Zhishi Shaoyaosan is the 34^th prescription in the Catalogue of Ancient Classic Formulas （Second Batch） published by the National Administration of Traditional Chinese Medicine in 2023. It is widely used in clinical practice and has a definite curative effect. However， there is currently a lack of its ancient literature analysis and textual research， and there is no corresponding Chinese patent medicine preparation. By consulting and combing the relevant ancient books of traditional Chinese medicine， this paper analyzes and conducts textual research of the origin， composition， measurement， administration， and efficacy of Zhishi Shaoyaosan. The results show that Zhishi Shaoyaosan is derived from Essentials from the Golden Cabinet written by Zhang Zhongjing in the Eastern Han Dynasty. It is mainly recorded in the name of Zhishi Shaoyaosan in the literature of the past dynasties. The prescription is composed of Aurantii Fructus Immaturus and Paeoniae Radix Alba. The processing method is stir-frying Aurantii Fructus Immaturus to scorch and using raw Paeoniae Radix Alba. The dose of the prescription recorded in the ancient books is mainly an equal amount of Aurantii Fructus Immaturus and Paeoniae Radix Alba in one square-cun spoon， taken three times a day， which is converted into a modern dose of 1.5 g each time （0.75 g Aurantii Fructus Immaturus and 0.75 g Paeoniae Radix Alba each time）. The components of the prescription are ground into powder and taken with barley porridge， three times a day. The efficacy is to break stagnated Qi， harmonize blood， and relieve restlessness and pain. It is mainly used to treat postpartum abdominal pain， acute pelvic inflammatory disease， acute cholecystitis and intestinal diseases， stroke sequelae， and other diseases. This study combs and analyzes the ancient literature recording Zhishi Shaoyaosan and clarifies the key information of the prescription， which provides a basis for promoting the research and development of its patent medicine.

BACKGROUND: It remains unclear whether sleep duration and physical activity (PA) trajectories in middle-aged and older adults are associated with different risks of cardiovascular diseases (CVDs). This study aimed to explore the trajectories of total sleep duration and PA among middle-aged and older Chinese adults and their impact on CVD risk. METHODS: This study was based on the China Health and Retirement Longitudinal Study. 12009 adults aged 45 years and older from five waves were included. CVD events were measured by self-reports of heart disease and stroke. We first used group-based trajectory modeling to identify total sleep duration and PA trajectories from 2011 to 2020, and then employed logistic regression models to analyze their risk for CVD. RESULTS: We identified three sleep duration and PA trajectories. The risk of heart disease increased by 33% (OR = 1.31, 95% CI: 1.12-1.53) for the short sleep duration trajectory (vs. moderate sleep duration trajectory), by 40% (OR = 1.40, 95% CI: 1.06-1.84) for the high decreasing PA trajectory, and by 20% (OR = 1.20, 95% CI: 1.01-1.42) for the low stable PA trajectory (vs. high stable PA trajectory), respectively. Similar results for stroke and CVD as the outcomes were also observed, but the higher risk of stroke in the high decreasing PA trajectory group was not statistically significant. The joint effects of sleep and PA showed lower risks of heart disease and stroke in trajectories with moderate or long sleep duration and high stable PA compared with short sleep duration and a low stable PA trajectory. CONCLUSIONS Short total sleep duration, high decreasing PA, and low stable PA trajectories could increase the risk of CVDs among middle-aged and older adults. Long-term moderate to long total sleep durations and high stable PA trajectories might be optimal for preventing CVDs.

Objective To analyze the characteristics of methadone-related poisoning cases and provide a reference for forensic identification.Methods A total of 71 cases of methadone-related poisoning re-ported from 1998 to 2023 in China and 26 cases of methadone-related deaths reported from 2013 to 2018 in Italy were retrieved from databases including PubMed,Wanfang and CNKI.The general infor-mation,forensic pathological and toxicological characteristics were analyzed.Results Among the 71 methadone-related poisoning cases in China,there were 54 cases(76.06%)of poisoning without death and 17 cases(23.94%)of death from poisoning.There were 54 male cases(76.06%),and 51 cases(71.83%)aged 19 to 39 years old.There were 35 cases(49.30%)of poisoning caused by methadone alone,and 32 cases(45.07%)were poisoning caused by methadone combined with other substances or drugs including heroin and benzodiazepines.Most of the poisoned showed coma,respiratory depres-sion and miosis.Signs of asphyxia were often found by autopsy.The mass concentration of methadone detected in the blood of 6 deceased ranged from 0.112 to 3.000 mg/L.Among the 26 methadone-related deaths in Italy,22 cases were male(84.62%).There were 6 cases(23.08%)caused by methadone alone,and 20 cases(76.92%)died from methadone combined with other substances or drugs.The mass concentration of methadone in blood ranged from 0.181 to 4.059 mg/L.Conclusion The propor-tions of poisoning cases caused by methadone alone and methadone combined with other substances or drugs are comparable in China.The majority of deceased caused by methadone poisoning shows typi-cal triad of coma,respiratory depression and miosis,which helps forensic experts determine the cause of death related to methadone.Additionally,it is necessary to increase the routine testing of the con-centration of methadone and its combined substances or drugs in deceased,and collect data for the in-terpretation of the results of related cases.

Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

Chronic pain, frequently comorbid with neuropsychiatric disorders, significantly impairs patients' quality of life and functional capacity. Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key players in chronic pain pathogenesis. This review examines the regulatory mechanisms of the CCL2/CCR2 axis in chronic pain processing at three hierarchical levels: (1) Peripheral Sensitization: CCL2/CCR2 modulates TRPV1, Nav1.8, and HCN2 channels to increase neuronal excitability and CGRP signaling and calcium-dependent exocytosis in peripheral nociceptors to transmit pain. (2) Spinal Cord Central Sensitization: CCL2/CCR2 contributes to NMDAR-dependent plasticity, glial activation, GABAergic disinhibition, and opioid receptor desensitization. (3) Supraspinal Central Networks: CCL2/CCR2 signaling axis mediates the comorbidity mechanisms of pain with anxiety and cognitive impairment within brain regions, including the ACC, CeA, NAc, and hippocampus, and it also increases pain sensitization through the descending facilitation system. Current CCL2/CCR2-targeted therapeutic strategies and their development status are discussed, highlighting novel avenues for chronic pain management.
Humans ; Chronic Pain/physiopathology* ; Animals ; Neuroglia/metabolism* ; Chemokine CCL2/metabolism* ; Receptors, CCR2/metabolism*

ObjectiveTo explore the protective mechanism of paeoniflorin on mice with ulcerative colitis （UC） through the adenosine monophosphate-activated protein kinase （AMPK）/mammalian target of rapamycin （mTOR） autophagy pathway. MethodUC mouse model was established by allowing mice freely drink 4% DSS， and 56 BALB/c male mice were randomly divided into model group， AMPK inhibitor group （20 mg·kg^-1）， paeoniflorin （50 mg·kg^-1） + inhibitor （20 mg·kg^-1） group， and high dose （50 mg·kg^-1）， medium dose （25 mg·kg^-1）， and low dose （12.5 mg·kg^-1） paeoniflorin groups. After seven days of drug intervention， the protective effect of paeoniflorin on mice with UC was determined by comparing the body weight， disease activity index （DAI） changes， and Hematoxylin-eosin （HE） staining results. Enzyme linked immunosorbent assay （ELISA） was used to detect the levels of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in the serum of mice in each group， and immunofluorescence was utilized to detect microtubule-associated protein 1 light chain 3 （LC3） content in the colon， AMPK， mTOR proteins， and their phosphorylated proteins including p-AMPK and p-mTOR in the colon tissue were detected by Western blot， and the mRNA expression levels of AMPK， mTOR， Beclin1， LC3， and p62 were detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. ResultCompared with the blank group， the model group showed a decrease in body mass， an increase in DAI score， and severe pathological damage to the colon. The levels of inflammatory factors including TNF-α and IL-6 increased in serum （P<0.01）， while the protein levels of LC3 and p-AMPK/AMPK were down-regulated in colon tissue， and those of p-mTOR/mTOR were up-regulated （P<0.01）. The mRNA expression levels of AMPK and LC3 were down-regulated， while the mRNA expression levels of mTOR and p62 were up-regulated （P<0.01）. Compared with the model group and the paeoniflorin + inhibitor group， the mice treated with paeoniflorin showed an increase in body mass， a decrease in DAI score， a reduction in pathological damage to colon tissue， and a reduction in the levels of inflammatory factors of TNF-α and IL-6 in serum （P<0.05）. The protein levels of LC3 and p-AMPK/AMPK in colon tissue were up-regulated， while the protein levels of p-mTOR/mTOR were down-regulated （P<0.01）. The mRNA expression levels of AMPK， Beclin1， and LC3 were up-regulated， while the mRNA expression of mTOR and p62 were down-regulated （P<0.01）. The colon tissue of the inhibitor group was severely damaged， and the trend of various indicators was completely opposite to that of the high dose paeoniflorin group. ConclusionPaeoniflorin can enhance autophagy and reduce inflammatory damage in mice with UC by activating the AMPK/mTOR signaling pathway and thus play a protective role.

Background Silicosis is a diffuse fibrosis of the lungs caused by long-term inhalation of free silicon dioxide (SiO₂). It has a complex pathogenesis and lacks effective treatment. Brusatol (Bru) has a variety of biological activities, and its role in silicosis fibrosis is unclear yet. Objective To investigate the effects of different concentrations of Bru on SiO₂-induced silicosis fibrosis in mice. Methods Thirty male C57BL/6J mice were randomly divided into five groups: a control group, a silica group, and three Bru intervention groups with low, medium, and high doses (1, 2, and 4 mg·kg⁻¹), with 6 mice in each group. Except the control group, the remaining groups were established as SiO₂-induced silicosis mouse models by using a single tracheal infusion of 50 μL 60 mg·mL⁻¹ SiO₂ suspension. The control group was dosed with equal amount of saline. The Bru intervention groups were injected intraperitoneally with Bru for 5 consecutive days and then injected every other day. After 28 d of exposure, the mice were executed and lung tissues were collected. The lung coefficient of the mice was measured, and the pathological changes of the lung tissues were observed after hematoxylin-eosin (HE) and Masson staining. The levels of apoptotic protein Cleaved-caspase 3, fibrosis-related protein α-smooth muscle actin (α-SMA), type I collagen (Col-I), autophagy-associated protein Beclin1, microtubule-associated protein 1 light chain 3 (LC3), Sequestosome 1 (p62/SQSTM1), Kelch like ECH-associated protein-1 (Keap1), and nuclear factor erythroid 2 related factor 2 (Nrf2) were detected by Western blot. The mRNA levels of Caspase 3, α-SMA, and Col-I were measured by realtime fluorescence-based quantitative PCR. Results Compared with the control group, the lung coefficient of mice in the silica group was significantly increased (P < 0.01); the lung tissues of the silicosis mice showed damaged alveolar walls, along with infiltration of inflammatory cells, fibrous nodules, and collagen deposition; furthermore, the protein and mRNA levels of Cleaved-caspase 3, α-SMA, and Col-I were significantly increased (P < 0.01); the expression levels of Beclin1, LC3-II/I, p62, and Nrf2 were increased, while that of Keap1 was decreased (P < 0.05). The interventions with low and medium doses of Bru reduced lung coefficient (P < 0.05) and protected against pathological damage and collagen deposition in the lung tissues of the silicosis mice; the protein and mRNA expression levels of Cleaved-caspase 3, α-SMA, and Col-I were significantly decreased in the low and medium dose groups (P < 0.05, P < 0.01), the expression levels of Beclin1, LC3-II/I, p62, and Nrf2 were also decreased (P < 0.05, P < 0.01), and the expression level of Keap1 was increased in the medium dose group (P < 0.05). However, compared with the silica group, the differences in lung coefficient, pathological damage, and protein and mRNA expression levels of Cleaved-caspase 3, α-SMA, and Col-I in the Bru high dose group were not statistically significant (P > 0.05). In addition, the high dose of Bru decreased Beclin1, LC3-II/I, and Nrf2 expression levels (P < 0.01), did not change p62 protein expression level (P > 0.05), while increased Keap1 protein level (P < 0.01). Conclusion Low and medium doses of Bru might regulate autophagy through the Keap1-Nrf2 pathway, ameliorate autophagic degradation impairment, reduce pulmonary coefficient, attenuate apoptosis, and delay the progression of fibrosis in SiO₂-induced silicosis mice.

Objective For more focused prevention and management,this investigation examines the risk factors for multidrug resistant organisms(MDRO)infections in intensive care unit(ICU)patients.Methods Case-control studies and cohort studies of risk factors for MDRO infection in ICU patients were searched in the Embase,Website of Science,Cochrane Library,PubMed,CNKI,WanFang,and VIP databases from their start to October 26,2022.The Meta-analysis was carried out with RevMan 5.3.Results A total of 32 papers were included,with 10 985 cases studied,with the quality of the literature rated as moderate to high.The results of Meta-analysis of this study showed that gender[OR=1.21,95% CI=(1.08,1.36),P=0.002],ICU length of stay[WMD=5.36,95% CI=(3.99,6.73),P<0.000 01],total length of stay[WMD=8.96,95% CI=(6.51,11.41),P<0.000 01],hypertension[OR=1.33,95% CI=(1.10,1.60),P=0.003],abnormal renal function[OR=1.69,95% CI=(1.33,2.16),P<0.000 01],hypoproteinemia[OR=1.87,95% CI=(1.51,2.32),P<0.000 01],mechanical ventilation[OR=2.26,95% CI=(1.18,4.33),P=0.01],duration of mechanical ventilation[WMD=8.83,95% CI=(2.52,15.14),P=0.006],arteriovenous placement[OR=1.46,95% CI=(1.23,1.72),P<0.000 1],placement of urinary catheter[OR=1.71,95% CI=(1.25,2.36),P<0.000 01],gastrointestinal tube placement[OR=0.10,95% CI=(0.03,0.18),P=0.008],antimicrobial drug type≥3[OR=4.27,95% CI=(2.06,8.85),P<0.000 01],use of carbapenem antibiotics[OR=4.09,95% CI=(300,5.58),P<0.000 01],the use of the third-generation cephalosporin[OR=1.63,95% CI=(1.15,2.33),P=0.007],the use of quinolone antibacterials[OR=1.86,95% CI=(1.42,2.44),P<0.000 01],the use of aminoglycoside antibiotics[OR=1.99,95% CI=(1.49,2.67),P<0.000 01],use of piperacillin-tazobactam[OR=2.94,95% CI=(1.56,5.54),P=0.000 9],use of glycopeptide antibiotics[OR=3.78,95% CI=(2.48,5.78),P<0.000 01],use of sedatives[OR=3.25,95% CI=(2.06,5.14),P<0.000 01],and use of acid suppressants[OR=1.51,95% CI=(1.06,2.16),P=0.02]are risk factors for MDRO infection in ICU patients.Conclusion MDRO infections in ICU patients are associated with gender,duration of ICU stay,chronic lung disease,total length of stay,hypertension,abnormal renal function,hypoproteinemia,mechanical ventilation,duration of mechanical ventilation,arteriovenous placement,placement of urinary catheters,gastrointestinal placement,type of antimicrobial drugs≥3,use of carbapenem antibiotics,use of third-generation cephalosporin,use of quinolone antibacterials,use of aminoglycoside antibiotics,use of piperacillin-tazobactam,use of glycopeptide antibiotics,use of sedatives,use of acid suppressants,and other factors.Targeted controls of different factors such as underlying diseases,comorbidities,invasive procedures performed,and the use of antimicrobial medications and other therapeutic pharmaceuticals could limit the risk of infection in MDRO in ICU patients.

Objective To study the distribution of intestinal flora in osteoporosis patients with spleen deficiency syndrome.Methods According to the diagnostic criteria of osteoporosis of the World Health Organization(WHO)and the syndrome differentiation criteria of spleen deficiency syndrome in traditional Chinese medicine(TCM),26 healthy attenders with normal bone mass while without spleen deficiency were selected from the population visited Shunde Hospital of Guangzhou University of Chinese Medicine from January 2022 to September 2023 as the normal bone mass group,23 patients with bone mass reduction and spleen deficiency syndrome served as decreased bone mass with spleen deficiency group(shorten as DBM-SD group),and 69 patients with osteoporosis and spleen deficiency syndrome diagnosis were osteoporosis with spleen deficiency group(shorten as OS-SD group).A total of 118 attenders were enrolled in the analysis.The gender,age,body height,body weight,and body mass index(BMI)of the subjects were collected.The bone mineral density(BMD)and serum levels of calcium and alkaline phosphatase(ALP)of the subjects were measured.Stools were collected for the detection of the sequence of the 16SrRNA V3-V4 region,and the sequencing results were given species annotation,and then the correlation of community difference between groups and BMD with the intestinal flora was explored.Results(1)There were significant differences in the relative abundance of intestinal flora between the normal bone mass group and the OS-SD group:differences were shown in Firmicutes(t=2.490,P=0.016),Verrucomicrobia(t=2.180,P=0.003)and Fusobacteria(t=2.270,P=0.026),in Acidobacteria(t=3.003,P=0.003),Lactobacillus(t=3.150,P=0.002)and Bifidobacterium(t=7.248,P=0.001),and in Fecalibacterium(t=2.810,P=0.006)and Rothia(t=2.810,P=0.006).(2)There were significant differences in the relative abundance of intestinal flora between the normal bone mass group and the DBM-SD group:differences were shown in Lactobacillus(t=3.841,P=0.001)and Bifidobacterium(t=2.712,P=0.01),and in Faecalibacterium(t=2.466,P=0.017).(3)There were significant differences in the relative abundance of intestinal flora between the OS-SD group and DBM-SD group:differences were shown in Firmicutes(t=2.321,P=0.025),Bacteroidetes(t=0.393,P=0.020)and Verrucomicrobia(t=3.109,P=0.031).(4)The results of logistic regression analysis showed that in the OS-SD group,lumbar BMD was negatively correlated with Lactobacillus(R=0.355,P=0.003)and Bifidobacterium(R=0.366,P=0.002),positively correlated with Bacteroides(R=0.245,P=0.042),and was negatively correlated Rothia(R=0.330,P=0.006).Conclusion Some bacteria in the intestinal flora are related to the BMD of osteoporosis patients with spleen deficiency syndrome,and significant difference exists in the distribution of intestinal flora between the normal bone mass group and the OS-SD group.The results will provide a theoretical basis for the prevention and treatment of osteoporosis patients with spleen deficiency syndrome from the perspective of the changes of intestinal flora.

Background: Currently, traditional methods of treating acute gastric ulcer (AGU) have many drawbacks, necessitating an alternative therapy with fewer adverse effects. Atractylodis Macrocephalae Rhizoma (BZ) is known for strengthening the spleen and harmonizing the stomach. BZ processed with Aurantii Fructus Immaturus juice (ZSZBZ), a classic decoction since the Han Dynasty, can enhance the efficacy of BZ. However, the key active components and targets of action of ZSZBZ remain undiscovered. Aim of the study: This study aimed to investigate the bioactive chemical constituents of ZSZBZ against AGU and their possible mechanisms of action, elucidating the scientific content of ZSZBZ processing. Materials and methods: Initially, we examined rat stomach histopathology and conducted ELISA for oxidative stress and inflammation. Subsequently, we investigated underlyingmechanisms using metabolomics. Further analysis of potent components and key targets in ZSZBZ was conducted through liquid chromatography-mass spectrometry analysis combined with network pharmacology. Finally, key targets were analyzed by Western blot. Results: ZSZBZ improved gastric histopathology, reversing high alcohol-induced oxidative stress (SOD, CAT) and inflammatory level (TNF-α, IL-6) disorders. This is associated with ZSZBZ’s regulation of amino acid metabolism, energy metabolism, and inflammatory response-related metabolic pathways, along with key targets PTGS2, MAPK1, and KDR. The significant increase in potency of ZSZBZ may be attributed to elevated levels of naringenin, hesperidin, hesperidin, and rhamnoceroside after concoction. Conclusions: Combining metabolomics and network pharmacology, this study elucidated that ZSZBZ enhanced gastroprotection by modulating amino acid metabolism, antioxidant, and inflammation-related targets and pathways, providing insights into the bioactive compounds and potential mechanisms of herbal concoctions.