, mercury, arsenic, and manganese were 191.93, 3.92, 4.66, 3.11, 11.35, and 16.33 µg/L, respectively. GLM, LASSO, qgcomp, and BKMR models consistently identified lead, cadmium, mercury, and arsenic as the primary contributors to kidney toxicity. Based on our epidemiological analysis, we used a computational toxicology method to construct a chemical-genetic-phenotype-disease network (CGPDN) from the Comparative Toxicogenomics Database (CTD), DisGeNET, and GeneCard databases, and further linked key events (KEs) related to kidney toxicity from the AOP-Wiki and PubMed databases. Finally, an AOP framework of multiple metals was constructed by integrating the common molecular initiating events (reactive oxygen species) and KEs (MAPK signaling pathway, oxidative stress, mitochondrial dysfunction, DNA damage, inflammation, hypertension, cell death, and kidney toxicity). This is the first AOP network to elucidate the internal association between multiple metal co-exposures and CKD, providing a crucial basis for the risk assessment of multiple metal co-exposures.

Pan-cancer characterization of cellular senescence reveals its inter-tumor heterogeneity associated with the tumor microenvironment and prognosis.

Cellular senescence (CS) is characterized by the irreversible cell cycle arrest and plays a key role in aging and diseases, such as cancer. Recent years have witnessed the burgeoning exploration of the intricate relationship between CS and cancer, with CS recognized as either a suppressing or promoting factor and officially acknowledged as one of the 14 cancer hallmarks. However, a comprehensive characterization remains absent from elucidating the divergences of this relationship across different cancer types and its involvement in the multi-facets of tumor development. Here we systematically assessed the cellular senescence of over 10,000 tumor samples from 33 cancer types, starting by defining a set of cancer-associated CS signatures and deriving a quantitative metric representing the CS status, called CS score. We then investigated the CS heterogeneity and its intricate relationship with the prognosis, immune infiltration, and therapeutic responses across different cancers. As a result, cellular senescence demonstrated two distinct prognostic groups: the protective group with eleven cancers, such as LIHC, and the risky group with four cancers, including STAD. Subsequent in-depth investigations between these two groups unveiled the potential molecular and cellular mechanisms underlying the distinct effects of cellular senescence, involving the divergent activation of specific pathways and variances in immune cell infiltrations. These results were further supported by the disparate associations of CS status with the responses to immuno- and chemo-therapies observed between the two groups. Overall, our study offers a deeper understanding of inter-tumor heterogeneity of cellular senescence associated with the tumor microenvironment and cancer prognosis.

Corrigendum: A chain mediation model on organizational support and turnover intention among healthcare workers in Guangdong province, China.

[This corrects the article DOI: 10.3389/fpubh.2024.1391036.].

Gadoxetic acid-enhanced magnetic resonance imaging in the assessment of hepatic sinusoidal obstruction syndrome in a mouse model.

BACKGROUND: Neoadjuvant chemotherapy can cause hepatic sinusoidal obstruction syndrome (SOS) in patients with colorectal cancer liver metastases and increases postoperative morbidity and mortality. AIM: To evaluate T1 mapping based on gadoxetic acid-enhanced magnetic resonance imaging (MRI) for diagnosis of hepatic SOS induced by monocrotaline. METHODS: Twenty-four mice were divided into control (n = 10) and experimental (n = 14) groups. The experimental groups were injected with monocrotaline 2 or 6 days before MRI. MRI parameters were: T1 relaxation time before enhancement; T1 relaxation time 20 minutes after enhancement (T1post); a reduction in T1 relaxation time (△T1%); and first enhancement slope percentage of the liver parenchyma (ESP). Albumin and bilirubin score was determined. Histological results served as a reference. Liver parenchyma samples from the control and experimental groups were analyzed by western blotting, and organic anion transporter polypeptide 1 (OATP1) was measured. RESULTS: T1post, △T1%, and ESP of the liver parenchyma were significantly different between two groups (all P < 0.001) and significantly correlated with the total histological score of hepatic SOS (r = -0.70, 0.68 and 0.79; P < 0.001). △T1% and ESP were positively correlated with OATP1 levels (r = 0.82, 0.85; P < 0.001), whereas T1post had a negative correlation with OATP1 levels (r = -0.83; P < 0.001). CONCLUSION: T1 mapping based on gadoxetic acid-enhanced MRI may be useful for diagnosis of hepatic SOS, and MRI parameters were associated with OATP1 levels.

Janus kinase inhibitors and adverse events of acne in dermatologic indications: a systematic review and network meta-analysis.

Background: The occurrence of acne in patients treated with Janus kinase (JAK) inhibitors for skin diseases is a potential issue, which may reduce treatment adherence.Purpose: To systematically analyzes randomized clinical trials (RCTs) of JAK inhibitors in dermatological indications for the risk of acne as an adverse event.Methods: A meta-analysis of odds ratios (ORs) for acne incidence was conducted. Data were quantitatively synthesized using random-effects meta-analysis. Surface under the cumulative ranking curve (SUCRA) values representing the relative ranking probabilities of treatments were obtained. Analyses were performed using R statistical software version 4.4.0.Results: A total of 11,396 patients were included from 24 studies. The incidence of acne for JAK inhibitors was ranked according to the SUCRA as follows: JAK1 inhibitors > TYK2 inhibitors > combined JAK1 and JAK2 inhibitors > combined JAK1 and TYK2 inhibitors > JAK3 + TEC inhibitors > pan-JAK inhibitors. ORs were higher for longer durations of drug use and larger dosages. Subgroup analyses by disease indication revealed increased ORs for psoriasis (5.52 [95% CI, 1.39-21.88]), vitiligo (4.15 [95% CI, 1.27-13.58]), alopecia areata (3.86 [95% CI, 1.58-9.42]), and atopic dermatitis (2.82 [95% CI, 1.75-4.54]). The use of JAK inhibitors in patients with systemic lupus erythematosus (SLE) may not significantly increase the incidence of acne.Conclusions: There are higher rates of acne following treatment with JAK inhibitors for dermatologic indications, particularly with longer durations and larger dosages. Pan-JAK inhibitors exhibit the lowest incidence of acne.

EBV-associated epithelial cancers cells promote vasculogenic mimicry formation via a secretory cross-talk with the immune microenvironment.

Background: Vasculogenic mimicry (VM) induced by Epstein-Barr virus (EBV) infection plays an important role in resistance to anti-vascular endothelial growth factor (VEGF) therapy in EBV-associated epithelial cancers; however, the interaction between VM and the immune microenvironment has not been systematically investigated. Methods: IHC and multiplex IHC analysis the relationships among tumour-associated macrophage (TAM), VM and EBV infection in EBV-associated epithelial cancer biopsies. In vitro and in vivo evidence using CRISPR-Cas9 system engineered EBV-infected epithelial cancer cells and mouse models support functional role and mechanism for M2c-like macrophages in the VM formation. The prediction of VM in the effectiveness of anti-angiogenic agent was analysed using clinical datasets. Results: EBV-associated epithelial cancer biopsies revealed that infiltration of the TAM surrounding the VM is closely associated with EBV infection. AKT/mTOR/HIF-1α pathway in EBV-infected epithelial cancer cells control the secretion of CCL5 and CSF-1, enabling the recruitment of monocytes and their differentiation into M2c macrophages which promote VM formation by MMP9. Combination of anti-angiogenesis agents and HIF-1α inhibitor caused marked decreases in CD31-positive micro-vessels, VM, and M2c-like macrophages. VM scores can be used as biomarkers to predict the efficacy of anti-angiogenic agent therapy in EBV-associated epithelial cancers. Conclusions: Our findings define a secretory cross-talk between tumour cells and the immune microenvironment in EBV-associated epithelial cancer, revealing an unexpected role of EBV in epithelial cancer cells, controlling VM formation via M2c-like macrophages.

Longitudinal associations between deviant peer affiliation and externalizing behavior in Chinese preadolescence: Differentiating between-person effects from within-person effects.

The present study employed the cross-lagged panel model and the random intercepts cross-lagged panel model to investigate the longitudinal association between deviant peer affiliation and externalizing behavior in Chinese preadolescents. A sample of 1987 students, comprising 56.10% male participants with a mean age of 12.32 years (SD = 0.53), from Guangdong and Shandong provinces, completed the Deviant Peer Affiliation Scale and the Externalizing Behavior Scale in biannual surveys. The surveys were conducted in the autumn semester of 7th grade, the spring semester of 7th grade, and the autumn semester of 8th grade. The cross-lagged panel model illustrated a bidirectional association between adolescents' involvement with deviant peers and externalizing behavior. Conversely, the random intercepts cross-lagged panel model indicated a positive association between deviant peer affiliation and externalizing behavior at the between-person level. At the within-person level, a significant predictive correlation was identified between the association with deviant peers and subsequent externalizing behavior, whereas the reverse pathway was determined to be statistically insignificant. To comprehend the connection between deviant peer association and externalizing behavior in preadolescence, it is essential to differentiate between between-person and within-person effects and utilize a sophisticated research methodology.

Role of gadoxetic acid-enhanced MRI in the differential diagnosis of chemotherapy-induced focal nodular hyperplasia-like lesions and liver metastases in patients with colorectal cancer.

PURPOSE: To describe the gadoxetic acid-enhanced magnetic resonance imaging (MRI) features and follow-up changes of hepatic focal nodular hyperplasia (FNH)-like lesions induced by chemotherapy in patients with colorectal cancer (CRC) and the differential diagnosis of FNH-like lesions and liver metastases. METHODS: We retrospectively analyzed the data of patients with CRC who received chemotherapy and gadoxetic-enhanced MRI at our hospital. Based on imaging features and pathological findings, the patients were classified into two groups: FNH-like lesions and liver metastases. Two abdominal radiologists reviewed and compared the signal intensities of all images in each phase for both groups. The characteristics of the FNH-like lesions in the hepatobiliary phase were evaluated, and changes in size of lesions were monitored. RESULTS: Thirty patients with 82 FNH-like lesions and 30 with 49 liver metastases following chemotherapy were included in the study. All MRI findings were statistically significantly different between the two groups (p < 0.05). In FNH-like lesions, three enhancement patterns were observed in the hepatobiliary phase: hyperintense/isointense (18.3%), heterogeneous hyperintense (8.5%), and ring-like enhancement (73.2%). The median time from completion of chemotherapy to development of FNH-like lesions was 31 months. During 4-87 months of follow-up, 27 patients with 73 lesions showed the following outcomes: 41 lesions (56.16%) showed stability, 21 lesions (28.77%) growth, and 11 lesions (15.07%) reduction or disappearance. CONCLUSION: Gadoxetic acid-enhanced MRI can distinguish between chemotherapy-induced FNH-like lesions and liver metastases in patients with CRC. The FNH-like lesions exhibited three enhancement patterns in the hepatobiliary phase, and the changes varied during follow-up.

Research Progress on the Mechanism, Monitoring, and Prevention of Cardiac Injury Caused by Antineoplastic Drugs-Anthracyclines.

Anthracyclines represent a highly efficacious class of chemotherapeutic agents employed extensively in antitumor therapy. They are universally recognized for their potency in treating diverse malignancies, encompassing breast cancer, gastrointestinal tumors, and lymphomas. Nevertheless, the accumulation of anthracyclines within the body can lead to significant cardiac toxicity, adversely impacting both the survival rates and quality of life for tumor patients. This limitation somewhat restricts their clinical utilization. Determining how to monitor and mitigate their cardiotoxicity at an early stage has become an urgent clinical problem to be solved. Therefore, this paper reviews the mechanism of action, early monitoring, and strategies for the prevention of anthracycline-induced cardiotoxicity for clinical reference.

The key metabolic signatures and biomarkers of polycyclic aromatic hydrocarbon-induced blood glucose elevation in chinese individuals exposed to diesel engine exhaust.

Due to the complexity of environmental exposure factors and the low levels of exposure in the general population, identifying the key environmental factors associated with diabetes and understanding their potential mechanisms present significant challenges. This study aimed to identify key polycyclic aromatic hydrocarbons (PAHs) contributing to increased fasting blood glucose (FBG) concentrations and to explore their potential metabolic mechanisms. We recruited a highly PAH-exposed diesel engine exhaust testing population and healthy controls. Our findings found a positive association between FBG concentrations and PAH metabolites, identifying 1-OHNa, 2-OHPh, and 9-OHPh as major contributors to the rise in FBG concentrations induced by PAH mixtures. Specifically, each 10 % increase in 1-OHNa, 2-OHPh, and 9-OHPh concentrations led to increases in FBG concentrations of 0.201 %, 0.261 %, and 0.268 %, respectively. Targeted metabolomics analysis revealed significant alterations in metabolic pathways among those exposed to high levels of PAHs, including sirtuin signaling, asparagine metabolism, and proline metabolism pathway. Toxic function analysis highlighted differential metabolites involved in various dysglycemia-related conditions, such as cardiac arrhythmia and renal damage. Mediation analysis revealed that 2-aminooctanoic acid mediated the FBG elevation induced by 2-OHPh, while 2-hydroxyphenylacetic acid and hypoxanthine acted as partial suppressors. Notably, 2-aminooctanoic acid was identified as a crucial intermediary metabolic biomarker, mediating significant portions of the associations between the multiple different structures of OH-PAHs and elevated FBG concentrations, accounting for 16.73 %, 10.84 %, 10.00 %, and 11.90 % of these effects for 1-OHPyr, 2-OHFlu, the sum concentrations of 2- and 9-OHPh, and the sum concentrations of total OH-PAHs, respectively. Overall, our study explored the potential metabolic mechanisms underlying the elevated FBG induced by PAHs and identified 2-aminooctanoic acid as a pivotal metabolic biomarker, presenting a potential target for intervention.

Engineering high-brightness and long-lived organic room-temperature phosphorescence via systematic molecular design.

We report a systematic molecular design in BF2bdk-based afterglow emitters with photoluminescence quantum yields up to 46.3% and lifetimes around 1 s. Suitable excited-state types, diverse excited state species, relatively small singlet-triplet energy gaps and strong dipole-dipole interactions are critical in determining the afterglow properties.

Successful replacement for recurrent nasopharyngeal carcinoma with cholecystitis induced by PD-1 antibody: a case report.

The occurrence of immune-related cholecystitis and the subsequent immunotherapy re-challenge has been rarely reported. A patient diagnosed with recurrent nasopharyngeal carcinoma, developed immune-related cholecystitis after the sixth and eighth cycles of camrelizumab respectively. The patient's symptoms and laboratory test results showed improvement after conservative treatment. Then we chose zimberelimab, a fully humanized PD-1 antibody, as a replacement for camrelizumab in maintenance therapy and successfully completed 37 cycles of zimberelimab (240 mg every 2 weeks per cycle). Surprisingly, the patient experienced no immune-related adverse event and remained in complete remission with a progression-free survival of 28.8 months. The use of Zimberelimab as rechallenge immunotherapy may be an optional choice after managing immune-related cholecystitis induced by other PD-1 antibodies.

Immunotherapy is a new and effective way to treat tumors, but it also brings many side effects. One of the side effects is gallbladder inflammation. Less than 1% of patients developed the gallbladder inflammation. It could lead to many kinds of uncomfortable symptoms and interrupt the tumor treatment. It is still unclear whether immunotherapy can be resumed after the gallbladder inflammation is resolved. We shared a patient who experienced gallbladder inflammation after immunotherapy, then we used another drug successfully to resume the immunotherapy. The patient did not develop any side effects, and the result of tumor treatment was very good. We are hoping this case can provide a reference for other similar patients.

Mechanochemical "Cage-on-MOF" Strategy for Enhancing Gas Adsorption and Separation through Aperture Matching.

Post-modification of porous materials with molecular modulators has emerged as a well-established strategy for improving gas adsorption and separation. However, a notable challenge lies in maintaining porosity and the limited applicability of the current method. In this study, we employed the mechanochemical "Cage-on-MOF" strategy, utilizing porous coordination cages (PCCs) with intrinsic pores and apertures as surface modulators to improve the gas adsorption and separation properties of the parent MOFs. We demonstrated the fast and facile preparation of 28 distinct MOF@PCC composites by combining 7 MOFs with 4 PCCs with varying aperture sizes and exposed functional groups through a mechanochemical reaction in 5 mins. Only the combinations of PCCs and MOFs with closely matched aperture sizes exhibited enhanced gas adsorption and separation performance. Specifically, MOF-808@PCC-4 exhibited a significantly increased C2H2 uptake (+64%) and a longer CO2/C2H2 separation retention time (+40%). MIL-101@PCC-4 achieved a substantial C2H2 adsorption capacity of 6.11 mmol/g. This work not only highlights the broad applicability of the mechanochemical "Cage-on-MOF" strategy for the functionalization of a wide range of MOFs but also establishes potential design principles for the development of hybrid porous materials with enhanced gas adsorption and separation capabilities, along with promising applications in catalysis and intracellular delivery.

The Diagnostic Ability of GPT-3.5 and GPT-4.0 in Surgery: Comparative Analysis.

BACKGROUND: ChatGPT (OpenAI) has shown great potential in clinical diagnosis and could become an excellent auxiliary tool in clinical practice. This study investigates and evaluates ChatGPT in diagnostic capabilities by comparing the performance of GPT-3.5 and GPT-4.0 across model iterations. OBJECTIVE: This study aims to evaluate the precise diagnostic ability of GPT-3.5 and GPT-4.0 for colon cancer and its potential as an auxiliary diagnostic tool for surgeons and compare the diagnostic accuracy rates between GTP-3.5 and GPT-4.0. We precisely assess the accuracy of primary and secondary diagnoses and analyze the causes of misdiagnoses in GPT-3.5 and GPT-4.0 according to 7 categories: patient histories, symptoms, physical signs, laboratory examinations, imaging examinations, pathological examinations, and intraoperative findings. METHODS: We retrieved 316 case reports for intestinal cancer from the Chinese Medical Association Publishing House database, of which 286 cases were deemed valid after data cleansing. The cases were translated from Mandarin to English and then input into GPT-3.5 and GPT-4.0 using a simple, direct prompt to elicit primary and secondary diagnoses. We conducted a comparative study to evaluate the diagnostic accuracy of GPT-4.0 and GPT-3.5. Three senior surgeons from the General Surgery Department, specializing in Colorectal Surgery, assessed the diagnostic information at the Chinese PLA (People's Liberation Army) General Hospital. The accuracy of primary and secondary diagnoses was scored based on predefined criteria. Additionally, we analyzed and compared the causes of misdiagnoses in both models according to 7 categories: patient histories, symptoms, physical signs, laboratory examinations, imaging examinations, pathological examinations, and intraoperative findings. RESULTS: Out of 286 cases, GPT-4.0 and GPT-3.5 both demonstrated high diagnostic accuracy for primary diagnoses, but the accuracy rates of GPT-4.0 were significantly higher than GPT-3.5 (mean 0.972, SD 0.137 vs mean 0.855, SD 0.335; t285=5.753; P<.001). For secondary diagnoses, the accuracy rates of GPT-4.0 were also significantly higher than GPT-3.5 (mean 0.908, SD 0.159 vs mean 0.617, SD 0.349; t285=-7.727; P<.001). GPT-3.5 showed limitations in processing patient history, symptom presentation, laboratory tests, and imaging data. While GPT-4.0 improved upon GPT-3.5, it still has limitations in identifying symptoms and laboratory test data. For both primary and secondary diagnoses, there was no significant difference in accuracy related to age, gender, or system group between GPT-4.0 and GPT-3.5. CONCLUSIONS: This study demonstrates that ChatGPT, particularly GPT-4.0, possesses significant diagnostic potential, with GPT-4.0 exhibiting higher accuracy than GPT-3.5. However, GPT-4.0 still has limitations, particularly in recognizing patient symptoms and laboratory data, indicating a need for more research in real-world clinical settings to enhance its diagnostic capabilities.

Draft genome sequence data of Pythium cedri Chen 4, the causal pathogen of deodar cedar root rot.

Pythium species are distributed globally, with certain members playing significant roles as plant and animal pathogens. Pythium cedri Chen 4 has been identified as a pathogenic isolate responsible for causing root rot on Cedrus deodara. Here, a comprehensive genome-wide sequence of P. cedri strain Chen 4 utilizing the Illumina NovaSeq sequencing platform and a Pacific Biosciences Sequel sequencing platform is presented. The genome of P. cedri strain Chen 4 was assembled into 150 contigs containing a combined size of 41.25 Mb, N50 value of 1,717,859 bp and N90 value of 431,829 bp. Genome annotation revealed 14,077 protein-encoding genes and 364 of the 1016 predicted proteins were putative effectors. The present work enriches the genetic resources of P. cedri for studying its evolution and can contribute to a better understanding of P. cedri-host interaction.

Rodent model of metabolic dysfunction-associated fatty liver disease: a systematic review.

Although significant progress has been made in developing preclinical models for metabolic dysfunction-associated steatotic liver disease (MASLD), few have encapsulated the essential biological and clinical outcome elements reflective of the human condition. We conducted a comprehensive literature review of English-language original research articles published from 1990 to 2023, sourced from PubMed, Embase, and Web of Science, aiming to collate studies that provided a comparative analysis of physiological, metabolic, and hepatic histological characteristics between MASLD models and control groups. The establishment of a robust metabolic dysfunction-associated steatotic liver rodent model hinges on various factors, including animal species and strains, sex, induction agents and methodologies, and the duration of induction. Through this review, we aim to guide researchers in selecting suitable induction methods and animal species for constructing preclinical models aligned with their specific research objectives and laboratory conditions. Future studies should strive to develop simple, reliable, and reproducible models, considering the model's sensitivity to factors such as light-dark cycles, housing conditions, and environmental temperature. Additionally, the potential of diverse in vitro models, including 3D models and liver organ technology, warrants further exploration as valuable tools for unraveling the cellular mechanisms underlying fatty liver disease.

Pentagalloylglucose alleviates acetaminophen-induced acute liver injury by modulating inflammation via cGAS-STING pathway.

BACKGROUND: The cGAS-STING pathway is an important component of the innate immune system and plays significant role in acetaminophen-induced liver injury (AILI). Pentagalloylglucose (PGG) is a natural polyphenolic compound with various beneficial effects, including anti-cancer, antioxidant, anti-inflammatory, and liver-protective properties; however, whether it can be used for the treatment of AILI and the specific mechanism remain unclear. MATERIALS AND METHODS: A cell culture model was created to study the effect of PGG on cGAS-STING pathway activation using various techniques including western blotting (WB), real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence (IF), and immunoprecipitation (IP). The effect of PGG was investigated in vivo by establishing a dimethylxanthenone acetic acid (DMXAA)-mediated activation model. An AILI model was used to evaluate the hepatoprotective and therapeutic effects of PGG by detecting liver function indicators, liver histopathology, and cGAS-STING pathway-related indicators in mice with AILI. RESULTS: PGG blocked cGAS-STING pathway activation in bone marrow-derived macrophages (BMDMs), THP-1 cells, and peripheral blood mononuclear cells (PBMCs) in vitro. Furthermore, PGG inhibited the generation of type I interferons (IFN-I) and the secretion of inflammatory factors in DMXAA-induced in vivo experiments. In addition, PGG also reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), improved liver tissue damage and apoptosis, and inhibited the cGAS-STING pathway activation caused by acetaminophen. In terms of the mechanism, PGG disrupted the connection between STING and TBK1. CONCLUSIONS: PGG exerts a protective effect against AILI by blocking the cGAS-STING pathway, offering a promising treatment strategy.

Causal relationship between gut microbiota and diabetic complications: a two-sample Mendelian randomization study.

BACKGROUND: Imbalances in gut microbiota (GM) have been proposed as a potential contributing factor to diabetic complications; however, the causal relationship remains incompletely understood. METHODS: Summary statistics were obtained from genome-wide association studies (GWAS) of 196 gut microbial taxa, including 9 phyla, 16 classes, 20 orders, 32 families, and 119 genera. These data were then analyzed using mediation Mendelian randomization (MR) analyses to explore the potential mediating effect of diabetes complications risk factors on the relationship between gut microbiota and specific diabetic complications such as diabetic kidney disease (DKD), ketoacidosis, and diabetic retinopathy (DR). RESULTS: In our Mendelian analysis, we observed negative associations between Bifidobacterial order and Actinomycete phylum with DKD in type 1 diabetes (T1D) as well as early DKD in T1D. Conversely, these taxa showed positive associations with ketoacidosis in type 2 diabetes (T2D). In reverse Mendelian analysis, we found that DR in both T1D and T2D as well as ketoacidosis in T2D affected the abundance of Eubacterium fissicaten genus and LachnospiraceaeUCG010 family within the gut microbiota. CONCLUSIONS: Our findings provide compelling evidence for causal relationships between specific GM taxa and various diabetes complications. These insights contribute valuable knowledge for developing treatments targeting diabetes-related complications.