The prescription Mahuang Shengmatang in the Treatise on Cold Damage （《伤寒论》） has sparked considerable debate among medical practitioners throughout history， with varying opinions on its indications， pathogenesis described in the text， principle of compatibility， and clinical applications. Both ancient and modern interpreters of Mahuang Shengmatang often focus on herbal compatibility as a primary approach to deduce the pathogenesis and treatment methods. Building upon this foundation， this paper utilizes herbal dosage as a clue to discern the primary and secondary herbs in the prescription. It further analyzes the principle of compatibility based on herbal indications， summarizing the indications and therapeutic principles of this prescription. Ultimately， it reveals the underlying pathogenesis reflected in the text. The internal closure of heat and toxin leads to the stagnation of Qi， preventing Yang Qi from reaching the extremities and causing cold hands and feet. When the pathogenic Qi finds no outlet， it floods both the upper and lower regions of the body， attacking the throat and causing cough with expectoration of pus and blood， and descending to the large intestine to consume Yin fluids， resulting in persistent diarrhea. Based on this pathogenesis， the paper expands the scope of symptoms and signs associated with the prescription， providing a more detailed portrayal of the applicable patient population and enhancing the basis for clinical prescription references. Additionally， the paper presents considerations on several controversial topics， suggesting that the "lower pulse" described in the text refers to the lower limb arterial pulsation， and the symptoms and signs resemble those of septic shock in modern medicine. Therefore， Mahuang Shengmatang should be categorized as a prescription for treating warm diseases and it is not developed by ZHANG Zhongjing. By employing a detailed discussion on the syndrome， pathogenesis， and clinical application in the texts of Mahuang Shengmatang from the dosage， principle of compatibility， and herbal indications， this paper not only enriches the theoretical foundation of Mahuang Shengmatang but also provides a comprehensive perspective and fresh ideas for understanding its clinical application.

ObjectiveTo explore the main mechanism of self-precipitation formed during the decoction of Sinitang（SNT）， and to provide a research basis for exploring the differences in the toxic and effective components of this compound. MethodsThe average precipitation yields of SNT， Glycyrrhizae Radix et Rhizoma（GRR）-Aconiti Lateralis Radix Praeparata（ALRP） decoction（GF）， ALRP-Zingiberis Rhizoma（ZR） decoction（FJ）， GRR-ZR decoction（GJD）， ALRP decoction（FZ）， ZR decoction（GJ） and GRR decoction（GC） were determined. The four main self-precipitation samples of SNT， GF， FZ and GC were physically characterized by particle size， scanning electron microscopy（SEM）， pH， total dissolved solids（TDS）， conductivity， and Fourier transform infrared spectroscopy（FT-IR） analysis. The chemical compositions of SNT decoction and its different phases was identified by ultra-performance liquid chromatography-quadrupole-electrostatic field orbitrap high-resolution mass spectrometry（UPLC-Q-Exactive Orbitrap-MS） for SNT， SNT self-precipitation and SNT supernatant， and the contents of its main toxic and effective components were determined by high performance liquid chromatography（HPLC）. ResultsPrecipitation yield results of the 7 samples of SNT decoction and single decoction showed that SNT had the highest self-precipitation yield. The formation of SNT self-precipitation was mainly related to the reaction between ALRP and GRR components to form complexes， and FT-IR showed that GRR had the greatest influence on the formation of self-precipitation. A total of 110 components were identified in the SNT decoction， including 100 components in the SNT self-precipitation and 106 components in the SNT supernatant. And quantitative results of the main toxic and effective components revealed that the reaction between ALRP and GRR components formed complexes， resulting in the following content hierarchy for free components：SNT decoctionsupernatantself-precipitation， these components included free liquiritin， benzoylmesaconine， benzoylaconitine， benzoylhypacoitine， liquiritigenin， aconitine， hypoaconitine， isoliquiritigenin and ammonium glycyrrhizinate. ConclusionSNT exhibits spontaneous precipitation during compound decoction， with GRR exerting the greatest influence on its formation. This suggests GRR plays a significant role in the detoxification of SNT. The differences in the self-precipitated toxic-effective components of SNT compound decoction primarily manifest as changes in component content， reflecting the characteristics of SNT "deposition in vitro and sustained release in vivo" and the importance of "administered at draught" in the clinical application of SNT.

BACKGROUND: Chronic liver disease (CLD), mainly non-alcoholic fatty liver disease (NAFLD), is a significant public health concern worldwide. This study aims to quantify the burden of NAFLD in CLD globally and within China, using data from the Global Burden of Disease (GBD) Study 2021, providing crucial insights for global and local health policies. METHODS: The study used comprehensive data from the GBD study 2021. It included estimates of prevalence, incidence, mortality, and disability-adjusted life years (DALYs). Age-standardized rates and average annual percent change (AAPC) from 2011 to 2021 were reported. A meticulous decomposition analysis was conducted. RESULTS: In 2021, there were 1582.5 million prevalent cases, 47.6 million incident cases, 1.4 million deaths, and 44.4 million DALYs attributable to CLD, globally. Among these, NAFLD has emerged as the predominant cause, accounting for 78.0% of all prevalent CLD cases (1234.7 million) and 87.2% of incident cases (41.5 million). Correspondingly, NAFLD had the highest age-standardized prevalence (15,017.5 per 100,000 population) and incidence (876.5 per 100,000 population) rates among CLDs. In addition, China's CLD age-standardized prevalence rate was 21,659.5 per 100,000 population, and the age-standardized incidence rate was 752.6 per 100,000 population, higher than the global average. From 2011 to 2021, the global prevalence rate of CLD increased slowly (AAPC = 0.17), consistent with the trend in China (AAPC = 0.23). Furthermore, the prevalence rate of NAFLD rose significantly in China (AAPC = 1.30) compared with the global average (AAPC = 0.91). Decomposition analysis also showed the worldwide increase in deaths and DALYs for NAFLD, which were primarily attributable to population growth and aging. CONCLUSIONS The burden of CLD and NAFLD remains substantial globally and within China in terms of high prevalence and incidence. As such, this underscores the need for targeted prevention and treatment strategies. These findings emphasize the importance of continued surveillance and research to mitigate the growing impact of liver diseases on global and Chinese health systems.
Humans ; Non-alcoholic Fatty Liver Disease/mortality* ; Global Burden of Disease ; China/epidemiology* ; Prevalence ; Male ; Disability-Adjusted Life Years ; Female ; Incidence ; Middle Aged ; Chronic Disease ; Adult ; Quality-Adjusted Life Years ; Liver Diseases/epidemiology* ; Aged

Although clinical evidence suggests that nonalcoholic fatty liver disease is an established major risk factor for heart failure, it remains unexplored whether sleep disorder-caused hepatic damage contributes to the development of cardiovascular disease (CVD). Here, our findings revealed that sleep fragmentation (SF) displayed notable hepatic detrimental phenotypes, including steatosis and oxidative damage, along with significant abnormalities in cardiac structure and function. All these pathological changes persisted even after sleep recovery for 2 consecutive weeks or more, displaying memory properties. Mechanistically, persistent higher expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in the liver was the key initiator of SF-accelerated damage phenotypes. SF epigenetically controlled the acetylation of histone H3 lysine 27 (H3K27ac) enrichment at the Nox4 promoter and markedly increased Nox4 expression in liver even after sleep recovery. Moreover, fine coordination of the circadian clock and hepatic damage was strictly controlled by BMAL1-dependent Sirtuin 1 (Sirt1) transcription after circadian misalignment. Accordingly, genetic manipulation of liver-specific Nox4 or Sirt1, along with pharmacological intervention targeting NOX4 (GLX351322) or SIRT1 (Resveratrol), could effectively erase the epigenetic modification of Nox4 by reducing the H3K27ac level and ameliorate the progression of liver pathology, thereby counteracting SF-evoked sustained CVD. Collectively, our findings may pave the way for strategies to mitigate myocardial injury from persistent hepatic detrimental memory in diabetic patients.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint damage, accompanied by the accumulation of plasma cells, which contributes to its pathogenesis. Understanding the genetic alterations occurring during plasma cell differentiation in RA can deepen our comprehension of its pathogenesis and guide the development of targeted therapeutic interventions. Here, our study elucidates the intricate molecular mechanisms underlying plasma cell differentiation by demonstrating that PRDX1 interacts with DOK3 and modulates its degradation by the autophagy-lysosome pathway. This interaction results in the inhibition of plasma cell differentiation, thereby alleviating the progression of collagen-induced arthritis. Additionally, our investigation identifies Salvianolic acid B (SAB) as a potent small molecular glue-like compound that enhances the interaction between PRDX1 and DOK3, consequently impeding the progression of collagen-induced arthritis by inhibiting plasma cell differentiation. Collectively, these findings underscore the therapeutic potential of developing chemical stabilizers for the PRDX1-DOK3 complex in suppressing plasma cell differentiation for RA treatment and establish a theoretical basis for targeting PRDX1-protein interactions as specific therapeutic targets in various diseases.

Objective To retrospectively analyze multicenter data from domestic sources, aiming to explore the link between intrahepatic cholangiocarcinoma (ICC) tumor size and prognosis, establishing a classification system based on tumor size. Methods Between December 2011 and September 2018, 280 ICC patients from 13 hospitals were included. The tumor size prognosis cutoff was identified by the minimum P-value method, and the classification's overall survival related effectiveness was assessed by Kaplan-Meier analysis. Results All 280 patients were divided into the group of tumor maximum diameter ≤4 cm and >4 cm. Tumor size was confirmed as an independent prognosis factor by multivariate COX regression analysis (HR=2.110, 95% CI: 1.358-3.280). Conclusions The tumor size dichotomy classification system based on the Chinese patient group can expediently predict ICC prognosis and offers an important basis for selecting post-operative individualized adjuvant therapy and follow up plans.

Interactions between brain-resident and peripheral infiltrated immune cells are thought to contribute to neuroplasticity after cerebral ischemia. However, conventional bulk sequencing makes it challenging to depict this complex immune network. Using single-cell RNA sequencing, we mapped compositional and transcriptional features of peri-infarct immune cells. Microglia were the predominant cell type in the peri-infarct region, displaying a more diverse activation pattern than the typical pro- and anti-inflammatory state, with axon tract-associated microglia (ATMs) being associated with neuronal regeneration. Trajectory inference suggested that infiltrated monocyte-derived macrophages (MDMs) exhibited a gradual fate trajectory transition to activated MDMs. Inter-cellular crosstalk between MDMs and microglia orchestrated anti-inflammatory and repair-promoting microglia phenotypes and promoted post-stroke neurogenesis, with SOX2 and related Akt/CREB signaling as the underlying mechanisms. This description of the brain's immune landscape and its relationship with neurogenesis provides new insight into promoting neural repair by regulating neuroinflammatory responses.
Humans ; Ischemic Stroke ; Brain/metabolism* ; Macrophages ; Brain Ischemia/metabolism* ; Microglia/metabolism* ; Gene Expression Profiling ; Anti-Inflammatory Agents ; Neuronal Plasticity/physiology* ; Infarction/metabolism*

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Objective:To investigate the prevalence and associated risk of cardiovascular event of resistant hypertension in treated outpatients.Methods:This study was a nationwide multi-center prospective cohort study. The participants were treated outpatients enrolled in the China Nationwide Ambulatory and Home Blood Pressure Registry study of 42 hospitals in 19 provinces across the country from August 2009 to October 2017. Apparent resistant hypertension was defined as uncontrolled office blood pressure (≥140/90 mmHg, 1 mmHg=0.133 kPa) in spite of the use of three antihypertensive drugs or controlled office blood pressure (<140/90 mmHg) with four antihypertensive drugs or more. Subjects diagnosed with uncontrolled office blood pressure were further subdivided as pseudo-resistant hypertension and true resistant hypertension based on 24 h ambulatory blood pressure monitoring. The primary endpoint was fatal and non-fatal cardiovascular and cerebrovascular events, which was a composite endpoint consisting of cardiovascular and cerebrovascular death, ischemic and hemorrhagic stroke, myocardial infarction, coronary artery revascularization, unstable angina, heart failure, and coronary artery stenosis≥50% confirmed by coronary angiography. Secondary outcomes included fatal and non-fatal stroke or cardiac events. Patients with controlled office blood pressure after taking only 1 or 2 antihypertensive drugs were included as control. Kaplan-Meier survival curves, log-rank test, and Cox proportional risk model were used to evaluate the risk of apparent refractory hypertension in relation to cardiovascular and cerebrovascular prognosis.Results:A total of 2 782 treated hypertensive patients, aged (58.1±12.3) years were enrolled, including 1 403 (50.4%) men. The prevalence of apparent and true resistant hypertension was 15.1% (420/2 782) and 10.5% (293/2 782), respectively. Among patients with apparent resistant hypertension, during a median of 5 years follow-up, the cumulative incidence rate was 28.2, 11.2 and 19.1 per 1 000 person-years for fatal and non-fatal cardiovascular events ( n=58), stroke ( n=24) and cardiac events ( n=40), respectively. The Kaplan-Meier curve and log-rank test showed that those patients with true resistant hypertension, had the highest cumulative incidence rate of fatal and non-fatal cardiovascular events, stroke, and cardiac events. Multivariable Cox regression analyses showed that true resistant hypertension was associated with a significantly higher risk of fatal and non-fatal cardiovascular events ( HR=1.73, 95% CI 1.17-2.56, P=0.006) and stroke ( HR=2.81, 95% CI 1.53-5.17, P=0.001). Conclusion:Resistant hypertension, especially true resistant hypertension, is associated with a higher risk of fatal and non-fatal cardiac and cerebrovascular events.

Objective To investigate the differential diagnostic value of 18F-fluorodeoxyglucose(18F-FDG)/PET/CT combined with serum lactate dehydrogenase(LDH),β2-microglobulin(β2-MG),and C-reactive protein(CRP)in sarcoidosis and lymphoma.Methods The 18F-FDG PET/CT images of 19 patients with sarcoidosis and 33 patients with lymphoma were analyzed retrospectively.The lymph node maximum diameter,density,distribution morphology,maximum standardized uptake value(SUVmax),extra-nodal involvement,and serum LDH,β2-MG,and CRP results were analyzed and compared.Results There was no statistically significant difference between sarcoidosis and lymphoma in lymph node density,necrosis rate,and SUVmax(P＞0.05).There was statistically significant difference in the maximum diameter between lymph nodes in sarcoidosis(2.4±0.7)cm and lymphoma(3.3±1.3)cm(P＜0.05).The incidence of symmetric enlargement of mediastinal and hilar lymph nodes was 84.2％in sarcoidosis,the lymph node fusion rate was 21.1％,the lung involvement rate was 57.8％,the spleen involvement rate was 10.5％,and the rates of lymphoma were 15.2％,63.6％,0.0％,and 36.4％,with statistically significant differences(P＜0.05).There were statistically significant differences in LDH and β2-MG between the two groups(P＜0.05),but the differences in CRP were not statistically significant(P＞0.05).Conclusion PET/CT can show the anatomy of mediastinal and hilar lymph nodes and extra-nodal affected organs as well as glucose metabolism,showing a certain differential diagnostic value of sarcoidosis and lymphoma when combined with serum LDH and β2-MG levels.