ObjectiveTo construct a novel KPC mouse model of type 2 diabetes mellitus （T2DM） comorbid with spontaneous pancreatic cancer based on the gene editing-metabolic intervention dual-driven strategy， and to compare it with traditional models. MethodsA total of 14 male KPC mice were randomly divided into novel model group （T2DM-KPC group with 7 mice） and control group （KPC group with 7 mice）， and 14 male BALB/c-nu nude mice were randomly divided into traditional model group （T2DM-pancreatic cancer group with 7 mice） and control group （pancreatic cancer group with 7 mice）. The mice in the KPC group and the pancreatic cancer group were fed with normal diet， and those in the T2DM-KPC group and the T2DM-pancreatic cancer group were fed with a high-fat diet. After 4 weeks， the mice in the T2DM-KPC group and the T2DM-pancreatic cancer group were given intraperitoneal injection of streptozotocin. Subsequently， the mice in the KPC group and the T2DM-KPC group developed primary pancreatic tumor spontaneously over time， while those in the T2DM-pancreatic cancer group and the pancreatic cancer group were inoculated with tumor cells to form subcutaneous tumor xenograft at 2 weeks after stabilization of blood glucose. The 4 groups were observed in terms of tumor formation rate， tumor formation time， body weight， and the change in blood glucose； RNA sequencing was performed for tumors from the KPC group and the T2DM-KPC group， and then molecular subtyping was performed； HE staining， Masson staining， and immunohistochemical staining were used to assess the histopathological features and tumor microenvironment of pancreatic tumor from the T2DM-KPC group， which were compared with those of the T2DM-pancreatic cancer group. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups； the Fisher’s exact test was used for comparison of categorical data between multiple groups. ResultsThe T2DM-KPC group had a tumor formation rate of 85.71% and a tumor formation time of 104.40±2.87 days， while the T2DM-pancreatic cancer group had a tumor formation rate of 71.43% and a tumor formation time of 95.20±9.47 days， and there were no significant differences between the two groups in tumor formation rate， tumor formation time， body weight， and blood glucose （all P>0.05）. Molecular subtyping showed that the model in the KPC group highly resembled the pancreatic progenitor subtype of human pancreatic ductal adenocarcinoma （PDAC）， and the model in the T2DM-KPC group highly resembled the immunogenic subtype of PDAC. HE staining showed that tumor cells in the T2DM-KPC group were arranged into glandular tubular structures of varying shapes， exhibiting significant cellular atypia， and this model faithfully recapitulated the pathological features of primary pancreatic cancer and showed greater invasiveness than the KPC group. Immunohistochemical staining and Masson staining showed that compared with the T2DM-pancreatic cancer group， the T2DM-KPC group had significantly higher degrees of tumor proliferation （assessed by Ki-67 expression） and fibrosis （assessed by α-SMA and Masson） （all P<0.05）， suggesting that the mouse model in the T2DM-KPC group could better recapitulate the features of hyperproliferation and pronounced desmoplasia in human pancreatic cancer. ConclusionA novel KPC mouse model of T2DM comorbid with spontaneous pancreatic cancer is successfully constructed in this study. This model can accurately mimic the histopathological architecture and stromal microenvironment of T2DM comorbid with pancreatic cancer， realize the longitudinal simulation of the progression of pancreatic tissue from intraepithelial neoplasia to invasive carcinoma and metastasis in the presence of T2DM， and support the translational research on immunotherapy， thereby providing a novel experimental carrier for in vivo studies on spontaneous pancreatic cancer in T2DM.

Objective To investigate the prevalence and influencing factors of work-related musculoskeletal disorders (WMSDs) in neck, shoulders and lower back among power grid workers. Methods A total of 371 workers from a power grid enterprise in Guangdong Province were selected as the research subjects using the convenience sampling method. A cross-sectional survey of WMSDs in the neck, shoulders and waist of the workers was conducted using the modified Musculoskeletal Disorders Questionnaire. Results The overall prevalence of WMSDs among the power grid workers was 62.8%, with prevalence of 37.2%, 33.7% and 32.1% for WMSDs in neck, shoulders and lower back, respectively. Binary logistic regression analysis showed that power grid workers who did not maintain a good sitting posture or were unable to maintain good sitting posture over prolonged periods had a higher risk of neck WMSDs than those who maintained a good sitting posture (both P<0.01). A higher frequency of head-down posture during work was associated with an increased risk of neck WMSDs (both P<0.05). Female workers had a higher risk of shoulder WMSDs than male workers (P<0.05). A higher frequency of early awakening with inability to fall back asleep, as well as a higher frequency of head-down posture during work, were both associated with an increased risk of shoulder WMSDs (all P<0.05). Workers with a sedentary habit had a higher risk of shoulder WMSDs than those without (P<0.01). Workers with insufficient rest time had a higher risk of shoulder WMSDs than those with sufficient rest time (P<0.01). Both maintenance workers and managers had a higher risk of lower back WMSDs than workers in other occupational categories (all P<0.05). Workers who experienced nocturnal awakening with difficulty falling back asleep at frequency of several times per year, ≥1 time /month, ≥1 time /week, had higher risk of lower back WMSDs than those who never experienced such problem (all P<0.05). Workers with a sedentary habit and those uncertain about having a sedentary habit both had a higher risk of lower back WMSDs than those without (both P<0.05). Greater forward neck flexion during work was associated with an increased risk of lower back WMSDs (both P<0.05). Workers who occasionally tilted their necks to the side while working had a higher risk of lower back WMSDs than those who did not (P<0.05). Conclusion WMSDs are highly prevalent among power grid workers, particularly affecting the neck, shoulder, and waist. Influencing factors include individual characteristics, behavioral habits, work organization, work posture, and workload. Maintaining proper posture and adequate rest may reduce the risk of WMSDs.

Renal fibrosis is the common pathological endpoint of many forms of chronic kidney disease (CKD), yet the mechanisms determining effective repair versus persistent fibrotic remodeling remain incompletely understood. Peritubular capillaries (PTCs) are not merely passive targets of fibrotic injury, but form a dynamic vascular microenvironment linking regional perfusion, oxygen delivery, tubular metabolism, endothelial barrier integrity, pericyte support, immune-cell trafficking, and extracellular matrix (ECM) remodeling. We propose that PTC abnormalities should not be interpreted simply as reduced capillary density, but as a multidimensional disturbance of microvascular structure and function. Structural vascular preservation does not necessarily indicate effective microcirculation: anatomically detectable capillaries may still exhibit impaired perfusion, barrier dysfunction, abnormal endothelial-pericyte interactions, disturbed oxygen metabolism, or reduced network connectivity. Conversely, increased angiogenesis does not necessarily signify successful vascular repair if vessels remain immature, poorly perfused, or inadequately integrated into the existing network. To organize these abnormalities, we conceptualize PTC remodeling into four predominant but nonexclusive states: endothelial barrier disruption with inflammatory adhesion; endothelial-pericyte uncoupling with no-reflow; dysregulated angiogenesis with network simplification; and capillary rarefaction with fibrotic matrix locking. These states are not sequential stages of CKD. They may coexist within the same kidney, overlap within the same anatomical region, and vary with disease etiology, injury phase, vascular compartment, and treatment exposure. We further propose six dimensions for evaluating PTC status—structural presence, functional perfusion, barrier integrity, pericyte coupling, oxygen metabolism, and network connectivity—so that vascular quantity, function, and reparative capacity are assessed separately rather than inferred from a single endothelial marker or capillary-density measurement. Mechanistically, these states converge on a bidirectional microvascular-fibrotic feedback loop. Barrier disruption facilitates leukocyte recruitment and alters vascular paracrine signaling. Endothelial-pericyte uncoupling compromises capillary stability, whereas abnormal pericyte contraction may increase local vascular resistance and contribute to no-reflow before overt capillary loss. Dysregulated angiogenesis may generate vessels that fail to mature or connect to an effective perfusion network. Progressive capillary rarefaction compromises oxygen delivery, while sustained tubular transport demand and mitochondrial dysfunction may aggravate regional oxygen supply-demand mismatch. Injured tubules, immune cells, endothelial cells, pericytes, and fibroblasts communicate through soluble mediators, extracellular vesicles, direct cell contact, and cell-matrix signaling. Importantly, fibrosis is not merely a downstream consequence of microvascular injury. Altered ECM may increase diffusion distance, modify mechanotransduction, impair endothelial survival and migration, and restrict capillary reopening and regeneration. We use the term matrix locking to describe this sustained constraint on vascular repair, while emphasizing that current evidence does not establish irreversible disease in humans. This framework also has therapeutic implications. PTC-directed treatment should not be reduced to increasing vessel number or uniformly promoting angiogenesis. Instead, intervention should be matched to the dominant and potentially reversible abnormality: preserving endothelial barrier function; restoring endothelial-pericyte stability and reducing pathological microvascular resistance; normalizing angiogenesis so that vascular growth is accompanied by maturation, barrier competence, network integration, and effective perfusion; and, in advanced rarefaction, relieving matrix-related constraints while supporting vascular regeneration. The context- and time-dependent effects of signaling through VEGF, Tie2, PDGF-B/PDGFRβ, eNOS/NO, and related pathways indicate that the same molecular signal may exert different effects depending on disease context and timing. Therapeutic efficacy should therefore be evaluated by restoration of effective microcirculation and tissue function rather than by isolated molecular changes or capillary counts alone. Despite increasing mechanistic evidence, the translational basis for this framework remains limited. Most causal and interventional data derive from animal or cell models, whereas human evidence is largely limited to pathological observations, patient-sample associations, and prognostic studies. Currently available circulating and urinary candidate biomarkers generally lack sufficient specificity for PTC injury or state assignment, and no standardized quantitative thresholds have been externally validated. The four-state model should therefore be regarded as a hypothesis-generating analytical framework rather than a clinicopathological classification system. Future studies should integrate spatially resolved tissue phenotyping, blood and urine biomarkers, and dynamic microcirculatory assessment in longitudinal cohorts. They should test reproducibility, assess prognostic value beyond conventional pathology, estimated glomerular filtration rate, and proteinuria, and determine whether changes in PTC status precede or mediate therapeutic benefit. Linking reproducible microvascular phenotypes to defined mechanisms, treatment response, and long-term renal outcomes will be essential to determine whether state-directed assessment and restoration of the PTC microenvironment can ultimately inform patient stratification and therapeutic decision-making.

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

ObjectiveTo investigate the influence of histone deacetylase 3 (HDAC3) on the occurrence, development of psoriasis-like inflammation in mice, and the relative immune mechanisms. MethodsHealthy C57BL/6 mice aged 6-8 weeks were selected and randomly divided into 3 groups: control group (Control), psoriasis model group (IMQ), and HDAC3 inhibitor RGFP966-treated psoriasis model group (IMQ+RGFP966). One day prior to the experiment, the back hair of the mice was shaved. After a one-day stabilization period, the mice in Control group was treated with an equal amount of vaseline, while the mice in IMQ group was treated with imiquimod (62.5 mg/d) applied topically on the back to establish a psoriasis-like inflammation model. The mice in IMQ+RGFP966 group received intervention with a high dose of the HDAC3-selective inhibitor RGFP966 (30 mg/kg) based on the psoriasis-like model. All groups were treated continuously for 5 d, during which psoriasis-like inflammation symptoms (scaling, erythema, skin thickness), body weight, and mental status were observed and recorded, with photographs taken for documentation. After euthanasia, hematoxylin-eosin (HE) staining was used to assess the effect of RGFP966 on the skin tissue structure of the mice, and skin thickness was measured. The mRNA and protein expression levels of HDAC3 in skin tissues were detected using reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB), respectively. Flow cytometry was employed to analyze neutrophils in peripheral blood and lymph nodes, CD4⁺ T lymphocytes, CD8⁺ T lymphocytes in peripheral blood, and IL-17A secretion by peripheral blood CD4⁺ T lymphocytes. Additionally, spleen CD4⁺ T lymphocyte expression of HDAC3, CCR6, CCR8, and IL-17A secretion levels were analyzed. Immunohistochemistry was used to detect the localization and expression levels of HDAC3, IL-17A, and IL-10 in skin tissues. ResultsCompared with the Control group, the IMQ group exhibited significant psoriasis-like inflammation, characterized by erythema, scaling, and skin wrinkling. Compared with the IMQ group, RGFP966 exacerbated psoriasis-like inflammatory symptoms, leading to increased hyperkeratosis. The psoriasis area and severity index (PASI) skin symptom scores were higher in the IMQ group than those in the Control group, and the scores were further elevated in the IMQ+RGFP966 group compared to the IMQ group. Skin thickness measurements showed a trend of IMQ+RGFP966>IMQ>Control. The numbers of neutrophils in the blood and lymph nodes increased sequentially in the Control, IMQ, and IMQ+RGFP966 groups, with a similar trend observed for CD4⁺ and CD8⁺ T lymphocytes in the blood. In skin tissues, compared with the Control group, the mRNA and protein levels of HDAC3 decreased in the IMQ group, but RGFP966 did not further reduce these expressions. HDAC3 was primarily located in the nucleus. Compared with the Control group, the nuclear HDAC3 content decreased in the skin tissues of the IMQ group, and RGFP966 further reduced nuclear HDAC3. Compared with the Control and IMQ groups, RGFP966 treatment decreased HDAC3 expression in splenic CD4⁺ and CD8⁺ T cells. RGFP966 treatment increased the expression of CCR6 and CCR8 in splenic CD4⁺ T cells and enhanced IL-17A secretion by peripheral blood and splenic CD4⁺ T lymphocytes. Additionally, compared with the IMQ group, RGFP966 reduced IL-10 protein levels and upregulated IL-17A expression in skin tissues. ConclusionRGFP966 exacerbates psoriatic-like inflammatory responses by inhibiting HDAC3, increasing the secretion of the cytokine IL-17A, and upregulating the expression of chemokines CCR8 and CCR6.

OBJECTIVE: To assess the efficacy of Qingda Granule (QDG) in ameliorating hypertension-induced cardiac damage and investigate the underlying mechanisms involved. METHODS: Twenty spontaneously hypertensive rats (SHRs) were used to develope a hypertension-induced cardiac damage model. Another 10 Wistar Kyoto (WKY) rats were used as normotension group. Rats were administrated intragastrically QDG [0.9 g/(kg•d)] or an equivalent volume of pure water for 8 weeks. Blood pressure, histopathological changes, cardiac function, levels of oxidative stress and inflammatory response markers were measured. Furthermore, to gain insights into the potential mechanisms underlying the protective effects of QDG against hypertension-induced cardiac injury, a network pharmacology study was conducted. Predicted results were validated by Western blot, radioimmunoassay immunohistochemistry and quantitative polymerase chain reaction, respectively. RESULTS: The administration of QDG resulted in a significant decrease in blood pressure levels in SHRs (P<0.01). Histological examinations, including hematoxylin-eosin staining and Masson trichrome staining revealed that QDG effectively attenuated hypertension-induced cardiac damage. Furthermore, echocardiography demonstrated that QDG improved hypertension-associated cardiac dysfunction. Enzyme-linked immunosorbent assay and colorimetric method indicated that QDG significantly reduced oxidative stress and inflammatory response levels in both myocardial tissue and serum (P<0.01). CONCLUSIONS Both network pharmacology and experimental investigations confirmed that QDG exerted its beneficial effects in decreasing hypertension-induced cardiac damage by regulating the angiotensin converting enzyme (ACE)/angiotensin II (Ang II)/Ang II receptor type 1 axis and ACE/Ang II/Ang II receptor type 2 axis.
Animals ; Drugs, Chinese Herbal/therapeutic use* ; Hypertension/pathology* ; Renin-Angiotensin System/drug effects* ; Rats, Inbred SHR ; Oxidative Stress/drug effects* ; Male ; Rats, Inbred WKY ; Blood Pressure/drug effects* ; Myocardium/pathology* ; Rats ; Inflammation/pathology*

This study was aimed at investigating the immunoregulatory function of Mycobacterium tuberculosis Rv3641c gene in modulating host type Ⅰ interferon responses.The shuttle plasmid pMV261 was used to construct Rv3641c overexpression recombinant Mycobacterium smegmatis,and the biological characteristics of the recombinant bacteria were analyzed to explore the effect of Rv3641c on the growth curve,colony morphology and stress resistance of Mycobacterium.Subsequently,RAW264.7 cells were infected with Rv3641c overexpressing Mycobacterium smegmatis,and the transcriptional expression of genes related to the inhibition of type I inter-feron pathway was determined by RT-PCR.The expression level of IFN-βprotein was determined by ELISA,and the intracellular sur-vival level was determined.As a result,the recombinant rMS::pMV261-Rv3641c was successfully constructed.The results of biologi-cal characteristics analysis showed that Rv3641c did not affect the growth of mycobacteria,but significantly changed the colony mor-phology of mycobacteria and improved its resistance to H2O2.The results of recombinant bacteria infection experiments showed that Rv3641c significantly down-regulated the transcription levels of IFN-α,IFN-βand downstream ISGs genes CXCL10,IFIT2 and IL-1β in host cells,and Rv3641c significantly down-regulated the transcription levels of IFN-α,IFN-βand downstream ISGs genes CXCL10,IFIT2 and IL-1βin host cells.The results of intracellular colonization experiments showed that the intracellular mycobacte-ria in the overexpression recombinant bacteria infection group were significantly higher than those in the empty vector group,indicat-ing that Rv3641c could promote the intracellular surviv al of mycobacteria.In summary,the Rv3641c gene of M.tuberculosis can inhibit the host type I interferon response and promote the intracellular survival of M.tuberculosis,which provides a new idea for further explor-ing the immune escape function of M.tuberculosis and the discovery of new targets for anti-tuberculosis drugs.

Objective:To observe the effects of auricular point compression and exercise therapy on glycolipid metabolism,oxidative stress and sleep quality in type 2 diabetes mellitus(T2DM)patients with poor glycemic control.Methods:This study was a single-center randomized controlled study,86 T2DM patients with poor glycemic control who were treated in our hospital from June 2022 to June 2024 were divided into control group(received conventional treatment,n=43)and observation group(received auricular point compression and exercise therapy,n=43)by using the random number table method.The clinical efficacy,blood lipid indexes,blood glucose indexes,oxidative stress indexes and sleep quality were compared between the two groups.Results:The total clinical effective rate,high-density lipoprotein cholesterol(HDL-C),superoxide dismutase(SOD)and Glutathione peroxidase(GSH-Px)of the observation group after treatment were higher than those of the control group,and the fasting blood glucose(FBG),glycated hemoglobin(HbA1c),Homeostatic Model Assessment of Insulin Resistance(HOMA-IR),total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),triglycerides(TG),reactive oxygen species(ROS),malondialdehyde(MDA)and Pittsburgh sleep Quality Index(PSQI)score were lower than those of the control group(P＜0.05).Conclusion:Auricular point compression and exercise therapy can regulate glycolipid metabolism in T2DM patients with poor glycemic control,improve the degree of oxidative stress and sleep quality.

Objective To observe the clinical efficacy of Lingnan fire needling in the treatment of plaque psoriasis.Methods A total of 60 cases of patients with plaque psoriasis admitted to Bao'an Hospital of Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine from August 2021 to January 2023 were selected,and the patients were randomly divided into the observation group and the control group according to the random number table method,with 30 cases in each group.The observation group was given Lingnan fire needling for treatment,and the control group was given topical application of Calcipotriol Ointment.The course of treatment covered eight weeks continuously.After eight weeks of treatment,the clinical efficacy of the two groups was evaluated,and the changes of Psoriasis Area and Severity Index(PASI)scores and Dermatology Life Quality Index(DLQI)scores,as well as the diameter of glomus under dermoscopy of the patients in the two groups were observed before the treatment and after 2,4,6,and 8 weeks of treatment.Changes in Generalized Anxiety Disorder Scale(GAD-7)scores before treatment and after 2,4,6,and 8 weeks of treatment were compared between the two groups.Results(1)After 2,4,6 and 8 weeks of treatment,the scores of PASI,DLQI and GAD-7 of patients in the two groups were improved significantly(P<0.05),and the improvement in the observation group was significantly superior to that in the control group,the difference being statistically significant(P<0.05).(2)The cured and markedly rate of the observation group was 86.67%(26/30);and that of the control group was 66.67%(20/30).The efficacy of the observation group was superior to that of the control group,the difference being statistically significant(P<0.05).(3)After 2,4,6,and 8 weeks of treatment,the diameter of glomus under dermoscopy of the patients in the two groups were improved significantly(P<0.05),and the improvement in the observation group was significantly superior to that in the control group,the difference being statistically significant(P<0.05).Conclusion Lingnan fire needling therapy for plaque psoriasis can effectively improve the clinical symptoms of the patients,relieve the anxiety symptoms induced by skin lesions and itching,so as to improve their quality of life.

Objective To investigate the effect of four traditional Chinese drugs for reinforcing kidney combined with Tongqiao Huoxue Decoction on serum neurotransmitters and neurological func-tion in patients with post-stroke cognitive impairment(PSCI).Methods A total of 110 patients with PSCI were randomly divided into treatment group and control group,with 55 cases in each group.The control group was treated with donepezil tablet,while the treatment group was treated with four tradi-tional Chinese drugs for reinforcing kidney and Tongqiao Huoxue Decoction on the basis of the control group.The total effective rate,the Mini-Mental State Examination(MMSE)score,the Montreal Cogni-tive Assessment(MoCA)score,the National Institutes of Health Stroke Scale(NIHSS)score and the Barthel Index(BI)as well as serum levels of acetylcholine(ACh),dopamine(DA),norepinephrine(NE),5-hydroxytryptamine(5-HT),neuron-specific enolase(NSE),visinin-like protein-1(VILIP-1),myelin basic protein(MBP),and heat shock protein 70(HSP70)before and after treatment were compared between the two groups.Adverse reactions in both groups were recorded.Results The total effective rate was 90.91％in the treatment group,which was significantly higher than 76.36％in the control group(P＜0.05).After treatment,the MMSE score,MoCA score and BI as well as serum levels of ACh,DA,NE,5-HT and HSP70 in the treatment group were significantly higher than those in the control group,while the NIHSS score and serum levels of NSE,VILIP-1 and MBP were significantly lower than those in the control group(P＜0.05).The total incidence rate of adverse reactions in the treatment group and the control group was 12.73％and 9.09％respectively,which showed no significant between-group difference(P＞0.05).Conclusion Four traditional Chinese drugs for reinforcing kidney combined with Tongqiao Huoxue Decoction can promote the secretion of cognition-related neurotransmitters in patients with PSCI,accelerate the repair of neurological damage,and safety is relatively high.