Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

Acupuncture, a therapeutic treatment defined as the insertion of needles into the body at specific points (ie, acupoints), has growing in popularity world-wide to treat various diseases effectively, especially acute and chronic pain. In parallel, interest in the physiological mechanisms underlying acupuncture analgesia, particularly the neural mechanisms have been increasing. Over the past decades, our understanding of how the central nervous system and peripheral nervous system process signals induced by acupuncture has developed rapidly by using electrophysiological methods. However, with the development of neuroscience, electrophysiology is being challenged by calcium imaging in view field, neuron population and visualization in vivo. Owing to the outstanding spatial resolution, the novel imaging approaches provide opportunities to enrich our knowledge about the neurophysiological mechanisms of acupuncture analgesia at subcellular, cellular, and circuit levels in combination with new labeling, genetic and circuit tracing techniques. Therefore, this review will introduce the principle and the method of calcium imaging applied to acupuncture research. We will also review the current findings in pain research using calcium imaging from in vitro to in vivo experiments and discuss the potential methodological considerations in studying acupuncture analgesia.
Calcium ; Acupuncture Therapy ; Acupuncture ; Acupuncture Analgesia/methods* ; Acupuncture Points ; Technology

Objective:To explore the effects of Liuwei Dihuang Wan on the behaviors and Toll-like receptor 4/nuclear factor kappa-B(TLR4/NF-κB) signal transduction pathway of amyloid β-precursor protein/presenilin-1(APP/PS1) double transgenic mice.Methods:Forty 3-month-old female APP/PS1 mice were randomly divided into model group, low-dose group(0.59 g/kg), medium-dose group(1.18 g/kg), high-dose group(2.36 g/kg)of Liuwei Dihuang Wan(gavaged according to grouped doses), and ibuprofen group(0.04 g/kg, gavage) using a random number table method, with 8 mice in each group.Eight 3-month-old wild-type female C57BL/6 mice with matched body weight were used as the control group.The mice in control group and model group were given an equal volume of 0.9% sodium chloride solution by gavage.The gavage administration was twice a day for a continuous period of 3 months.Morris water maze test was used to detect the learning and memory abilities of mice. ELISA was used to detect the serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β(IL-1β) and immunohistochemistry was used to detect the levels of amyloid β-protein (Aβ), glial fibrillary acidic protein(GFAP) and NF-κB in hippocampal tissue.Western blot was used to detect the expression levels of TLR4, myeloid differentiation primary response gene 88(MyD88), and phosphorylated NF-κB(p-NF-κB) proteins in hippocampal tissue.The SPSS 20.0 software was used for data analysis. Multiple group comparisons were conducted by repeated measure ANOVA or one-way ANOVA.Results:The results of repeated measure ANOVA showed that as for the escape latency of the 6 groups of mice, the interaction effect between time and group was significant ( Finteraction=117.219, P<0.001). The escape latencies of mice in the 6 groups on the 5th day were all lower than those on the 1st day (all P<0.05). The escape latencies of mice in the ibuprofen group and the medium-dose and high-dose groups of Liuwei Dihuang Wan were lower than that in the model group from 1st day to 5th day(all P<0.05). On the 3rd to 5th day, the escape latencies of mice in the medium-dose and high-dose groups of Liuwei Dihuang Wan were lower than those in the low-dose group of Liuwei Dihuang Wan (all P<0.05). There were statistically significant differences in the percentage of residence time in the platform quadrant and the numbers of crossing platform among the 6 groups of mice ( F=5.451, 4.824, both P<0.05). The percentage of residence time in the platform quadrant (50.77±5.49)%, (54.39±5.71)%, (51.98±6.12)%), and the numbers of crossing platform((5.9±1.1) times, (6.0±1.3) times, (5.1±0.8) times) in the high-dose and medium-dose groups of Liuwei Dihuang Wan and the ibuprofen group were all higher than those in the model group ((27.32±3.22)%, (2.2±1.0) times )(all P<0.05). The immunohistochemical results showed that there were statistically significant differences in the integrated optical density values of Aβ, GFAP and NF-κB in the hippocampal tissues of 6 groups of mice ( F=57.52, 45.37, 79.10, all P<0.05). The integrated optical density values of Aβ, GFAP and NF-κB in the high-dose and medium-dose groups of Liuwei Dihuang Wan and the ibuprofen group were all lower than those in the model group (all P<0.05). And the integrated optical density values of Aβ, GFAP, and NF-κB in the high-dose and medium-dose groups of Liuwei Dihuang Wan were all lower than those in the low-dose group of Liuwei Dihuang Wan (all P<0.05). There were statistically significant differences in the levels of serum TNF-α and IL-1β detected by ELISA ( F=3.996, 6.395, both P<0.05) and the proteins levels of TLR4, MyD88, and p-NF-κB in hippocampal tissue detected by Western blot among the 6 groups( F=15.710, 3.522, 4.119, all P<0.05). The serum TNF-α and IL-1β levels in the high-dose and medium-dose groups of Liuwei Dihuang Wan and ibuprofen group were all lower than those in the model group (all P<0.05). The serum TNF-α ((18.90±2.33) ng/L, (21.56±2.49) ng/L) and IL-1β ((5.88±0.80) ng/L, (6.75±0.83) ng/L) levels in the high-dose and medium-dose groups of Liuwei Dihuang Wan were lower than those in the low-dose group ((30.77±2.89) ng/L, (9.11±1.27) ng/L) (all P<0.05). The protein expression levels of TLR4, MyD88, and p-NF-κB in the hippocampus of the high-dose and medium-dose groups of Liuwei Dihuang Wan and ibuprofen group were lower than those of the model group (all P<0.05). The protein expression levels of TLR4 ((0.254±0.091), (0.318±0.122)), MyD88 ((0.229±0.077), (0.386±0.119)), and p-NF-κB ((0.412±0.188), (0.358±0.119)) in the hippocampus of the high-dose and medium-dose groups of Liuwei Dihuang Wan were lower than those of the low-dose group ((0.617±0.172), (0.672±0.166), (0.799±0.227)) (all P<0.05). Conclusion:Liuwei Dihuang Wan can significantly alleviate learning and memory impairment in Alzheimer's disease model mice, possibly by inhibiting TLR4/NF-κB signal pathway, reducing TNF-α and IL-1β expression, thereby alleviate central immune inflammatory response and exert anti Alzheimer's disease effects.

Objective:To investigate the current status of endoscopic treatment for gastroesophageal varices in portal hypertension in China, and to provide supporting data and reference for the development of endoscopic treatment.Methods:In this study, initiated by the Liver Health Consortium in China (CHESS), a questionnaire was designed and distributed online to investigate the basic condition of endoscopic treatment for gastroesophageal varices in portal hypertension in 2022 in China. Questions included annual number and indication of endoscopic procedures, adherence to guideline for preventing esophagogastric variceal bleeding (EGVB), management and timing of emergent EGVB, management of gastric and isolated varices, and improvement of endoscopic treatment. Proportions of hospitals concerning therapeutic choices to all participant hospitals were calculated. Guideline adherence between secondary and tertiary hospitals were compared by using Chi-square test.Results:A total of 836 hospitals from 31 provinces (anotomous regions and municipalities) participated in the survey. According to the survey, the control of acute EGVB (49.3%, 412/836) and the prevention of recurrent bleeding (38.3%, 320/836) were major indications of endoscopic treatment. For primary [non-selective β-blocker (NSBB) or endoscopic therapies] and secondary prophylaxis (NSBB and endoscopic therapies) of EGVB, adherence to domestic guideline was 72.5% (606/836) and 39.2% (328/836), respectively. There were significant differences in the adherence between secondary and tertiary hospitals in primary prophylaxis of EGVB [71.0% (495/697) VS 79.9% (111/139), χ2=4.11, P=0.033] and secondary prophylaxis of EGVB [41.6% (290/697) VS 27.3% (38/139), χ2=9.31, P=0.002]. A total of 78.2% (654/836) hospitals preferred endoscopic therapies treating acute EGVB, and endoscopic therapy was more likely to be the first choice for treating acute EGVB in tertiary hospitals (82.6%, 576/697) than secondary hospitals [56.1% (78/139), χ2=46.33, P<0.001]. The optimal timing was usually within 12 hours (48.5%, 317/654) and 12-24 hours (36.9%, 241/654) after the bleeding. Regarding the management of gastroesophageal varices type 2 and isolated gastric varices type 1, most hospitals used cyanoacrylate injection in combination with sclerotherapy [48.2% (403/836) and 29.9% (250/836), respectively], but substantial proportions of hospitals preferred clip-assisted therapies [12.4% (104/836) and 26.4% (221/836), respectively]. Improving the skills of endoscopic doctors (84.2%, 704/836), and enhancing the precision of pre-procedure evaluation and quality of multidisciplinary team (78.9%, 660/836) were considered urgent needs in the development of endoscopic treatment. Conclusion:A variety of endoscopic treatments for gastroesophageal varices in portal hypertension are implemented nationwide. Participant hospitals are active to perform emergent endoscopy for acute EGVB, but are inadequate in following recommendations regarding primary and secondary prophylaxis of EGVB. Moreover, the selection of endoscopic procedures for gastric varices differs greatly among hospitals.

ObjectiveGastric cancer (GC) seriously affects human health and life, and research has shown that it is closely related to the serine/glycine metabolism. The proliferation ability of tumor cells is greatly influenced by the metabolism of serine and glycine. The aim of this study was to investigate the molecular mechanism of serine/glycine metabolism can affect the proliferation of gastric cancer cells. MethodsIn this work, a stable metabolic dynamic model of gastric cancer cells was established via a large-scale metabolic network dynamic modeling method in terms of a potential landscape description of stochastic and non-gradient systems. Based on the regulation of the model, a quantitative analysis was conducted to investigate the dynamic mechanism of serine/glycine metabolism affecting the proliferation of gastric cancer cells. We introduced random noise to the kinetic equations of the general metabolic network, and applied stochastic kinetic decomposition to obtain the Lyapunov function of the metabolic network parameter space. A stable metabolic network was achieved by further reducing the change in the Lyapunov function tied to the stochastic fluctuations. ResultsDespite the unavailability of a large number of dynamic parameters, we were able to successfully construct a dynamic model for the metabolic network in gastric cancer cells. When extracellular serine is available, the model preferentially consumes serine. In addition, when the conversion rate of glycine to serine increases, the model significantly upregulates the steady-state fluxes of S-adenosylmethionine (SAM) and S-adenosyl homocysteine (SAH). ConclusionIn this paper, we provide evidence supporting the preferential uptake of serine by gastric cancer cells and the important role of serine/glycine conversion rate in SAM generation, which may affect the proliferation ability of gastric cancer cells by regulating the cellular methylation process. This provides a new idea and direction for targeted cancer therapy based on serine/glycine metabolism.

Objective To investigate the correlation between the level of N-terminal pro-Brain natriuretic peptide(NT-proBNP)and cardiorespiratory fitness following acute exposure to high altitude.Methods Forty-six subjects were recruited from the Second Affiliated Hospital of Army Medical University in June 2022,including 19 males and 27 females.After completing cardiopulmonary exercise test(CPET),serological detection of myocardial cell-related markers,and multiple metabolites at a plain altitude(300 meters above sea level),all subjects flew to a high-altitude location(3900 meters above sea level).Biomarker testing and CPET were repeated on the second and third days after arrival at high altitude.Changes in serum biomarker and key CPET indicators before and after rapid ascent to high altitude were compared,and the correlation between serum levels of various myocardial cell-related markers and metabolites and high altitude cardiorespiratory fitness was analyzed.Results Compared with the plain altitude,there was a significant decrease in maximal oxygen uptake after rapid ascent to high altitude[(25.41±6.20)ml/(kg.min)vs.(30.17±5.01)ml/(kg.min),P<0.001].Serum levels of NT-proBNP,Epinephrine(E),plasma renin activity(PRA),angiotensin Ⅱ(Ang Ⅱ),angiotensin-converting enzyme 2(ACE2)and leptin(LEP)significantly increased,with all differences being statistically significant(P<0.05)after acute high altitude exposure.In contrast,no statistically significant differences were observed for creatine kinase MB(CK-MB),cardiac troponin I(cTnI),myoglobin(Myo)and norepinephrine(NE)(P>0.05).Correlation analysis showed a significant negative correlation between NT-proBNP at plain altitude(r=-0.768,P<0.001)and at high altitude(r=-0.791,P<0.001)with maximal oxygen uptake at high altitude.Multivariate linear regression analysis indicated that maximal oxygen uptake at plain altitude(t=2.069,P=0.045),NT-proBNP at plain altitude(t=-2.436,P=0.020)and at high altitude(t=-3.578,P=0.001)were independent influencing factors of cardiorespiratory fitness at high altitude.Conclusion Cardiorespiratory fitness significantly decreases after rapid ascent to high altitude,and the baseline NT-proBNP level at plain altitude is closely related to cardiorespiratory fitness at high altitude,making it a potential predictor indicator for high altitude cardiorespiratory fitness.

Purpose::Cerebral edema (CE) is the main secondary injury following traumatic brain injury (TBI) caused by road traffic accidents (RTAs). It is challenging to be predicted timely. In this study, we aimed to develop a prediction model for CE by identifying its risk factors and comparing the timing of edema occurrence in TBI patients with varying levels of injuries.Methods::This case-control study included 218 patients with TBI caused by RTAs. The cohort was divided into CE and non-CE groups, according to CT results within 7 days. Demographic data, imaging data, and clinical data were collected and analyzed. Quantitative variables that follow normal distribution were presented as mean ± standard deviation, those that do not follow normal distribution were presented as median (Q 1, Q 3). Categorical variables were expressed as percentages. The Chi-square test and logistic regression analysis were used to identify risk factors for CE. Logistic curve fitting was performed to predict the time to secondary CE in TBI patients with different levels of injuries. The efficacy of the model was evaluated using the receiver operator characteristic curve. Results::According to the study, almost half (47.3%) of the patients were found to have CE. The risk factors associated with CE were bilateral frontal lobe contusion, unilateral frontal lobe contusion, cerebral contusion, subarachnoid hemorrhage, and abbreviated injury scale (AIS). The odds ratio values for these factors were 7.27 (95% confidence interval ( CI): 2.08 -25.42, p = 0.002), 2.85 (95% CI: 1.11 -7.31, p = 0.030), 2.62 (95% CI: 1.12 -6.13, p = 0.027), 2.44 (95% CI: 1.25 -4.76, p = 0.009), and 1.5 (95% CI: 1.10 -2.04, p = 0.009), respectively. We also observed that patients with mild/moderate TBI (AIS ≤ 3) had a 50% probability of developing CE 19.7 h after injury (χ 2= 13.82, adjusted R2 = 0.51), while patients with severe TBI (AIS > 3) developed CE after 12.5 h (χ 2= 18.48, adjusted R2 = 0.54). Finally, we conducted a receiver operator characteristic curve analysis of CE time, which showed an area under the curve of 0.744 and 0.672 for severe and mild/moderate TBI, respectively. Conclusion::Our study found that the onset of CE in individuals with TBI resulting from RTAs was correlated with the severity of the injury. Specifically, those with more severe injuries experienced an earlier onset of CE. These findings suggest that there is a critical time window for clinical intervention in cases of CE secondary to TBI.

AIM To investigate the renal protective effects of Shiwei Ruxiang Powder on gouty nephritis in rats based on mitophagy.METHODS Rats were randomly divided into the blank group,the model group,the low-dose,medium-dose,and high-dose Shiwei Ruxiang Powder groups(200,400,800 mg/kg)and allopurinol group(10 mg/kg).The rat model of gouty nephropathy was established by gavage of potassium oxyzinate(750 mg/kg)and uric acid(300 mg/kg).The rats had their levels of UA,SCr,BUN,XOD,SOD,MDA,ROS measured by automatic biochemical analyzer,ELISA and chemical fluorescence method;their renal pathological changes observed by HE staining;their apoptosis of renal tissue cells observed by TUNEL staining;and their mRNA and protein expressions of IL-1β,TNF-α,Bax,Bcl-2,caspase-3,caspase-9,PINK1,Parkin and LC3-Ⅱ detected by RT-qPCR and Western blot.RESULTS Compared with the model group,Shiwei Ruxiang Powder groups displayed dose-dependently decreased serum levels of UA,BUN and SCr,renal deposition of urate crystal and apoptosis(P<0.05);decreased renal levels of ROS and inflammatory factors IL-1β and TNF-α(P<0.05);and increased renal expressions of mitochondrial autophagy-related proteins PINK1,Parkin and LC3-Ⅱ(P<0.01).CONCLUSION Shiwei Ruxiang Powder may relieve gouty kidney injury in rats by reducing the uric acid level,the renal oxidative stress and inflammatory response,and activating mitophagy pathway as well.

Objective:To investigate the association of urinary cadmium levels with peripheral leukocyte classification counts among middle-aged and older adults aged 40 to 89 years in selected areas of China.Methods:The research was based on the survey of the impact of soil quality of agricultural land on human health in typical areas conducted in 2019-2020. A total of 5 600 middle-aged and older adults aged 40 to 89 years were included by using a multi-stage stratified random sampling method. Baseline characteristics of the subjects were collected and physical examinations were performed. Random midstream urine was collected to measure urinary cadmium and urinary creatinine and fasting venous blood was collected to measure the leukocyte count, neutrophil count, lymphocyte count, monocyte count and eosinophil count. The linear mixed effect model was used to analyse the association of urinary cadmium levels with leukocyte classification counts, and the dose-response relationship between them was analyzed by using the restricted cubic spline (RCS) function.Results:The age of the subjects was (63.17±12.02) years; 2 851 (50.91%) were males; and the M ( Q 1, Q 3) of urinary creatinine-corrected urinary cadmium levels was 2.69 (1.52, 4.69) μg/g·creatinine. After adjusting for confounding factors, the results of linear mixed effects model analysis showed that for each 1-unit increase in urinary creatinine-corrected urinary cadmium level, the percentage change [% (95% CI)] of leukocyte count and lymphocyte count was -1.70% (-2.61%, -0.79%) and -1.57% (-2.86%, -0.26%), respectively. RCS function showed a negative linear relationship between urinary creatinine-corrected urinary cadmium levels and leukocyte counts and lymphocyte counts, respectively (all Pnon-linear>0.05). Conclusion:Urinary cadmium levels are negatively associated with leukocyte count and lymphocyte count among middle-aged and older adults aged 40 to 89 years in selected areas of China.

Objective:To investigate the association of urinary cadmium levels with peripheral leukocyte classification counts among middle-aged and older adults aged 40 to 89 years in selected areas of China.Methods:The research was based on the survey of the impact of soil quality of agricultural land on human health in typical areas conducted in 2019-2020. A total of 5 600 middle-aged and older adults aged 40 to 89 years were included by using a multi-stage stratified random sampling method. Baseline characteristics of the subjects were collected and physical examinations were performed. Random midstream urine was collected to measure urinary cadmium and urinary creatinine and fasting venous blood was collected to measure the leukocyte count, neutrophil count, lymphocyte count, monocyte count and eosinophil count. The linear mixed effect model was used to analyse the association of urinary cadmium levels with leukocyte classification counts, and the dose-response relationship between them was analyzed by using the restricted cubic spline (RCS) function.Results:The age of the subjects was (63.17±12.02) years; 2 851 (50.91%) were males; and the M ( Q 1, Q 3) of urinary creatinine-corrected urinary cadmium levels was 2.69 (1.52, 4.69) μg/g·creatinine. After adjusting for confounding factors, the results of linear mixed effects model analysis showed that for each 1-unit increase in urinary creatinine-corrected urinary cadmium level, the percentage change [% (95% CI)] of leukocyte count and lymphocyte count was -1.70% (-2.61%, -0.79%) and -1.57% (-2.86%, -0.26%), respectively. RCS function showed a negative linear relationship between urinary creatinine-corrected urinary cadmium levels and leukocyte counts and lymphocyte counts, respectively (all Pnon-linear>0.05). Conclusion:Urinary cadmium levels are negatively associated with leukocyte count and lymphocyte count among middle-aged and older adults aged 40 to 89 years in selected areas of China.