AIM:To explore the mechanism of ac-tion and clinical significance of NLRC4 in multiple myeloma by analyzing the relative expression and clinical significance of NLRC4 mRNA in bone mar-row fluid of patients with multiple myeloma(MM),so as to guide the formulation of disease treatment and the evaluation of clinical prognosis.METHODS:MMRF database and GTEx database were used to compare the expression and survival correlation of inflammatory bodies between myeloma patients and normal controls.Real-time fluorescent quanti-tative polymerase chain reaction(qPCR)was used to detect the expression of inflammatory bodies in bone marrow fluid of 26 newly diagnosed myeloma patients and 19 post-treatment myeloma patients and peripheral blood of 28 normal volunteers ad-mitted to the First Affiliated Hospital of Anhui Medi-cal University from January to September 2023.The mRNA expression differences of each inflammatory body and the correlation between NLRC4 inflamma-tory body expression and clinicopathologic fea-tures,inflammatory factor/chemokine expression of newly diagnosed patients were analyzed.RE-SULTS:Compared with the control group and the treatment group,the expression of inflammasome mRNA in the newly diagnosed group was increased except for NLRP3,and the expression of NLRC4 mRNA was significantly increased(P<0.01).The he-moglobin count,creatinine level and calcium ion level were linearly correlated with NLRC4 mRNA ex-pression level in newly diagnosed patients(P<0.05).The mRNA expression levels of IL-18,CCL-3 and NL-RC4 in newly diagnosed patients were linearly cor-related(P<0.05).CONCLUSION:NLRC4 inflammato-somes are highly expressed in MM,and promote the occurrence and development of tumor by pro-moting the production and release of inflammatory cytokines/chemokines IL-18 and CCL-3,which is of great significance for the formulation of treatment plan and clinical prognosis evaluation of multiple myeloma.

AIM To analyze the dynamic change patterns of aflatoxin B1,aflatoxin B2,aflatoxin G1,aflatoxin G2,T-2 toxin and deoxynivalenol contents during the fermentation of Massa Medicata Fermentata.METHODS The analysis was performed on a 40 ℃ thermostatic Waters ACQUITY UPLC HSS T3 column(100 mm×2.1 mm,1.8 μm),with the mobile phase comprising of 0.01％formic acid-[acetonitrile-methanol(1∶1)]flowing at 0.3 mL/min,and electron spray ionization source was adopted in positive ion scanning with multiple reaction monitoring mode.RESULTS Six mycotoxins showed good linear relationships within their own ranges(R2＞0.998 0),whose average recoveries were 76.1％-119.3％with the RSDs of 0.49％-9.27％,and except for deoxynivalenol,their contents demonstrated the trends of growing out of nothing and gradually increasing.CONCLUSION The risk of mycotoxin infection exists in the fermentation of Massa Medicata Fermentata.This simple,efficient,rapid and sensitive method can provide a reference for whole-process monitoring the fermentation process for Massa Medicata Fermentata.

AIM:To explore the mechanism of ac-tion and clinical significance of NLRC4 in multiple myeloma by analyzing the relative expression and clinical significance of NLRC4 mRNA in bone mar-row fluid of patients with multiple myeloma(MM),so as to guide the formulation of disease treatment and the evaluation of clinical prognosis.METHODS:MMRF database and GTEx database were used to compare the expression and survival correlation of inflammatory bodies between myeloma patients and normal controls.Real-time fluorescent quanti-tative polymerase chain reaction(qPCR)was used to detect the expression of inflammatory bodies in bone marrow fluid of 26 newly diagnosed myeloma patients and 19 post-treatment myeloma patients and peripheral blood of 28 normal volunteers ad-mitted to the First Affiliated Hospital of Anhui Medi-cal University from January to September 2023.The mRNA expression differences of each inflammatory body and the correlation between NLRC4 inflamma-tory body expression and clinicopathologic fea-tures,inflammatory factor/chemokine expression of newly diagnosed patients were analyzed.RE-SULTS:Compared with the control group and the treatment group,the expression of inflammasome mRNA in the newly diagnosed group was increased except for NLRP3,and the expression of NLRC4 mRNA was significantly increased(P<0.01).The he-moglobin count,creatinine level and calcium ion level were linearly correlated with NLRC4 mRNA ex-pression level in newly diagnosed patients(P<0.05).The mRNA expression levels of IL-18,CCL-3 and NL-RC4 in newly diagnosed patients were linearly cor-related(P<0.05).CONCLUSION:NLRC4 inflammato-somes are highly expressed in MM,and promote the occurrence and development of tumor by pro-moting the production and release of inflammatory cytokines/chemokines IL-18 and CCL-3,which is of great significance for the formulation of treatment plan and clinical prognosis evaluation of multiple myeloma.

Aim To investigate the regulatory mecha-nisms of donepezil on the expression and enzymatic ac-tivity of cytochrome P450 3A4(CYP3A4),elucidate the synergistic impact of hypoxia on CYP3A4 function,and reveal its potential association with drug-induced cardiotoxicity,particularly QT interval prolongation.Methods Western blot,co-immunoprecipitation,and gene knockdown techniques were employed to evaluate the effects of donepezil and hypoxia on CYP3A4 pro-tein expression.CYP3A4 enzymatic activity was as-sessed using an in vitro incubation system with rat liver microsomes combined with high-performance liquid chromatography(HPLC),and the half-maximal inhib-itory concentration(IC50)was determined.Results Donepezil(10 μmol·L-1)and hypoxia reduced CYP3A4 protein expression to 31.75％and 45.90％of the control levels,respectively.Both interventions activated the gp78-mediated ubiquitin-proteasome path-way,significantly increasing CYP3A4 ubiquitination levels by 2.1-fold compared to the control group,thereby promoting proteasomal degradation.Donepezil inhibited CYP3A4 enzyme activity with an IC50 of 83.4μmol·L-1,and hypoxia synergistically enhanced this inhibitory effect,reducing the IC50 to 20.79 μmol·L-1.Conclusion Donepezil downregulates CYP3A4 function through dual mechanisms involving ubiquitin-mediated proteasomal degradation and direct enzymatic inhibition.Hypoxia potentiates this effect,leading to impaired metabolism of CYP3A4 substrate drugs,ele-vated plasma drug concentrations(1.6-2.3-fold in-crease compared to normal metabolic conditions),and an increased risk of QT interval prolongation and other forms of cardiotoxicity.

Objective: To explore the association between preoperative aspartate transaminase to alanine transaminase (AST/ALT) ratio and the outcomes of urothelial cancers. Methods: After a systematic search of Web of Science，PubMed and Embase before Aug.2024，14 studies were included in the Meta-analysis.The hazard ratios (HRs) with 95% confidence interval (CI) for overall survival (OS)，cancer-specific survival (CSS)，and recurrence-free survival (RFS) were analyzed using STATA 15.0 software. Results: The Meta-analysis included a total of 8190 patients.Urothelial cancer patients with an elevated preoperative AST/ALT ratio had worse OS (HR=1.92，95% CI：1.38-2.67，P<0.001)，CSS (HR=2.12，95% CI：1.48-3.05，P<0.001)，and RFS (HR=1.63，95% CI：1.27-2.10，P<0.001).In subgroup analyses，preoperative AST/ALT ratio had a better predictive value for OS，CSS，and RFS in patients with bladder cancer than in patients with upper tract urothelial carcinoma，and a better predictive value in Asian population than in Caucasian population (P<0.001). Conclusion: A high preoperative AST/ALT ratio is associated with poor OS，CSS and RFS in urothelial cancers，particularly among the Asian population.

Aim To investigate the regulatory mecha-nisms of donepezil on the expression and enzymatic ac-tivity of cytochrome P450 3A4(CYP3A4),elucidate the synergistic impact of hypoxia on CYP3A4 function,and reveal its potential association with drug-induced cardiotoxicity,particularly QT interval prolongation.Methods Western blot,co-immunoprecipitation,and gene knockdown techniques were employed to evaluate the effects of donepezil and hypoxia on CYP3A4 pro-tein expression.CYP3A4 enzymatic activity was as-sessed using an in vitro incubation system with rat liver microsomes combined with high-performance liquid chromatography(HPLC),and the half-maximal inhib-itory concentration(IC50)was determined.Results Donepezil(10 μmol·L-1)and hypoxia reduced CYP3A4 protein expression to 31.75％and 45.90％of the control levels,respectively.Both interventions activated the gp78-mediated ubiquitin-proteasome path-way,significantly increasing CYP3A4 ubiquitination levels by 2.1-fold compared to the control group,thereby promoting proteasomal degradation.Donepezil inhibited CYP3A4 enzyme activity with an IC50 of 83.4μmol·L-1,and hypoxia synergistically enhanced this inhibitory effect,reducing the IC50 to 20.79 μmol·L-1.Conclusion Donepezil downregulates CYP3A4 function through dual mechanisms involving ubiquitin-mediated proteasomal degradation and direct enzymatic inhibition.Hypoxia potentiates this effect,leading to impaired metabolism of CYP3A4 substrate drugs,ele-vated plasma drug concentrations(1.6-2.3-fold in-crease compared to normal metabolic conditions),and an increased risk of QT interval prolongation and other forms of cardiotoxicity.

Growth arrest DNA damage-inducible protein 45 β (GADD45B) has been reported to be a regulatory factor for active DNA demethylation and is implicated in the modulation of synaptic plasticity and chronic stress-related psychopathological processes. However, its precise role and mechanism of action in stress susceptibility remain elusive. In this study, we found a significant reduction in GADD45B expression specifically in the ventral, but not the dorsal hippocampal CA1 (dCA1) of stress-susceptible mice. Furthermore, we demonstrated that GADD45B negatively regulates susceptibility to social stress and NMDA receptor-dependent long-term potentiation (LTP) in the ventral hippocampal CA1 (vCA1). Importantly, through pharmacological inhibition using the NMDA receptor antagonist MK801, we provided further evidence supporting the hypothesis that GADD45B potentially modulates susceptibility to social stress by influencing NMDA receptor-mediated LTP. Collectively, these results suggested that modulation of NMDA receptor-mediated synaptic plasticity is a pivotal mechanism underlying the regulation of susceptibility to social stress by GADD45B.
Animals ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; CA1 Region, Hippocampal/drug effects* ; Male ; Stress, Psychological/physiopathology* ; Mice ; Neuronal Plasticity/drug effects* ; Long-Term Potentiation/drug effects* ; Mice, Inbred C57BL ; Antigens, Differentiation/metabolism* ; Dizocilpine Maleate/pharmacology* ; Excitatory Amino Acid Antagonists/pharmacology* ; GADD45 Proteins

Objective:To compare the impact of manual right arm blood pressure measurement with computer-controlled blood pressure meter (CCBPM) on the detection rate of hypertension among elderly individuals.Method:This was a cross-sectional study. Elderly residents undergoing routine health check-up in a village in Jiangxi Province from April to June 2024 were enrolled. Manual blood pressure measurements were performed on the right arm using an electronic sphygmomanometer, while standardized dual-arm synchronized blood pressure assessments were conducted using the CCBPM. Blood pressure data were recorded from three sources: manual measurement on the right arm; the first CCBPM measurement on the arm with higher systolic blood pressure (CCBPM single); and the mean blood pressure of the arm with higher systolic blood pressure from two (if the difference between the first two measurements was less than 5 mmHg, 1 mmHg=0.133 kPa) or three (if the difference exceeded 5 mmHg) CCBPM measurements (CCBPM mean). Hypertension detection rates from these three datasets were compared. Subgroup analysis was performed according to age (60-74 years old as the elderly group,≥75 years old as the senior group) and gender. Intra-group correlation coefficient ( ICC) was analyzed to evaluate the consistency of blood pressure data of different blood pressure measurement methods, and Kappa value was analyzed to evaluate the consistency of hypertension classification determined by different blood pressure measurement methods. Results:A total of 1 498 participants were enrolled, aged (71.30±6.83) years old, including 678 males (45.26%). The blood pressure and heart rate measured by the artificial right arm blood pressure measurement were higher than those measured by CCBPM single (blood pressure: (140.09±17.19)/(82.40±10.93) mmHg vs. (135.31±18.98)/(81.23±10.51) mmHg; heart rate: (75.76±11.72) beats/min vs.(72.94±11.21) beats/min) and CCBPM mean (blood pressure: (140.09±17.19)/(82.40±10.93) mmHg vs. (134.64±18.39)/(80.28±9.78) mmHg; heart rate: (75.76±11.72) beats/min vs. (72.87±10.70) beats/min, all P<0.05). The detection rate of hypertension determined by CCBPM mean was significantly lower than that of artificial right arm (40.25% (603/1 498) vs.54.34% (814/1 498)) and CCBPM single (40.25% (603/1 498) vs. 44.79% (671/1 498), all P<0.05). Subgroup analysis showed that that the detection rate of hypertension determined by CCBPM mean was lower than that measured by artificial right arm regardless of gender and age (all P<0.05). The consistency of blood pressure data between artificial right arm and the CCBPM mean was moderate (systolic blood pressure: ICC=0.70; diastolic blood pressure: ICC=0.62), with less consistent classification ( Kappa=0.37). The consistency of blood pressure data between CCBPM single and CCBPM mean is extremely high (systolic blood pressure: ICC=0.94; diastolic blood pressure: ICC=0.91), with highly consistent classification ( Kappa=0.74). Conclusions:Artificial right arm blood pressure measurement in physical examinations may overestimate the hypertension detection rate, and the standardized dual-arm synchronized blood pressure measurement using CCBPM can reduce irregular blood pressure measurement.

OBJECTIVE: Varied acupoint selections represent a potential cause of the uncertainty surrounding the efficacy of acupuncture for knee osteoarthritis (OA). Skin temperature, a guiding factor for acupoint selection, may help to address this issue. This study explored thermal sensitization of acupoints used for the treatment of knee OA. METHODS: This cross-sectional case-control study enrolled cases aged 45-75 years with symptomatic knee OA and age- and gender-matched non-knee OA controls in a 1:1 ratio. All participants underwent infrared thermographic imaging. The primary outcome was the relative skin temperature of acupoint (STA), and the secondary outcome was the absolute STA of 11 acupoints. The Z test was used to compare the relative and absolute STAs between the groups. Principal component analysis was used to extract the common factors (CFs, acupoint cluster) in the STAs. A general linear model was used to identify factors affecting the STA in the knee OA cases. For the group comparisons of relative STA, P < 0.0045 (adjusted for 11 acupoints through Bonferroni correction) was considered to indicate statistical significance. For other analyses, P < 0.05 was used as the threshold for statistical significance. RESULTS: The analysis included 308 participants, consisting of 151 cases (mean age: [64.58 ± 6.67] years; male: 25.83%; mean body mass index: [25.70 ± 3.16] kg/m²) and 157 controls (mean age: [63.37 ± 5.96] years; male: 26.11%; mean body mass index: [24.47 ± 2.84] kg/m²). The relative STAs of ST34 (P = 0.0001), EX-LE2 (P < 0.0001), EX-LE5 (P = 0.0006), SP10 (P < 0.0001), BL40 (P = 0.0012) and GB39 (P = 0.0037) were higher in the knee OA group. No difference was found in the STAs of ST35, ST36, SP9, GB33 and GB34. Four CFs were identified for relative STA in both groups. The acupoints within each CF were consistent between the groups. The mean values of the relative STAs across each CF were higher in the knee OA group. In the knee OA cases, no factors were observed to affect the relative STA, while age and gender were found to affect the absolute STA. CONCLUSION Among patients with knee OA, thermal sensitization occurs in the acupoints of the lower extremity, exhibiting localized and regional thermal consistencies. The thermally sensitized acupoints that we identified in this study, ST34, SP10, EX-LE2, EX-LE5, GB39 and BL40, may be good choices for the acupuncture treatment of knee OA. Please cite this article as: Tu JF, Wang XZ, Yan SY, Wang YR, Yang JW, Shi GX, Zhang WZ, Jing LN, Yang LS, Liu DH, Wang LQ, Mi BH. Thermal sensitization of acupoints in patients with knee osteoarthritis: A cross-sectional case-control study. J Integr Med. 2025; 23(3): 289-296.
Humans ; Osteoarthritis, Knee/physiopathology* ; Male ; Cross-Sectional Studies ; Middle Aged ; Female ; Acupuncture Points ; Case-Control Studies ; Aged ; Skin Temperature ; Acupuncture Therapy

Microglia, the resident immune cells in the central nervous system (CNS), rapidly transition from a resting to an active state in the acute phase of ischemic brain injury. This active state mediates a pro-inflammatory response that can exacerbate the injury. Targeting the pro-inflammatory response of microglia in the semi-dark band during this acute phase may effectively reduce brain injury. Shionone (SH), an active ingredient extracted from the dried roots and rhizomes of the genus Aster (Asteraceae), has been reported to regulate the inflammatory response of macrophages in sepsis-induced acute lung injury. However, its function in post-stroke neuroinflammation, particularly microglia-mediated neuroinflammation, remains uninvestigated. This study found that SH significantly inhibited lipopolysaccharide (LPS)-induced elevation of inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS), in microglia in vitro. Furthermore, the results demonstrated that SH alleviated infarct volume and improved behavioral performance in middle cerebral artery occlusion (MCAO) mice, which may be attributed to the inhibition of the microglial inflammatory response induced by SH treatment. Mechanistically, SH potently inhibited the phosphorylation of serine-threonine protein kinase B (AKT), mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription 3 (STAT3). These findings suggest that SH may be a potential therapeutic agent for relieving ischemic stroke (IS) by alleviating microglia-associated neuroinflammation.
Animals ; Microglia/immunology* ; Mice ; Male ; Mice, Inbred C57BL ; Brain Ischemia/immunology* ; Neuroinflammatory Diseases/drug therapy* ; Neuroprotective Agents/administration & dosage* ; Interleukin-1beta/genetics* ; STAT3 Transcription Factor/genetics* ; TOR Serine-Threonine Kinases/genetics* ; Tumor Necrosis Factor-alpha/genetics* ; Proto-Oncogene Proteins c-akt/immunology* ; Nitric Oxide Synthase Type II/genetics* ; Lipopolysaccharides