BACKGROUND:The absence of effective animal models for sporadic Alzheimer's disease (AD) remains a pivotal barrier to therapy development. Because methanol metabolism produces endogenous formaldehyde, a neurotoxic agent linked to cognitive decline, this study investigated whether chronic, low-dose methanol exposure could recapitulate AD-like pathology and cognitive deficits in rhesus monkey, thereby establishing a nonhuman primate animal model driven by this environmental-metabolic insult. METHODS:Adult rhesus monkeys received low-concentration methanol for 9 months. Behavioral tests for cognition, locomotion, sleep, and vision were conducted. Postmortem analyses involved histopathological examination, immunohistochemistry, immunofluorescence, and Western blot to evaluate neuronal integrity, microglial activation, and the expression of key proteins associated with AD (amyloid-β [Aβ], phosphorylated tau, TAR DNA-binding protein 43 [TDP-43]) and cellular stress (synaptic markers, mitochondrial fission, autophagy, and apoptosis-related proteins). RESULTS:Chronic methanol exposure led to progressive cognitive and memory impairment without significant motor or visual deficits. Neuropathology revealed brain atrophy, neuronal loss, synaptic damage, microglial activation, and mitochondrial structural disorganization. Critically, the exposed animals exhibited hallmark AD-like molecular alterations, including increased Aβ deposition, tau hyperphosphorylation, and TDP-43 dysregulation. Furthermore, neurotoxicity was associated with elevated urinary formaldehyde, enhanced mitochondrial fission, increased autophagy, and elevated apoptosis. CONCLUSION:Chronic low-dose methanol exposure in rhesus monkeys recapitulates progressive cognitive deficits and AD-like neuropathological features. This model, driven by endogenous formaldehyde toxicity, effectively mimics key aspects of sporadic AD. Our findings shed light on the neurotoxic mechanisms of methanol and propose a reproducible and translationally relevant nonhuman primate model for studying AD pathogenesis and evaluating potential therapeutics.

Abstract Background Mutations in and functional inactivation of the Gorab gene cause gerodermia osteodysplastica (GO), a disease featuring wrinkled skin and osteoporosis, but the underlying mechanisms of skin aging remain incompletely understood. Methods By crossing the Gorab conditional knockout mouse model (Gorabflox/flox) with Col1a2‐cre/ERT tool mice, pregnant dams at embryonic day 16.5 (E16.5d) and 6‐week‐old offspring were induced with tamoxifen dissolved in a corn oil solution (3 mg/150 μL per mouse) to develop a dermal Gorab knockout mouse model. Then, aging phenotypes were analyzed, and mechanistic studies were performed. Results Conditional knockout of Gorab at two different time points (embryonic and postnatal) resulted in elevated levels of aging‐related proteins (P53, P21, P16) and a reduction in levels of extracellular matrix (ECM) components, including collagen, fibrillin‐1, vimentin, fibronectin, laminin, and versican in the ventral and dorsal skin of adult mice. Postnatal knockout had a relatively more pronounced effect on skin aging‐related changes. Mechanistically, Gorab knockout impaired the ubiquitination and promoted the accumulation of P53 protein, likely through regulating the E3 ligase RCHY1. This was accompanied by increased HDAC2 levels, reduced histone acetylation, and consequent downregulation of skin ECM proteins, outlining a potential pathway for accelerated skin aging. Conclusions This study elucidates that Gorab mutations in the dermis promote skin aging by causing P53 accumulation and disrupting ECM expression via epigenetic regulation. These findings clarify the biological role of Gorab in skin aging and provide a theoretical basis for related mechanistic research and potential preventive strategies.

Obesity is a global health crisis and a critical risk factor for male infertility, impairing testicular structure and function through hormonal imbalance and oxidative stress. Current therapeutic strategies are often unsatisfactory due to limited efficacy or adverse effects. This study investigated the protective effects and potential molecular mechanisms of Ganoderma lucidum (GL) polysaccharides and triterpenoids against testicular injury in high-fat diet-induced obese male rats. After 12-week GL intervention, reproductive function in obese male rats showed improvement: GL increased litter size, improved sperm motility, reduced sperm DNA fragmentation, and restored serum testosterone, inhibin B, and leptin levels. It also alleviated testicular histopathological damage, downregulated PPT1, and maintained vimentin expression. Notably, GL facilitated delayed fertility recovery and showed a trend toward improved cumulative reproductive success, although fixed-time pregnancy rates were not significantly changed. Mechanistically, GL is associated with enhanced Nrf2 pathway activity, increased SOD1, HO-1, NQO1, and GPX4 levels, and decreased MDA and ROS accumulation, thereby attenuating oxidative stress. It preserved mitochondrial integrity, suppressed germ cell apoptosis (downregulating Bax and caspase-3, upregulating Bcl-2), and promoted cell proliferation. These findings indicate that GL polysaccharides and triterpenoids effectively ameliorate obesity-induced testicular dysfunction, and these beneficial effects are associated with Nrf2-mediated antioxidant responses, mitochondrial homeostasis, apoptosis regulation, and hormonal balance. GL may serve as a promising candidate for obesity-related male infertility.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can cause skeletal muscle, myocardial, and gastrointestinal lesions. However, it is currently unclear whether these lesions are caused directly by viral infection or indirectly after infection and whether there are differences between different animal models. Here, we first compared the pathological changes of skeletal muscle, myocardium, and gastrointestinal smooth muscle of different COVID-19 animal models (rhesus monkey, hamster, ferret, hACE2 transgenic mice, hACE2-K18 transgenic mice, mink, and cat), and analyzed the possible mechanism of pathological changes. Within 5-7 days of being infected with SARS-CoV-2, the three types of muscles in these models were all damaged and inflammatory response to varying degrees, and infiltrating inflammatory cells and factors mainly included CD4T, CD8T cells, macrophages, a small amount of B cells, IL-6, TNF-α, and IFN-γ, and so on. Among them, the pathological changes of the three muscle tissues in the rhesus monkey model were the most significant and closely related to clinical manifestations. It was determined that SARS-CoV-2 can infect these three types of muscles through in situ hybridization and electron microscopy analysis. Therefore, the performance of muscle lesions in each model was not completely consistent and may be related to multiple factors after SARS-CoV-2 infection, including animal species, direct virus invasion, systemic inflammation after infection, and immune status of the body. This study provides a foundation for selecting models to study muscle lesion mechanisms and treatment strategies, highlighting the need for clinical attention to muscle tissue involvement in COVID-19 patients.

Alzheimer’s disease (AD) is a progressive neurodegenerative condition affecting around 50 million people worldwide. Bone marrow-derived mesenchymal stem cells (BMMSCs) have emerged as a promising source for cellular therapy due to their ability to differentiate into multiple cell types and their paracrine effects. However, the direct injection of BMMSCs can lead to potential unpredictable impairments, prompting a renewed interest in their paracrine effects for AD treatment. The specific mechanism and central role of cytokines in this process have not been fully elucidated. Mouse BMMSCs were isolated, validated, and then transplanted intracerebrally into APP/PS1 female mice. The behavioral tests, including open-field test, novel object recognition test, and Morris water maze were performed, followed by β-amyloidosis plaque and neuron apoptosis analyses. Then the tissue RNA sequencing and mBMMSC cytokine analysis were performed. A cytokine antibody array for BMMSCs and the brain slice models were performed with AD model tissues were used to elucidate the molecular mechanisms. Finally, APP/PS1 mice were administrated with cytokine mixture for cognitive recovery. Our results demonstrated that BMMSCs significantly improved cognitive function, reduced beta-amyloid plaque deposition, and decreased apoptotic neurons through the activation of the AKT signaling pathway. Using a cytokine antibody array, we identified three highly expressed AKT pathway regulated neuroprotective factors in BMMSCs: IGF1, VEGF, and Periostin2. These cytokines were found to upregulate inhibitors of apoptosis family proteins (IAPs) and suppress Caspase-3 activity in brain slices induced with beta amyloidosis (Aβ), okadaic acid (OA), and lipopolysaccharide (LPS). When injection of this cytokine mixture to APP/PS1 mice also resulted in a mitigation of cognitive impairment. These findings suggest that the secretory factors IGF1, VEGF, and Periostin2 derived from BMMSCs play a crucial role in neuroprotection by modulating the AKT/IAPs pathway to restore neuronal function. These cytokine sets could be a potential therapeutic strategy for AD and lay the groundwork for promising clinical applications.

PM2.5, recognized as a potential pathogenic factor for nervous system diseases, remains an area with many unknowns, particularly regarding its effects on human health. After five-month real-ambient PM2.5 exposure, we observed no significant pathological damage to the lung, liver, spleen, or kidney tissues. However, PM2.5 exposure led to neuronal degeneration in the hippocampal CA1 region of Brown Norway (BN) rats. The level of IL-6, IL-13, IL-1β, IL-12, IL-4, GRO/KC, MIP-1α, CM-CSF significantly increased in lung lavage fluid (P < 0.05 for all). Notably, we detected a slight impairment in spatial learning ability, as evidenced by the Barnes maze training outcomes. There were no significant changes in the bacterial community in lung lavage fluid (P = 0.621), but the bacterial community in the gut significantly changed (P < 0.001), with more species identified (P < 0.05). The metabolomic analysis revealed 147 and 149 significantly changed metabolites in the pulmonary system and serum, respectively (P < 0.05). PM2.5 exposure caused a decrease in Nervonic acid (NA) in both the lung and serum, which likely contributed to spatial learning impairment (P < 0.01). The correlation between lung metabolites, gut bacterial species, and serum metabolites indicated that PM2.5 exposure likely impaired spatial learning through the lung-gut-brain axis pathway. Lung and serum metabolic disorders and intestinal microbial imbalance occurred in BN rats post-five-month real-ambient PM2.5 exposure. There were two potential ways that PM2.5 exposure caused the decline of spatial learning ability in wild-type BN rats: (1) PM2.5 exposure led to a significant decrease of neuroprotective Nervonic acid in lung and serum metabolites. (2) PM2.5 exposure likely led to reduced spatial learning ability through the lung-gut-brain axis.

>Dear Editor,The case fatality rate of early SARS-CoV-2 infection is 3%(Ghebreyesus, 2020), and the severe case rate is 24.3%(Sun et al., 2020). From the prototypic SARS-CoV-2 strain to the emergence of Alpha, Beta, and Delta variants, which ultimately led to the outbreak of Omicron variants, these strains have undergone a series of evolutionary changes. Starting from BA.1, BA.2, BA.4, and BA.5 lineage to XBB lineage before branching out into the current dominant JN.1 lineage,

BACKGROUND:Previous studies showed airborne bacteria affect pneumonia incidence, but specific impacts of bacterial communities on Klebsiella pneumoniae infection were unknown. METHODS:Five different ratios of bacterial community structures were randomly generated. Mice were divided into control, artificial bacterial community exposure, and corresponding Klebsiella pneumoniae challenge groups. Changes in body weight, blood parameters, pulmonary pathology, inflammatory factors, metabolomics, and fecal microbiota were analyzed. RESULTS:Different bacterial community exposures had varying degrees of influence on body weight, complete blood count, inflammatory factors, alveolar lavage fluid and plasma metabolome, as well as intestinal microbiota at baseline and after infection. Metabolomic analysis showed that microbial exposure affected both bronchoalveolar lavage fluid and plasma metabolomes, suggesting systemic effects of microbial exposure on the organism. Differences in the structure of artificial microbiota had inconsistent effects on both the baseline state and the post-infection state, hinting at crosstalk between microbial exposure and Klebsiella pneumoniae infection. KEGG pathway analysis unveiled possible molecular mechanisms underlying the overall impact of microbial exposure on the lungs and the body as a whole. In the intestinal microbiota, differences were found in composition at the phylum and genus levels. Spearman correlation analysis established potential correlations between intestinal microbiota and differential metabolites, suggesting a potential link within the lung-gut axis. CONCLUSION:This study demonstrated the significant and systemic impact of air microbiota structure differences on health. Future research should explore the underlying mechanisms to enhance our understanding of the air-environment-health relationship and identify interventions for improving public health strategies.

BACKGROUND:Air harbors diverse microorganisms. However, the influence of airborne microbial communities on the recovery phase of pneumonia patients remains inadequately explored. METHOD:We randomly generated five distinct bacterial communities with varying compositions from a pool of 16 bacteria. Following infection with Klebsiella pneumoniae, convalescent BALB/c mice were exposed to either saline (control group, G1) or one of the five artificially constructed microbial communities (H1-H5 groups) during their recovery period. Body weight, lung tissue pathology, inflammatory cytokines, metabolomics, and fecal flora were analyzed. RESULTS:Exposure to varied microbial communities induced inflammatory cell infiltration around pulmonary blood vessels and bronchi. Overall, after microbiota exposure, peripheral neutrophil percentages showed a significant increase (p < 0.05). Concurrently, IL-1β was increased in bronchoalveolar lavage fluid (BALF), while IL-6 and IFN-γ were decreased in plasma (p < 0.05). Additionally, varying levels of inflammatory factors and hematological parameters were observed among different exposure groups. Metabolomic analysis revealed joint alterations in nucleotide metabolism and Nicotinate and nicotinamide metabolism in BALF, as well as broader metabolic pathway changes in plasma. Moreover, there were significant differences in metabolic pathways between the different exposure groups. Significant differences in the composition and richness of the gut microbiota were observed among the experimental groups. Pearson correlation analysis established a potential correlation between lung metabolites, gut microbiota, and plasma metabolites, suggesting a potential link within the lung-gut axis. CONCLUSIONS:Our findings demonstrate that varied airborne bacterial communities exposure exert differential effects on convalescent pneumonia in mice. This influence may be mediated, at least in part, by modulating disease progression through the lung-gut axis.

In northern China, haze events frequently occur during winter, and PM2.5 is recognized as the most significant particulate matter in haze, posing a major threat to human health. Therefore, we employed a PM2.5 inhalation exposure system to investigate the protective effects of Platycodon grandiflorum inulin-type fructan (PGPI-1-a) on low-concentration PM2.5-induced lung microenvironment changes. Our findings revealed that long-term (4-month) PM2.5 exposure did not cause apparent pathological alterations in rat lungs but induced lung inflammation, which was alleviated by PGPI-1-a intervention. Multi-omics analysis demonstrated that PGPI-1-a restored abnormally expressed lung proteins, improved lung microbiota disorders, and regulated serum metabolite imbalances related to lipid and amino acid metabolism, ameliorating low-concentration PM2.5-induced lung microenvironment changes. These results suggest that Platycodon grandiflorum inulin-type fructan could serve as a potential dietary supplement for mitigating PM2.5-induced lung injury.

Fine particulate matter 2.5 (PM2.5) is a prevalent atmospheric pollutant that is closely associated with asthma. Elderly patients have a high incidence of asthma with a long course of illness. Our previous studies revealed that exposure to PM2.5 diminishes lung function and exacerbates lung damage in elderly rats. In the present study, we investigated whether PM2.5 exposure influences susceptibility to allergic asthma in elderly rats. Brown-Norway elderly rats were treated with ovalbumin (OVA) for different durations before and after PM2.5 exposure. The results from pulmonary function tests and histopathology indicated that early exposure to allergens prior to PM2.5 exposure increased susceptibility to airway hyperresponsiveness and led to severe lung injury in elderly asthmatic rats. Cytokine microarray analysis demonstrated that the majority of cytokines and chemokines were upregulated in OVA-treated rats before and after PM2.5 exposure. Cytological examination showed no change in eosinophil (EOS) counts, yet the amounts of neutrophils (NEU), white blood cells (WBC), lymphocytes (LYM), and monocytes (MON) in the lung lavage fluid of OVA-treated rats were significantly higher than those in control rats before and after PM2.5 exposure, suggesting that PM2.5 affects noneosinophilic asthma in elderly rats. ELISA results from the plasma and lung lavage fluid revealed that the levels of IgG1, IgE, IgG2a and IgG2b were significantly elevated in OVA-treated rats, whereas the level of IgG2b in the lung lavage fluid was significantly lower in rats treated with OVA prior to PM2.5 exposure compared to those treated afterward. A non-targeted metabolomic analysis of plasma identified 202 metabolites, among which 31 metabolites were differentially abundant. Ten metabolites and 11 metabolic pathways were uniquely detected in OVA-treated rats before PM2.5 exposure. Specifically, there were positive or negative correlations between the levels of Th2-associated cytokines (IL-4, IL-5, and IL-13) and six metabolites in the OVA-treated group before PM2.5 exposure, whereas the levels of IL-4 and IL-5 were negatively correlated with five metabolites in the OVA-treated group after PM2.5 exposure. Our findings suggest that PM2.5 exposure could influence the susceptibility of allergic asthma in response to allergens in elderly rats, potentially through changes in plasma metabolites.

BACKGROUND:New variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to drive global epidemics and pose significant health risks. The pathogenicity of these variants evolves under immune pressure and host factors. Understanding these changes is crucial for epidemic control and variant research. METHODS:Human angiotensin-converting enzyme 2(hACE2) transgenic mice were intranasally challenged with the original strain WH-09 and the variants Delta, Beta, and Omicron BA.1, while BALB/c mice were challenged with Omicron subvariants BA.5, BF.7, and XBB.1. To compare the pathogenicity differences among variants, we conducted a comprehensive analysis that included clinical symptom observation, measurement of viral loads in the trachea and lungs, evaluation of pulmonary pathology, analysis of immune cell infiltration, and quantification of cytokine levels. RESULTS:In hACE2 mice, the Beta variant caused significant weight loss, severe lung inflammation, increased inflammatory and chemotactic factor secretion, greater macrophage and neutrophil infiltration in the lungs, and higher viral loads with prolonged shedding duration. In contrast, BA.1 showed a significant reduction in pathogenicity. The BA.5, BF.7, and XBB.1 variants were less pathogenic than the WH-09, Beta, and Delta variants when infected in BALB/c mice. This was evidenced by reduced weight loss, diminished pulmonary pathology, decreased secretion of inflammatory factors and chemokines, reduced macrophage and neutrophil infiltration, as well as lower viral loads in both the trachea and lungs. CONCLUSION:In hACE2 mice, the Omicron variant demonstrated the lowest pathogenicity, while the Beta variant exhibited the highest. Pathogenicity of the Delta variant was comparable to the original WH-09 strain. Among BALB/c mice, Omicron subvariants BA.5, BF.7, and XBB.1 showed no statistically significant differences in virulence.

Colorectal cancer is the third most common malignant tumor globally. The current clinical therapeutic outcome is often jeopardized by the complex pathological process that is highly heterogenous among individual patients. It becomes increasingly critical for successful treatments to have diverse valid therapeutic options in clinic, which urgently demands efficient preclinical animal model to develop new drug and screen effective and safe clinical interventions. Patient-derived xenograft (PDX) mouse models, created by implanting fresh tumor tissue into immunodeficient or humanized mice, serve as a crucial resource in translational cancer research. These models closely replicate the tissue, cellular, and genetic characteristics of the original tumors, supporting their use in precision medicine, drug discovery, biomarker research, and studies of drug resistance. However, repeated transplantation can introduce genomic instability, molecular shifts, and phenotype variability. This article explores the development, advantages, limitations, and future directions of PDX models in preclinical cancer research.

The expression levels of macrophage-associated cytokines are significantly greater in COVID-19 patients than in healthy individuals. Exploring strategies to modulate pathological cytokine storms can effectively prevent the development of severe coronavirus infection-induced pneumonia. Treatment with interleukin-37 (IL-37), an anti-inflammatory factor, has unique anti-inflammatory and antiviral effects on infections caused by various pathogens. In this study, we investigated the effect of IL-37 treatment on the SARS-CoV-2 Omicron-infection induced inflammatory response and its molecular mechanism. Our results demonstrated that IL-37 treatment effectively alleviated symptoms, reduced viral loads, suppressed the production of proinflammatory cytokines and chemokines both systemically (in serum) and locally (in the lungs), and attenuated lung lesions and inflammatory cell infiltration in Omicron-infected mice. The suppressed proinflammatory factors were macrophage-related, particularly CCL3 and CCL4, which were significantly inhibited. Furthermore, treatment with IL-37 significantly reduced the proportion of M1-type macrophages in lungs of Omicron-infected mice. In addition, we found that IL-37 targeted M1 macrophages through modulation of the NF-κB signaling pathway to suppress the production of proinflammtory factors during Omicron infection. This study elucidated the anti-inflammatory effect of IL-37 treatment on the Omicron-induced inflammatory response while identifying its specific target site, thereby providing fundamental insights for exploring potential clinical therapeutic interventions.

The environmental impact of harmful particles from tire and brake systems is a growing concern. This study investigated the health impacts of PM2.5 emissions from brake pad wear on adult C57BL/6 mice. The mice were exposed to brake pad particles via intratracheal infusion, and various health parameters were assessed. The results showed that brake pad particle exposure significantly reduced lung function parameters such as tidal volume, peak expiratory time ratio, and peak inspiratory flow rate, while increasing the apnea index and airway stenosis index. Histological analysis revealed particle deposition, inflammatory damage, and potential fibrosis in the lungs. Additionally, inflammatory markers and fibrosis indicators were elevated in the lung tissue. Metabolomic analysis indicated changes in metabolites related to purine metabolism, protein digestion, nucleic acid metabolism, and pathways involving Caffeine, Xanthine, Inosine, and others. Gut microbiota analysis showed increased abundance of Odoribacter and Tuzzerella, and decreased abundance of Desulfovibrio and Butyricimonas. Correlation analysis further suggested a significant link between the abundance of Odoribacter and plasma metabolic changes. Overall, this study underscores the health risks associated with brake dust pollution, particularly its adverse effects on lung function and induction of lung damage and fibrosis.

AIMS:Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the oral cavity, with chemoresistance is the greatest challenge in chemotherapeutic treatment. Stanniocalcin 1 (STC1) is correlated with tumor malignancy and chemoresistance in various cancers, but its role in OSCC paclitaxel (PTX) resistance remains elusive. This study aimed to clarify STC1's impact on OSCC PTX resistance and elucidate its underlying mechanism. MATERIALS AND METHODS:The PTX-resistant OSCC cell line CAL-27/PTX was established by stepwise exposure to increasing PTX concentrations. Transcriptomic sequencing, CCK-8 assays, western blotting, RT-qPCR, lentiviral-mediated silencing or overexpression, reactive oxygen species (ROS) detection, and ELISA were used to assess STC1 expression and function. In vivo validation was conducted using both cell line-derived (CDX) and patient-derived xenograft (PDX) models. KEY FINDINGS:The expression of STC1 was significantly increased in CAL-27/PTX cells and linked to cancer stem cell-like characteristics and epithelial-mesenchymal transition. Knockdown of STC1 expression suppresses tumor development. Mechanistically, STC1 activated the JAK/STAT signaling pathway, which mediated the upregulation of antioxidant genes (GPX4, FTH1, and SLC7A11) to attenuate PTX-induced oxidative stress. Additionally, STC1 promoted intercellular transfer of PTX resistance via a paracrine mechanism. In vivo, high STC1 expression mediated PTX resistance in both CDX and PDX tumor models. SIGNIFICANCE:This study identifies the STC1-STAT3-SLC7A11 axis as a key regulator of resistance to oxidative stress in OSCC, highlighting STC1 as a promising therapeutic target to overcome chemoresistance and improve outcomes in PTX-based therapies.

Oral squamous cell carcinoma (OSCC) constitutes 90% of oral tumors. Advanced cases severely impair patients' life quality of life due to anatomical location and limited therapies. Conventional treatments often induce drug resistance or recurrence. Patient-derived xenograft (PDX) models are widely used to simulate tumor progression and drug responses, serving as translational tools for precision medicine. This study aimed to establish drug-resistant OSCC PDX models. Human OSCC tissues were transplanted into immunodeficient mice and passaged (P1-P2). At P2 (tumor volume: 40-80 mm3), mice received cisplatin (1 mg/kg, three times/week) with cetuximab (1 mg/kg, weekly), GSK690693 (10 mg/kg, five times/week), or rapamycin (4 mg/kg, five times/week). PDX tissues from groups with less-therapeutic response (manifested as larger tumor volumes) were serially passaged to assess treatment efficacy. Tumor tissues with diminished drug sensitivity underwent histopathological analysis and identified stability of their tumor characteristics using hematoxylin-eosin (HE) and immunohistochemical staining after one additional passage and retreatment. Results demonstrated that successive passaging accelerates tumor growth. First-generation treatments showed universal sensitivity. At P2, cisplatin-cetuximab and rapamycin groups remained sensitive, whereas GSK690693 efficacy declined. Continued passaging of GSK690693-treated tumors confirmed resistance, as evidenced by exhibiting enhanced malignant characteristics at histological level. The GSK690693-resistant model was established first, whereas resistant models of other treatment groups were established according to similar protocols. These findings suggest that sequential passaging and drug exposure in PDX models recapitulated clinical tumor evolution, enabling the development of drug-resistant OSCC models. This study can offer methodological insights for precision therapy of OSCC.

Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes. Herein, we retrospectively analyzed pancreatic lesions in autopsy tissues from 67 SARS-CoV-2 infected non-human primates (NHPs) models and 121 vaccinated and infected NHPs from 2020 to 2023 and COVID-19 patients. Multi-label immunofluorescence revealed direct infection of both exocrine and endocrine pancreatic cells by the virus in NHPs and humans. Minor and limited phenotypic and histopathological changes were observed in adult models. Systemic proteomics and metabolomics results indicated metabolic disorders, mainly enriched in insulin resistance pathways, in infected adult NHPs, along with elevated fasting C-peptide and C-peptide/glucose ratio levels. Furthermore, in elder COVID-19 NHPs, SARS-CoV-2 infection causes loss of beta (β) cells and lower expressed-insulin in situ characterized by islet amyloidosis and necrosis, activation of α-SMA and aggravated fibrosis consisting of lower collagen in serum, an increase of pancreatic inflammation and stress markers, ICAM-1 and G3BP1, along with more severe glycometabolic dysfunction. In contrast, vaccination maintained glucose homeostasis by activating insulin receptor α and insulin receptor β. Overall, the cumulative risk of diabetes post-COVID-19 is closely tied to age, suggesting more attention should be paid to blood sugar management in elderly COVID-19 patients.