Intervention in chronically activated microglia-mediated neuroinflammation is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood‒brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acid-cleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 peptides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improvements in late APP/PS1 mice.

[This corrects the article DOI: 10.1016/j.jpha.2023.08.006.].

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

OBJECTIVE: Circadian rhythm disruption (CRD) is a risk factor that correlates with poor prognosis across multiple tumor types, including hepatocellular carcinoma (HCC). However, its mechanism remains unclear. This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity. METHODS: To quantify CRD, the HCC CRD score (HCCcrds) was developed. Using machine learning algorithms, we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort (n = 369), and the robustness of this method was validated. Furthermore, we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes. RESULTS: We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis. The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis, higher pathological grade, and advanced clinical stages, while the CRD-related subtype with low HCCcrds had better clinical outcomes. We also identified novel biomarkers for each subtype, such as nicotinamide n-methyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1. CONCLUSION We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers. Within these groups greater HCCcrds was associated with worse prognosis. This approach has the potential to improve prediction of an individual's prognosis, guide precision treatments, and assist clinical decision making for HCC patients. Please cite this article as: Li XJ, Chang L, Mi Y, Zhang G, Zhu SS, Zhang YX, et al. Integrated-omics analysis defines subtypes of hepatocellular carcinoma based on circadian rhythm. J Integr Med. 2025; 23(4): 445-456.
Humans ; Carcinoma, Hepatocellular/pathology* ; Liver Neoplasms/pathology* ; Circadian Rhythm/genetics* ; Prognosis ; Male ; Female ; Biomarkers, Tumor/genetics* ; Middle Aged ; Machine Learning ; Computational Biology

Objective To investigate the value of repeat renal biopsy in the treatment and prognosis of nephrotic syndrome(NS)and acute kidney injury(AKI)following immunosuppressive therapy in patients with lupus nephritis(LN). Methods A retrospective analysis was conducted for the clinicopathological data and follow-up records of LN patients undergoing repeat renal biopsy at Peking Union Medical College Hospital from January 1,2009 to December 31,2021. Results A total of 76 patients(55 females,72.4%)were included in this study,with the mean age at the first biopsy being(29.0±10.4)years,the median inter-biopsy interval of 4.0(2.0,7.0) years,and the median total follow-up duration of 7.5(5.0,13.8)years.Pathological transformation occurred in 46(60.5%)patients,and 2 patients had comorbid diabetic nephropathy.At repeat renal biopsy,50(65.8%) patients presented NS.These patients demonstrated lower estimated glomerular filtration rate(eGFR)(P<0.001),higher chronicity index(CI)(P=0.029),and higher complement C3(P<0.001)and C4(P<0.001)levels than those with NS at the first renal biopsy(n=50).Among the 28(36.8%) patients with AKI at repeat renal biopsy,8(28.6%)experienced acute exacerbation of chronic renal insufficiency.These patients exhibited higher serum creatinine level(P=0.002),C4 level(P=0.033),CI(P=0.042),and prevalence of thrombotic microangiopathy(P=0.046)than the patients showing AKI at the first renal biopsy(n=16),while the activity index(AI)showed no significant difference(P=0.051).Over 50% of NS and AKI patients underwent treatment modifications post-repeat renal biopsy,with clinical remission rates comparable to those after the first renal biopsy(both P>0.05).Elevated CI(≥5,P=0.001)and serum creatinine(≥140 μmol/L,P<0.001)at repeat renal biopsy were identified as independent risk factors for poor prognosis.The patients with AKI at repeat renal biopsy had higher incidence of endpoint events than the non-AKI patients(P=0.015).Neither AKI at the first renal biopsy nor NS at both biopsies had significant associations with prognosis. Conclusions Repeat renal biopsy reveals not only sustained high disease activity but also accelerates chronic progression in LN patients,which underscore its critical role in guiding the therapy for severe LN post-immunosuppression.AKI,CI≥5,and serum creatinine ≥140 μmol/L at repeat renal biopsy are strongly associated with poor prognosis.
Humans ; Lupus Nephritis/drug therapy* ; Female ; Retrospective Studies ; Adult ; Male ; Prognosis ; Biopsy ; Kidney/pathology* ; Acute Kidney Injury/pathology* ; Nephrotic Syndrome/pathology* ; Glomerular Filtration Rate ; Young Adult ; Immunosuppressive Agents/therapeutic use* ; Middle Aged

BACKGROUND:The re-injury rate of the anterior cruciate ligament continues to be high and the unclear relationship between neuromuscular function and biomechanical risk factors may be one of the reasons for poor injury prevention and rehabilitation.OBJECTIVE:To evaluate the biomechanics and neuromuscular function characteristics of the knee joint during landing movements after anterior cruciate ligament reconstruction,and to further explore the effects of muscle strength,proprioception,and dynamic postural control on the risk indicators of anterior cruciate ligament injury during landing maneuver.METHODS:Twenty-six male anterior cruciate ligament reconstruction patients and 26 healthy control males at the age of 18-35 years were recruited and randomized to undergo joint kinesthesia test,Y-balance test,and isometric muscle strength tests.Kinematic and kinetic data of the knee joints during single-legged jump landing tasks were collected using an infrared motion capture system and force plates.RESULTS AND CONCLUSION:(1)Compared with the healthy control group,patients after anterior cruciate ligament reconstruction demonstrated higher knee valgus angle(P=0.021),lower hamstring muscle strength(P＜0.001),lower quadriceps muscle strength(P＜0.001)and Y-balance anterior reach distance(P＜0.001),and worse knee flexion kinesthesia(P＜0.001)and extension kinesthesia(P=0.001).(2)The predictor variables of knee extension moment were quadriceps strength and knee flexion kinesthesia(R2=0.298,P=0.007).The predictor variable of knee varus and valgus angle was hamstring strength(R2=0.117,P=0.048).The predictor variable of knee internal and external rotation angle was the hamstring-to-quadriceps peak torque ratio(R2=0.134,P=0.037).(3)The results showed that after anterior cruciate ligament reconstruction,patients still had abnormal biomechanical action patterns and neuromuscular function defects in the frontal plane of the knee joint,and elevating the muscle strength of the hamstrings,avoiding excessive quadriceps muscle strength and enhancing the proprioception of the knee joint were helpful to improve the biomechanical patterns of the sagittal plane,frontal plane and horizontal plane of the knee joint and reduce the risk of anterior cruciate ligament injury during landing maneuvers.

Aim To explore the effects of high glucose on KIAA0753 and CCSAP and the relationship between KIAA0753 and CCSAP and osteogenic differentiation and calcium signaling pathway under high glucose con-ditions.Methods Mouse embryonic osteoblast pre-cursor cells(MC3T3-E1)were induced by osteoblast medium with glucose concentrations of 5.5 and 25 mmol·L-1,and the protein expressions of KIAA0753 and CCSAP were detected by Western blot.The over-expressed plasmid was transfected into human embry-onic kidney cells(HEK-293T),and the interaction between KIAA0753 and CCSAP was detected by co-im-munoprecipitation.MC3T3-E1 cells were treated in the osteogenic medium with different glucose concentrations and induction times.Alkaline phosphatase(ALP)ac-tivity was detected with a kit.The expression of KI-AA0753,CCSAP,osteopontin,osteocalcin,and other proteins were assessed using Western blot.and then 5.5,25 mmol·L-1,and 25 mmol·L-1+OE-CCSAP three groups of MC3T3-E1 cells were set.The expression of KIAA0753,OCN,OPN protein,and ALP activity were detected successively.The diabetic mouse model dataset in Gene Expression Omnibus was used to screen differential genes for bioinformatics a-nalysis.MC3T3-E1 cells were set up in three groups,5.5,25 mmol·L-1,and 25 mmol·L-1+OE-KI-AA0753,respectively.The calcium/calmodulin-de-pendent protein kinase Ⅱ beta(CAMK2B)and phos-pholamban(PLN)were detected by Western blot.Re-sults Compared with the 5.5 mmol·L-1 group,25 mmol·L-1 inhibited the expression of KIAA0753 and CCSAP proteins in osteoblasts,and there was an inter-action between KIAA0753 and CCSAP.At the same time,25 mmol·L-1 also inhibited the expression of ALP,OPN,and OCN proteins in osteoblasts.Overex-pression of CCSAP at 25 mmol·L-1 up-regulated the expression of KIAA0753,OCN,OPN,and ALP.The differential genes of the diabetic mouse model were mainly concentrated in the aspects of"signal receptor and signal regulation".25 mmol·L-1 glucose inhibi-ted the expression of CAMK2B and PLN proteins in os-teoblasts,and overexpression of KIAA0753 at 25 mmol·L-1 upregulated the expression of CAMK2B and PLN proteins.Conclusions High glucose inhibits the expression of KIAA0753 and CCSAP protein,inhibits the osteogenic differentiation and calcium signaling in mouse embryonic osteoblast precursor cells,overex-pression of CCSAP saves the inhibitory effect of high glucose on osteogenic differentiation,and overexpres-sion of KIAA0753 reverses the inhibitory effect of high glucose on calcium signaling pathway.

Objective To determine the effect of limb dominance on landing biomechanics and lower limb functional outcomes in patients with anterior cruciate ligament reconstruction(ACLR).Methods Forty-nine participants were recruited and divided into the ACLR on dominant limb(ACLR-D)group,ACLR on nondominant limb(ACLR-ND)group and healthy control group.Single-leg jump landing,knee isokinetic muscle strength,Y balance,and single-leg hop distance were tested on both limbs of all participants.Kinematics and kinetics data during the single-leg jump landing were collected by an infrared motion capture system and a force platform,and knee joint muscle strength was collected using the isokinetic muscle strength testing system.Two-way mixed-design ANOVAs were used to observe the effects of limb and group on the outcomes of each test.Results The non-surgical limbs had greater knee valgus,knee external rotation angles and knee valgus moments during single-leg jump landing in the ACLR-D group compared with those in the ACLR-ND group,and the ACLR-D group had significantly smaller bilateral knee flexion angles than the control group.There were no differences in knee muscle strength,Y-balance composite scores and single-leg hop distance between ACLR-D and ACLR-ND groups,but the Y balance scores in the ACLR-ND group were smaller than those in the control group.Conclusions Limb dominance has no effects on knee muscle strength,dynamic postural control,and single-leg hop function in ACLR patients.The non-surgical limbs of ACLR-D patients are at a higher risk of ACL injury due to the presence of greater knee valgus and external rotation angles and knee valgus moments.

Aim To investigate the effect of icariin(ICA)on chronic ulcerative colitis(UC)in mice.Methods Male SPF-grade C57BL/6J mice were ran-domly divided into the control group,model group,low-dose ICA group,and high-dose ICA group.Except for the control group,the rest of the mice were established as chronic UC models.Expressions of tight junction proteins,inflammatory factors,fibrosis markers,macro-phage markers,and MAPK signaling pathways in the colonic epithelium of each group were determined by Western blot,qPCR,immunohistochemistry;the degree of intestinal damage and fibrosis was detected by HE and Masson staining;the co-localization of different macrophage markers with related factors was examined by immunofluorescence.Results Treatment of ICA significantly improved the general condition of chronic UC mice,decreased the infiltration of M1-type macro-phages and the secretion of pro-inflammatory factors,inhibited the MAPK signaling pathway,reduced the co-localization expression of M1-type macrophages with the MAPK signaling pathway,and downregulated the infiltration of M2-type macrophages and the secretion of pro-fibrotic factors in the colon.Conclusion ICA mitigates the inflammatory damage and fibrosis of colon in chronic UC mice.

Following the evidence-based diagnosis and treatment guideline development method for common pediatric diseases,the The Guideline for the Diagnosis and Treatment of Pediatric Food Accumulation and Stagnation in Chinese Medicine was formed through literature retrieval,expert questionnaire survey,expert discussion meeting,and solicitation of opinions.The revised content includes the scope of the guideline,normative reference documents,terms and definitions,diagnosis,syndrome differentiation,treatment,pre-vention and nursing suggestions,etc.,aiming to update the clinical diagnosis and treatment plan of Chinese medicine for accumulation and provide important clinical decision-making references for clinical physicians to rationally apply the diagnosis and treatment plan of Chinese medicine in the prevention and treatment of accumulation and stagnation in Children.