This study compared the differences in intestinal absorption characteristics of eleven active components in Rubus multibracteatus(RM) extract(protocatechuic acid, tiliroside, scutellarin, luteoloside, astragalin, epicatechin, catechin, xanthotoxin, p-coumaric acid, caffeic acid, and apigenin-7-O-glucuronide) between normal rats and inflammatory pain model rats using the in-vitro everted intestinal sac model. The RM extract was administered at absorption concentrations of 25.0, 50.0, and 100.0 mg·mL~(-1). The contents of the eleven components in intestinal absorption solution samples were quantified by ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS), and their cumulative absorption(Q) and absorption rate constant(K_a) were calculated to evaluate the absorption characteristics of these components in normal rats and inflammatory pain model rats. The results show that except for catechin, epicatechin, and caffeic acid, the cumulative absorption-time curves of the other eight components(protocatechuic acid, tiliroside, scutellarin, luteoloside, astragalin, xanthotoxin, p-coumaric acid, and apigenin-7-O-glucuronide) exhibit an upward trend without saturation, with correlation coefficients(R~2) all > 0.9, indicating linear absorption. However, the overall absorption of all components is not dose-dependent with increasing concentration, suggesting that their absorption mechanisms are not solely passive diffusion. In both normal and model rats, the jejunum shows the highest absorption for all components except xanthotoxin. The overall absorption of seven components(excluding protocatechuic acid, caffeic acid, apigenin-7-O-glucuronide, and luteoloside) in normal rats is better than that in model rats across all intestinal segments. These findings indicate that the pathological state of inflammatory pain alters the intestinal absorption of RM extract, and its mechanism needs further investigation.
Animals ; Rats ; Intestinal Absorption/drug effects* ; Male ; Rats, Sprague-Dawley ; Drugs, Chinese Herbal/metabolism* ; Disease Models, Animal ; Pain/metabolism* ; Intestines/drug effects* ; Intestinal Mucosa/metabolism*

Triple-negative breast cancer is therapeutically challenging due to the low expression of tumor markers and 'cold' tumor immunosuppressive microenvironment. Here, we present a dual-targeting peptide-drug conjugate (PDC) for tumor inhibition. Our PDC efficiently and selectively delivers cytotoxic Monomethyl Auristatin E (MMAE) into tumor cells via C-X-C chemokine receptor type 4 (CXCR4) and folate receptor 1 (FOLR1) for synergistic inhibition of growth and metastasis. Our results show that the dual-targeting PDC has potent antitumor activity in cultured human cells and several murine transplanted tumor models without apparent toxicity. The combination of dual-targeting PDC and radiotherapy modulates the tumor immunosuppressive microenvironment by increasing CD8⁺ T cell infiltration and attenuating the proportion of myeloid-derived suppressor and regulatory T cells. Therefore, our dual-targeting PDC represents a promising new strategy for cancer therapy that rebalances the immune system and promotes tumor regression.

Osteoarthritis (OA), the most prevalent joint disease of late life, is closely linked to cellular senescence. Previously, we found that the senescence of fibroblast-like synoviocytes (FLS) played an essential role in the degradation of cartilage. In this work, single-cell sequencing data further demonstrated that cartilage acidic protein 1 (CRTAC1) is a critical secreted factor of senescent FLS, which suppresses mitophagy and induces mitochondrial dysfunction by regulating SIRT3 expression. In vivo, deletion of SIRT3 in chondrocytes accelerated cartilage degradation and aggravated the progression of OA. Oppositely, intra-articular injection of adeno-associated virus expressing SIRT3 effectively alleviated OA progression in mice. Mechanistically, we demonstrated that elevated CRTAC1 could bind with NRF2 in chondrocytes, which subsequently suppresses the transcription of SIRT3 in vitro. In addition, SIRT3 reduction could promote the acetylation of FOXO3a and result in mitochondrial dysfunction, which finally contributes to the degradation of chondrocytes. To conclude, this work revealed the critical role and underlying mechanism of senescent FLSs-derived CRTAC1 in OA progression, which provided a potential strategy for the OA therapy.

Approximately 30%-40% of epilepsy patients do not respond well to adequate anti-seizure medications (ASMs), a condition known as pharmacoresistant epilepsy. The management of pharmacoresistant epilepsy remains an intractable issue in the clinic. Its early prediction is important for prevention and diagnosis. However, it still lacks effective predictors and approaches. Here, a classical model of pharmacoresistant temporal lobe epilepsy (TLE) was established to screen pharmacoresistant and pharmaco-responsive individuals by applying phenytoin to amygdaloid-kindled rats. Ictal electroencephalograms (EEGs) recorded before phenytoin treatment were analyzed. Based on ictal EEGs from pharmacoresistant and pharmaco-responsive rats, a convolutional neural network predictive model was constructed to predict pharmacoresistance, and achieved 78% prediction accuracy. We further found the ictal EEGs from pharmacoresistant rats have a lower gamma-band power, which was verified in seizure EEGs from pharmacoresistant TLE patients. Prospectively, therapies targeting the subiculum in those predicted as "pharmacoresistant" individual rats significantly reduced the subsequent occurrence of pharmacoresistance. These results demonstrate a new methodology to predict whether TLE individuals become resistant to ASMs in a classic pharmacoresistant TLE model. This may be of translational importance for the precise management of pharmacoresistant TLE.
Epilepsy, Temporal Lobe/diagnosis* ; Animals ; Drug Resistant Epilepsy/drug therapy* ; Electroencephalography/methods* ; Rats ; Anticonvulsants/pharmacology* ; Neural Networks, Computer ; Male ; Humans ; Phenytoin/pharmacology* ; Adult ; Disease Models, Animal ; Female ; Rats, Sprague-Dawley ; Young Adult ; Convolutional Neural Networks

Effective axon regeneration is essential for the successful restoration of nerve functions in patients suffering from axon injury-associated neurological diseases. Certain self-regeneration occurs in injured peripheral axonal branches of dorsal root ganglion (DRG) neurons but does not occur in their central axonal branches. By performing rat sciatic nerve or dorsal root axotomy, we determined the expression of the dysbindin domain containing 2 (DBNDD2) in the DRGs after the regenerative peripheral axon injury or the non-regenerative central axon injury, respectively, and found that DBNDD2 is down-regulated in the DRGs after peripheral axon injury but up-regulated after central axon injury. Furthermore, we found that DBNDD2 expression differs in neonatal and adult rat DRGs and is gradually increased during development. Functional analysis through DBNDD2 knockdown revealed that silencing DBNDD2 promotes the outgrowth of neurites in both neonatal and adult rat DRG neurons and stimulates robust axon regeneration in adult rats after sciatic nerve crush injury. Bioinformatic analysis data showed that transcription factor estrogen receptor 1 (ESR1) interacts with DBNDD2, exhibits a similar expression trend as DBNDD2 after axon injury, and may targets DBDNN2. These studies indicate that reduced level of DBNDD2 after peripheral axon injury and low abundance of DBNDD2 in neonates contribute to axon regeneration and thus suggest the manipulation of DBNDD2 expression as a promising therapeutic approach for improving recovery after axon damage.
Animals ; Ganglia, Spinal/metabolism* ; Nerve Regeneration/genetics* ; Rats ; Axons/metabolism* ; Sciatic Nerve/injuries* ; Rats, Sprague-Dawley ; Male

Objective To evaluate the efficacy of transfrontal neuroendoscopic surgery in the treatment of chronic subdural hematoma.Methods Analysis of clinical data of 80 cases of chronic subdural hematoma.According to the surgical method,40 cases were divided into traditional external drainage of parietaltuber,40 cases were divided into transfrontal neuroendoscopic small bone window hematoma removal.The treatment efficiency,hematoma recurrence rate,operation time and intraoperative blood loss were compared between the two groups.Results Treatment efficiency of neuroendoscopic group was 95.0%,significantly higher than drainage group 75.0%,hematoma recurrence rate one month after surgery of neuroendoscopic group was 5.0%,significantly lower than that in drainage group 25.0%,operation time of neuroendoscopic group was(54.1±7.5)min,longer than that of drainage group(40.7±9.4)min,the differences were statistically significant(P<0.05).The intraoperative blood loss of neuroendoscopic group was(30.1±4.5)mL,compared with(27.1±6.4)mL in the drainage group,the difference was not statistically significant(P>0.05).Conclusion Transfrontal neuroendoscopic surgery can significantly improve the efficacy of chronic subdural hematoma,and hematoma recurrence rate is extremely low.It is worthy of clinical application.

Objective Air pollution is a leading public health issue.This study investigated the effect of air quality and pollutants on pulmonary function and inflammation in patients with asthma in Shanghai. Methods The study monitored 27 asthma outpatients for a year,collecting data on weather,patient self-management[daily asthma diary,peak expiratory flow(PEF)monitoring,medication usage],spirometry and serum markers.To explore the potential mechanisms of any effects,asthmatic mice induced by ovalbumin(OVA)were exposed to PM2.5. Results Statistical and correlational analyses revealed that air pollutants have both acute and chronic effects on asthma.Acute exposure showed a correlation between PEF and levels of ozone(O3)and nitrogen dioxide(NO2).Chronic exposure indicated that interleukin-5(IL-5)and interleukin-13(IL-13)levels correlated with PM2.5 and PM10 concentrations.In asthmatic mouse models,exposure to PM2.5 increased cytokine levels and worsened lung function.Additionally,PM2.5 exposure inhibited cell proliferation by blocking the NF-κB and ERK phosphorylation pathways. Conclusion Ambient air pollutants exacerbate asthma by worsening lung function and enhancing Th2-mediated inflammation.Specifically,PM2.5 significantly contributes to these adverse effects.Further research is needed to elucidate the mechanisms by which PM2.5 impacts asthma.

Programmed cell death 1 ligand 1 (PD-L1) is an important immunosuppressive molecule, which inhibits the function of T cells and other immune cells by binding to the receptor programmed cell death-1. The PD-L1 expression disorder plays an important role in the occurrence, development, and treatment of sepsis or other inflammatory diseases, and has become an important target for the treatment of these diseases. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells with multiple differentiation potential. In recent years, MSCs have been found to have a strong immunosuppressive ability and are used to treat various inflammatory insults caused by hyperimmune diseases. Moreover, PD-L1 is deeply involved in the immunosuppressive events of MSCs and plays an important role in the treatment of various diseases. In this review, we will summarize the main regulatory mechanism of PD-L1 expression, and discuss various biological functions of PD-L1 in the immune regulation of MSCs.

Cryoablation therapy with explicit anti-tumor mechanisms and histopathological manifestations has a long history.A large number of clinical practice has shown that cryoablation therapy is safe and effective,making it an ideal tumor treatment method in theory.Previously,its efficacy and clinical application were constrained by the limitations of refrigerants and refrigeration equipment.With the development of the new generation of cryoablation equipment represented by argon helium knives,significant progress has been made in refrigeration efficien-cy,ablation range,and precise temperature measurement,greatly promoting the progression of tumor cryoablation technology.This consensus systematically summarizes the mechanism of cryoablation technology,indications for oral mucosal melanoma(OMM)cryotherapy,clinical treatment process,adverse reactions and management,cryotherapy combination therapy,etc.,aiming to provide reference for carrying out the standardized cryoablation therapy of OMM.

Objective:To investigate the safety and short-term efficacy of yttrium-90 [ 90Y] resin microspheres transarterial radioembolization (TARE) for the treatment of initial unresectable malignant hepatic tumor. Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 10 patients with initial unresectable malignant hepatic tumor who were admitted to The First Affiliated Hospital of Army Medical University from June 2022 to June 2023 were collected. All patients were males, aged (57±4)years. Measurement data with normal distribution were represented as Mean± SD, and comparison before and after treatment within the group was conducted using the paired t test. Measurement data with skewed distribution were represented as M( Q1, Q3) or M(range), and comparison before and after treatment within the group was conducted using the paired rank sum test. Count data were described as absolute numbers or proportions. Results:(1) Pre-treatment assessment. All 10 patients completed pre-treatment assessment, with 8 cases undergoing once of technetium 99-polymerised protein perfusion test and 2 cases under-going ≥ twice of technetium 99-polymerised protein perfusion test. The ratio of uptake of techne-tium 99-polymerised protein in tumor tissue to normal tissue, the hepatopulmonary shunting ratio and the therapeutic requirement of 90Y resin microspheres in 10 patients were 5.8±1.2, 4.8%±0.8% and (1.10±0.20)GBq, respectively. (2) Treatment strategy of 90Y resin microspheres TARE. Of the 10 patients, cases treated with whole tumor radioembolisation, radioembolisation of the main target lesion+non-target lesion radiofrequency ablation, radioembolisation of the main target lesion+non-target lesion iodine-125 particles implantation, radioembolisation of the liver lobe or liver segment were 6, 2, 1, 1, respectively. During the treatment period, one elderly case did not receive target therapy combined with immunotherapy due to intolerance, and the remaining 9 cases received target therapy combined with immunotherapy. Of the 10 patients, there were 7 cases receiving once of 90Y resin microspheres TARE, and 3 cases receiving twice of 90Y resin microspheres TARE. (3) Follow-up. All 10 patients were followed up for 4.5(range, 3.0-12.0)months. During the follow-up, none of patient had adverse event associated with 90Y resin microspheres TARE. The tumor diameter, alpha-fetoprotein (AFP), abnormal prothrombin, alanine aminotransferase (ALT), aspartate amino-transferase (AST), albumin (Alb), total bilirubin (TBiL), glutamyltransferase (GGT) of the 10 patients were 96(72,135)mm, 26(6,833)μg/L, 290(56,2 997)Au/L, (36±13)IU/L, (41+16)IU/L, (40±4)g/L, (15.3±4.1)μmol/L, (99±68)IU/L before receiving 90Y microspheres TARE. The above indicators of the 10 patients were 63(43,97)mm, 4(3,357)μg/L, 38(25, 142) Au/L, (40±16)IU/L, (51±28)IU/L, (39±4)g/L, (14.4±1.2) μmol/L, (134±93)IU/L after 90 days of receiving 90Y microspheres TARE. There were significant differences in tumor diameter and abnormal prothrombin ( Z=-2.08, -2.24, P<0.05) and there was no significant difference in AFP, ALT, AST, Alb, TBil, GGT ( Z=-1.27, t=0.63, 1.69, 1.73, 0.67, 1.30, P>0.05). During the follow-up period, 5 cases achieved clinical complete response, 4 cases achieved clinical partial remission, and 1 case experienced non-target lesion progression within 30 days after receiving 90Y resin microspheres TARE. The disease remission rate and disease control rate of the 10 patients were 9/10 and 9/10, respectively. None of patient died during follow-up period. Conclusion:90Y resin microspheres TARE for the treatment of initial unresectable malignant hepatic tumor is safe and feasible, and can achieve satisfactory short-term efficacy when combined with other treatment methods.