OBJECTIVE To investigate the effects and mechanisms of oliceridine fumarate （TRV130） in improving postoperative cognitive dysfunction （POCD） in elderly rats based on the Toll-like receptor 4 （TLR4）/nuclear factor-κB （NF-κB） pathway. METHODS Rats were randomly divided into the control group （normal saline）， the model group （normal saline）， the TRV130 group （2.8 mg/kg）， the TLR4/NF-κB pathway inhibitor （TAK-242） group （3 mg/kg）， the β -arrestin inhibitor （Barbadin） group （3 mg/kg）， and the traditional opioid drug （morphine） group （2.8 mg/kg）， with 15 rats in each group. Except for the control group， POCD models were established in all other groups. From the first day after surgery， drugs/normal saline were administered via caudal vein injection once daily for 3 consecutive days. After the last administration， the pathological damage of hippocampal tissue was observed； the cognitive function， serum inflammatory factor levels， hippocampal neurons apoptosis rate， and the expression of ionized calcium-binding adapter molecule 1 （Iba-1）， glial fibrillary acidic protein （GFAP）， and TLR4/NF-κB pathway-related mRNA and protein in hippocampal tissue were detected. RESULTS In the model group， the neurons in the CA1 region of the hippocampus were disordered and sparse， with decreased number， pyknotic and fragmented nuclei accompanied by inflammatory cell infiltration. Compared with the control group， the escape latency， serum levels of tumor necrosis factor α （TNF-α）， interleukin-6 （IL-6）， and IL-1β， hippocampal neurons apoptosis rate， average fluorescence intensities of Iba-1 and GFAP， mRNA expression levels of TLR4 and NF-κB p65， and their protein expression/phosphorylation levels in hippocampal tissue were significantly increased/elevated in the model group （ P ＜0.05）； the time spent in the target quadrant and the number of platform crossings were significantly shortened/decreased （ P ＜0.05）. Compared with the model group， the cognitive function， pathological， inflammatory， and apoptosis-related indicators were significantly improved in the TRV130 group， TAK-242 group， and Barbadin group （ P ＜0.05）； the mRNA expression levels of TLR4 and NF-κB p65 and their protein expression/phosphorylation levels were significantly decreased in the TRV130 group and TAK-242 group （ P ＜0.05）. CONCLUSIONS TRV130 may improve POCD in elderly rats by inhibiting the TLR4/NF-κB pathway and alleviating postoperative central nervous system inflammatory responses.

Mammalian male germline development depends on a specialized gonadal somatic microenvironment. However, itsin vitro reconstruction remains challenging. Major barriers include the generation of appropriate supporting-cell lineages, organized tissue architecture, and culture conditions that sustain germ-cell maturation. Yoshino et al. established a mouse pluripotent stem cell-derived testicular organoid model. This model reconstitutes the sex-determining region Y (Sry)-SRY-box transcription factor 9 (Sox9)‑mediated sex-determination program and generates testicular somatic cell-like cells (TesLCs). When assembled with primordial germ cell-like cells (PGCLCs), TesLCs formed seminiferous tubule-like structures and supported male germline progression toward prospermatogonia and germline stem cell-like cells (GSCLCs). After transplantation into infertile recipient testes, organoid-derived GSCLCs produced fertilization-competent sperm and generated fertile offspring. The major significance of this work extends beyond sperm production. It integrates sex determination, germ-cell fate transition, and testicular niche self-organization into an experimentally tractable organoid system. This commentary discusses the technical strategy, sex-determination mechanism, value of testicular niche reconstruction, and translational limitations of this study. It also highlights its implications for in vitro gametogenesis, male infertility modeling, and reproductive medicine.

OBJECTIVE: To observe the therapeutic effect of electroacupuncture (EA) in improving early enteral nutrition tolerance in patients with acute pancreatitis (AP) under the concept of accelerated rehabilitation, and to explore the related mechanism based on the changes in autonomic nerve characteristics. METHODS: A total of 42 patients with AP were randomized into an observation group (21 cases, 1 case dropped out) and a control group (21 cases, 1 case dropped out). The control group received standard basic treatment for AP. On the basis of the treatment in the control group, EA was applied in the observation group, bilateral Zusanli (ST36), Yixian point (Extra), Tianshu (ST25), Neiguan (PC6) and Zhongwan (CV12) were selected as the main points, and the supplementary points were selected according to syndrome differentiation. Ipsilateral Zusanli (ST36) and Yixian point (Extra) were connected to EA, using discontinuous wave, in frequency of 2 Hz, 30 min a time, once a day for 6 continuous days. The enteral nutrition tolerance score was observed before treatment and after 3 and 5 days of treatment; the visual analogue scale (VAS) score for abdominal pain was observed before treatment and after 3 days of treatment; the time of reaching the feeding goal and hospital stay was recorded; the levels of C-reactive protein (CRP) and amylase were measured before treatment and after 5 days of treatment; the heart rate variability (HRV) indexes (standard deviation of NN intervals [SDNN], average standard deviation of NN intervals [SDANN], root mean square of successive NN interval differences [rMSSD], low frequency [LF] and high frequency [HF], ratio of low frequency to high frequency [LF/HF]) were monitored in the two groups. RESULTS: After 3 and 5 days of treatment, the enteral nutrition tolerance scores were decreased compared with those before treatment in both groups (P<0.01), the reductions in the observation group were larger than those in the control group (P<0.01). After 3 days of treatment, the VAS scores for abdominal pain were decreased compared with those before treatment in both groups (P<0.01), the reduction in the observation group was larger than that in the control group (P<0.01). The time of reaching the feeding goal and hospital stay in the observation group was shorter than that in the control group (P<0.05). After 5 days of treatment, the CRP and amylase levels were decreased compared with those before treatment in both groups (P<0.01), the reduction of CRP level in the observation group was larger than that in the control group (P<0.01). In the observation group, SDNN, SDANN and LF/HF were lower than those in the control group (P<0.05, P<0.01), while rMSSD was higher than that in the control group (P<0.01). SDNN, SDANN and LF/HF were positively correlated with the enteral nutrition tolerance scores after 3 and 5 days of treatment (P<0.05), while rMSSD was negatively correlated with the enteral nutrition tolerance scores after 3 and 5 days of treatment (P<0.01). CONCLUSION Electroacupuncture can improve enteral nutrition tolerance in patients with AP by regulating autonomic nervous function, alleviating the inflammation, promoting accelerated recovery, and reducing the length of hospital stay.
Humans ; Electroacupuncture ; Male ; Female ; Enteral Nutrition ; Middle Aged ; Adult ; Pancreatitis/physiopathology* ; Aged ; Acupuncture Points ; Young Adult ; Acute Disease/therapy* ; Autonomic Pathways/physiopathology*

OBJECTIVE: Gastric cancer (GC) is one of the most common malignancies seen in clinic and requires novel treatment options. Morin is a natural flavonoid extracted from the flower stalk of a highly valuable medicinal plant Prunella vulgaris L., which exhibits an anti-cancer effect in multiple types of tumors. However, the therapeutic effect and underlying mechanism of morin in treating GC remains elusive. The study aims to explore the therapeutic effect and underlying molecular mechanisms of morin in GC. METHODS: For in vitro experiments, the proliferation inhibition of morin was measured by cell counting kit-8 assay and colony formation assay in human GC cell line MKN45, human gastric adenocarcinoma cell line AGS, and human gastric epithelial cell line GES-1; for apoptosis analysis, microscopic photography, Western blotting, ubiquitination analysis, quantitative polymerase chain reaction analysis, flow cytometry, and RNA interference technology were employed. For in vivo studies, immunohistochemistry, biomedical analysis, and Western blotting were used to assess the efficacy and safety of morin in a xenograft mouse model of GC. RESULTS: Morin significantly inhibited the proliferation of GC cells MKN45 and AGS in a dose- and time-dependent manner, but did not inhibit human gastric epithelial cells GES-1. Only the caspase inhibitor Z-VAD-FMK was able to significantly reverse the inhibition of proliferation by morin in both GC cells, suggesting that apoptosis was the main type of cell death during the treatment. Morin induced intrinsic apoptosis in a dose-dependent manner in GC cells, which mainly relied on B cell leukemia/lymphoma 2 (BCL-2) associated agonist of cell death (BAD) but not phorbol-12-myristate-13-acetate-induced protein 1. The upregulation of BAD by morin was due to blocking the ubiquitination degradation of BAD, rather than the transcription regulation and the phosphorylation of BAD. Furthermore, the combination of morin and BCL-2 inhibitor navitoclax (also known as ABT-737) produced a synergistic inhibitory effect in GC cells through amplifying apoptotic signals. In addition, morin treatment significantly suppressed the growth of GC in vivo by upregulating BAD and the subsequent activation of its downstream apoptosis pathway. CONCLUSION Morin suppressed GC by inducing apoptosis, which was mainly due to blocking the ubiquitination-based degradation of the pro-apoptotic protein BAD. The combination of morin and the BCL-2 inhibitor ABT-737 synergistically amplified apoptotic signals in GC cells, which may overcome the drug resistance of the BCL-2 inhibitor. These findings indicated that morin was a potent and promising agent for GC treatment. Please cite this article as: Wang Y, Sun XY, Ma FQ, Ren MM, Zhao RH, Qin MM, Zhu XH, Xu Y, Cao ND, Chen YY, Dong TG, Pan YF, Zhao AG. Morin inhibits ubiquitination degradation of BCL-2 associated agonist of cell death and synergizes with BCL-2 inhibitor in gastric cancer cells. J Integr Med. 2025; 23(3): 320-332.
Humans ; Flavonoids/therapeutic use* ; Stomach Neoplasms/pathology* ; Animals ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Cell Line, Tumor ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Ubiquitination/drug effects* ; Mice ; Drug Synergism ; Mice, Inbred BALB C ; Mice, Nude ; Xenograft Model Antitumor Assays ; Flavones

OBJECTIVE: Psoriasis, a common chronic inflammatory skin condition with genetic underpinnings, is traditionally managed with cupping therapy. Although used historically, the precise mechanical effects and therapeutic mechanisms of cupping in psoriasis remain largely unexamined. This study aimed to evaluate cupping therapy's efficacy for psoriasis and investigate its role in modulating inflammatory responses and cellular metabolism. METHODS: Psoriasis was induced in mice using topical imiquimod (IMQ). The effects of cupping on psoriatic lesions were assessed using the Psoriasis Area and Severity Index score, histology, immunohistochemistry, and immunofluorescence staining. polymerase chain reaction sequencing (RNA-seq) and Western blotting were conducted to examine changes in mRNA expression and the AMP-activated protein kinase (AMPK) signaling pathway. RESULTS: Cupping therapy significantly reduced inflammation, epidermal thickness, and inflammatory cell infiltration in mice with IMQ-induced psoriasis. Immunohistochemistry and immunofluorescence showed lower expression of inflammatory markers and a shift in T-cell populations. RNA-seq and Western blotting indicated that cupping upregulated Piezo1 and activated the AMPK pathway, improving energy metabolism in psoriatic skin. CONCLUSION Cupping therapy reduces epidermal hyperproliferation and inflammation in psoriasis, rebalancing the local immune microenvironment. Mechanistically, cupping promotes calcium influx via Piezo1, activates AMPK signaling, and supports metabolic homeostasis, suggesting therapeutic potential for psoriasis. Please cite this article as: Xi RF, Liu X, Wang Y, Lu HZ, Yuan SJ, Guo DJ, Zhu JY, Li FL, Duan YJ. Mechanosensory activation of Piezo1 via cupping therapy: Harnessing neural networks to modulate AMPK pathway for metabolic restoration in a mouse model of psoriasis. J Integr Med. 2025; 23(6):721-732.
Animals ; Psoriasis/chemically induced* ; Mice ; AMP-Activated Protein Kinases/metabolism* ; Disease Models, Animal ; Cupping Therapy/methods* ; Signal Transduction ; Imiquimod ; Ion Channels/genetics* ; Male ; Mechanotransduction, Cellular

Cervical spinal cord injury without fracture-dislocation (CSCIWFD) is referred to as a special type of cervical spinal cord injury characterized by traumatic spinal cord dysfunction and no significant bony structural abnormalities on imagines. Duo to the high risk of missed diagnosis during the initial consultation, CSCIWFD may lead to progressive neurological deterioration or even complete paralysis, severely impacting patients′ prognosis. Currently, there are no established consensuses over the diagnosis and treatment of CSCIWFD, such as the lack of evidence-based standards for indications of non-surgical treatment and risk of secondary neurological injury, as well as debates over the optimal timing for surgical intervention and indications for different surgical approaches. To address these issues, the Spine Trauma Group of the Orthopedic Branch of the Chinese Medical Doctor Association organized experts in the relevant fields to formulate Diagnosis and treatment guideline for acute cervical spinal cord injury without fracture- dislocation in adults ( version 2025) . Based on evidence-based medicine and the principles of scientific rigor and clinical applicability, the guidelines proposed 11 recommendations covering terminology, diagnosis, evaluation treatment, and rehabilitation, etc., aiming to standardize the management of CSCIWFD.

Thoracolumbar spine fracture often leads to severe pain, functional impairments, and neurological deficits, for which open reduction and internal fixation can effectively restore the spinal structural stability. Open decompression and reduction with internal fixation can help relieve spinal cord compression and improve spinal function in cases of concomitant cord injury. Although spinal stability can be restored through surgery, patients often face chronic pain and functional impairments postoperatively. A postoperative rehabilitation program is critical in optimizing therapeutic outcomes, reducing complications, and minimizing the risk of secondary injuries. However, current rehabilitation methods, such as physical therapy, functional training, and pain management, are confronted with problems in clinical practice, including significant variation in efficacy, poor patient adherence, and prolonged rehabilitation period. There is an urgent need for a unified rehabilitation strategy to address these problems. To this end, the Spinal Trauma Group of the Orthopedic Physicians Branch of the Chinese Medical Association and the Spine Health Professional Committee of the Chinese Human Health Technology Promotion Association organized experts from relevant fields to formulate Evidence-based guidelines for rehabilitation treatment after internal fixation of thoracolumbar spine fracture in adults ( version 2025) by integrating evidences from clinical researches and advanced rehabilitation concepts at home and abroad. A total number of 14 recommendations concerning the rehabilitation treatment with multimodal analgesia, psychological intervention, deep vein thrombosis prevention, core muscle and extremity exercise, appropriate use of braces, early weight-bearing, device-aided rehabilitation exercise, neuroregulatory therapy, rehabilitation team were put forward, aiming to standardize the post-operative rehabilitation process following internal fixation, promote the functional recovery, and enhance patients′ quality of life.

Objective To explore the protective effects of genetically modified porcine erythrocyte suspension as a subnormothermic normoxic mechanical perfusate on hypoxic-ischemic brain injury in cynomolgus monkeys caused by traumatic hemorrhage.Methods Cynomolgus monkeys were randomly divided into positive and negative control groups(a total of 3 monkeys,with 3 left cerebral hemispheres as the positive control group and 3 right cerebral hemispheres as the negative control group)and the subnormothermic perfusion group(n=3).The positive control group was directly sampled 1 hour after circulatory arrest,while the negative control group was placed at subnormothermic conditions for 6 hours after circulatory arrest.The subnormothermic perfusion group underwent 6 hours of subnormothermic normoxic mechanical perfusion of the bilateral common carotid arteries of the cynomolgus monkey hypoxic-ischemic brain injury model using genetically modified porcine erythrocyte suspension 1 hour after circulatory arrest.Before perfusion,cross-matching experiments were conducted between the six genetically modified pig and the cynomolgus monkeys.After the start of perfusion,the levels of routine blood indicators in the perfusate were detected at 0,1,2,3,4,5 and 6 hours.Blood oxygen saturation was recorded,and the levels of Na+,K+,Ca2+,glucose and blood pH in the perfusate were measured,as well as the levels of IgG and IgM in the perfusate.After 6 hours of perfusion,the water content of the brain tissue was measured.Nissl staining was performed on the frontal cortex and hippocampal regions,and immunofluorescence staining was used to detect the expression of glial fibrillary acidic protein(GFAP),ionized calcium-binding adapter molecule 1(Iba1)and neuronal nuclear antigen(NEUN).Results The cross-matching results between the six genetically modified pig and the cynomolgus monkeys were negative.The number of red blood cells in the perfusate decreased significantly at 3 hours of perfusion,and the hemoglobin level showed a downward trend at 1,3,5 and 6 hours.The number of white blood cells and platelets decreased at all time points.The blood oxygen saturation in the subnormothermic perfusion group remained stable at 95%-98%,and the levels of blood oxygen saturation,Na+,Ca2+,glucose and pH were stable,while the K+level first increased and then decreased.There was no significant difference in the levels of IgG and IgM before and after perfusion.The water content of brain tissue at the end of perfusion in the subnormothermic perfusion group was significantly higher than that in the positive control group(P<0.001).Nissl staining results showed that compared with the positive control group,the pyramidal neurons in the prefrontal cortex of the subnormothermic perfusion group maintained better morphological integrity,with no significant increase in enlarged and deformed cells.In the hippocampal CA1 region,there was a slight increase in enlarged and deformed cells,and a few cells with undamaged structures showed reduced cell size.In the hippocampal dentate gyrus,fewer granule neurons had compromised structural integrity,with increased cell edema.NEUN immunofluorescence staining showed that compared with the positive control group,the pyramidal neurons in the prefrontal cortex and hippocampal CA1 region of the subnormothermic perfusion group had better morphological states,with clear axons.The granule cells in the hippocampal dentate gyrus were well preserved,but the nuclei were less well protected.GFAP immunofluorescence staining showed that compared with the positive control group,the subnormothermic perfusion group had sparser protrusions that were more tightly associated with neurons.Iba1 immunofluorescence staining showed that compared with the positive control group,the subnormothermic perfusion group had thicker and fewer protrusions.Conclusions Compared with the positive control group,subnormothermic normoxic mechanical perfusion with genetically modified porcine erythrocyte perfusate increases brain tissue edema in cynomolgus monkeys,but better preserves the morphological integrity of neurons and glial cells.The protective effects may be related to the continuous oxygen and energy supply,maintenance of ion homeostasis and perfusate pH,reduced rejection,and low metabolic state of the whole brain.

ObjectiveTo explore the molecular mechanism by which gypenoside L （Gyp-L） promotes apoptosis and inhibits ovarian cancer （OC） through the FK506-binding protein （FKBP） prolyl isomerase 8 （FKBP8）/B-cell lymphoma-2 （Bcl-2） axis， with the piR-hsa-2804461 pathway as a breakthrough point. MethodsThe effects of different concentrations of Gyp-L and cis-platinum on the proliferation of OVCAR3 cells were determined by the cell count kit-8 method to identify the appropriate intervention concentration for subsequent experiments. OVCAR3 cells were allocated into blank， low-dose Gyp-L （Gyp-L-L， 50 µmol·L^-1）， high-dose Gyp-L （Gyp-L-H， 100 µmol·L^-1）， and cis-platinum （15 µmol·L^-1） groups. The migration， colony formation， and apoptosis of OVCAR3 cells were detected by the cell scratch assay， colony formation assay， and flow cytometry， respectively. The mRNA levels of piR-hsa-2804461 and FKBP8/Bcl-2 axis-related genes in OVCAR3 cells were determined by Real-time PCR， and the expression levels of FKBP8/Bcl-2 axis-related proteins were determined by simple Western blot. Further， an OVCAR3 cell model with piR-hsa-2804461 knocked out was constructed. The cells were allocated into blank， NC-inhibitor， inhibitor， NC-inhibitor+Gyp-L， and inhibitor+Gyp-L groups. The colony formation of OVCAR3 cells was detected by the colony formation assay. The mRNA levels of piR-hsa-2804461 and FKBP8/Bcl-2 axis-related genes and the expression levels of FKBP8/Bcl-2 axis-related proteins were determined by Real-time PCR and simple Western blotting， respectively. ResultsGyp-L inhibited the migration and proliferation （P<0.01）， promoted the apoptosis （P<0.05）， up-regulated the mRNA level of piR-hsa-2804461 （P<0.05）， and down-regulated the mRNA and protein levels of FKBP8 and Bcl-2 （P<0.05） in OVCAR3 cells. Furthermore， Gyp-L increased the mRNA and protein levels of Bcl-2-associated X protein （Bax）， cysteinyl aspartate-specific proteinase （Caspase）-3， and Caspase-9， which are related to the FKBP8/Bcl-2 axis （P<0.05）. ConclusionGyp-L may promote apoptosis by regulating the piR-hsa-2804461/FKBP8/Bcl-2 axis， thus affecting the occurrence of ovarian cancer.

ObjectiveTo explore the molecular mechanism of gypenoside L （Gyp-L） in the treatment of ovarian cancer （OC） by taking the glycolytic pathway of OC as the key point. MethodsThe proliferation activity of OVCAR3 cells was measured by the cell counting kit-8 （CCK-8） assay to determine the appropriate intervention concentration for subsequent experiments. The cell clone formation assay and the scratch healing assay were employed to assess the proliferation and migration capabilities of OVCAR3 cells. OVCAR3 cells were divided into a blank group， a Gyp-L-L group （low concentration of Gyp-L， 50 µmol·L^-1）， a Gyp-L-H group （high concentration of Gyp-L， 100 µmol·L^-1）， and a cisplatin （15 µmol·L^-1） group. The glucose consumption in OC cells was determined using a kit， and the expression levels of related mRNAs in OVCAR3 cells were detected by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. The expressions of related proteins were detected by Wes automatic Western blot quantitative analysis. ResultsValidated by the cell scratch assay， the scratch healing rate of OVCAR3 cells was decreased after Gyp-L intervention， reflecting that Gyp-L could significantly inhibit the migration of OVCAR3 cells （P<0.05）. According to the clone formation assay， the cell colony formation ability of the Gyp-L-L group， Gyp-L-H group， and cisplatin group was significantly lower than that of the control group （P<0.05）. In OVCAR3 cells， compared with those in the control group， the levels of glucose consumption and lactate generation in the Gyp-L-L group and Gyp-L-H group were significantly reduced （P<0.05）， indicating that Gyp-L could effectively inhibit the glycolysis level of OC cells. Meanwhile， Gyp-L could suppress the expression levels of glucokinase （GCK）， phosphofructokinase liver （PFKL）， signal transducer and activator of transcription 3 （STAT3）， lactate dehydrogenase D （LDHD）， phosphoglycerate mutase 1 （PGAM1）， mRNAs， and proteins related to the glycolytic pathway in OC cells. ConclusionGyp-L may inhibit the occurrence and development of OC by influencing the GCK-mediated glycolytic pathway.