BACKGROUND: Enzalutamide, a second-generation androgen receptor (AR) pathway inhibitor, is widely used in the treatment of castration-resistant prostate cancer. However, after a period of enzalutamide treatment, patients inevitably develop drug resistance. In this study, we characterized leucine-rich repeated G-protein-coupled receptor 5 (LGR5) and explored its potential therapeutic value in prostate cancer. METHODS: A total of 142 pairs of tumor and adjacent formalin-fixed paraf-fin-embedded tissue samples from patients with prostate cancer were collected from the Pathology Department at Sun Yat-sen Memorial Hos-pital. LGR5 was screened by sequencing data of enzalutamide-resistant cell lines combined with sequencing data of lesions with different Gleason scores from the same patients. The biological function of LGR5 and its effect on enzalutamide resistance were investigated in vitro and in vivo . Glutathione-S-transferase (GST) pull-down, coimmunoprecipitation, Western blotting, and immunofluorescence assays were used to explore the specific binding mechanism of LGR5 and related pathway changes. RESULTS: LGR5 was significantly upregulated in prostate cancer and negatively correlated with poor patient prognosis. Overexpression of LGR5 promoted the malignant progression of prostate cancer and reduced sensitivity to enzalutamide in vitro and in vivo . LGR5 promoted the phosphorylation of glycogen synthase kinase-3β (GSK-3β) by binding heat shock protein 90,000 alpha B1 (HSP90AB1) and mediated the activation of the Wingless/integrated (WNT)/β-catenin signaling pathway. The increased β-catenin in the cytoplasm entered the nucleus and bound to the nuclear AR, promoting the transcription level of AR, which led to the enhanced tolerance of prostate cancer to enzalutamide. Reducing HSP90AB1 binding to LGR5 significantly enhanced sensitivity to enzalutamide. CONCLUSIONS LGR5 directly binds to HSP90AB1 and mediates GSK-3β phosphorylation, promoting AR expression by regulating the WNT/β-catenin signaling pathway, thereby conferring resistance to enzalutamide treatment in prostate cancer.
Male ; Humans ; Phenylthiohydantoin/pharmacology* ; Benzamides ; Receptors, G-Protein-Coupled/genetics* ; Nitriles ; Cell Line, Tumor ; HSP90 Heat-Shock Proteins/metabolism* ; Drug Resistance, Neoplasm/genetics* ; Prostatic Neoplasms/drug therapy* ; beta Catenin/metabolism* ; Receptors, Androgen/genetics* ; Animals ; Mice ; Wnt Signaling Pathway/physiology*

Objective To explore the effect of rehmanniae radix extract(RRE)on chondrocyte apoptosis in the rabbit model of knee osteoarthritis(KOA)by regulating the miR-485-5p/heat shock protein 90 beta family member 1(Hsp90b1)axis.Methods New Zealand rabbits were randomly assigned into control,KOA,low-dose RRE,medium-dose RRE,high-dose RRE,celecoxib,high-dose RRE+antagonist control,and high-dose RRE+miR-485-5p antagonist groups,with 12 rabbits in each group.Rabbits in other groups except the control group were modeled for KOA with the improved Hulth method.After modeling for 8 weeks,the rabbits were administrated with corresponding agents for 4 weeks.The changes in the activity rating of rabbits were recorded.ELISA was employed to measure the levels of tumor necrosis factor-α(TNF-α)and interleukin(IL)-6 in the serum.Safranine O-fast green staining was conducted to reveal the pathological changes in the cartilage tissue and Mankin scoring was performed.TUNEL was employed to detect chondrocyte apoptosis.Real-time fluorescence quantitative PCR was performed to determine the expression of miR-485-5p in the cartilage tissue.Western blot was employed to determine the protein levels of Hsp90b1,cleaved cysteinyl aspartate-specific proteinase-3(Caspase-3),and Bcl2-associated-X(Bax)in the cartilage tissue.The dual-luciferase reporter assay was employed to examine the relationship between miR-485-5p and Hsp90b1.Results Compared with the control group,the KOA group showed down-regulated expression of miR-485-5p,elevated levels of TNF-α and IL-6 in the serum,cartilage erosion and losses,and increases in activity rating,Mankin score,chondrocyte apoptosis rate,and protein levels of Hsp90b1,cleaved Caspase-3,and Bax(all P<0.001).Compared with the KOA group,RRE at low,medium,and high doses,and celecoxib up-regulated the expression of miR-485-5p,lowered the levels of TNF-α and IL-6 in the serum,alleviated the pathological damage to the cartilage tissue,and decreased the activity rating,Mankin score,chondrocyte apoptosis rate,and protein levels of Hsp90b1,cleaved Caspase-3,and Bax(all P<0.05).Compared with the high-dose RRE group and the high-dose RRE+antagonist control group,high-dose RRE+miR-485-5p antagonist down-regulated the expression of miR-485-5p,elevated the levels of TNF-α and IL-6 in the serum,exacerbated the pathological damage to the cartilage tissue,and increased the activity rating,Mankin score,chondrocyte apoptosis rate,and protein levels of Hsp90b1,cleaved Caspase-3,and Bax(all P<0.05).The results indicated that there was a targeted regulatory relationship between miR-485-5p and Hsp90b1.Conclusion RRE may inhibit the expression of Hsp90b1 by up-regulating miR-485-5p,thereby inhibiting chondrocyte apoptosis in the rabbit model of KOA.
Animals ; Rabbits ; Apoptosis/drug effects* ; Chondrocytes/pathology* ; Osteoarthritis, Knee/drug therapy* ; MicroRNAs/metabolism* ; Rehmannia/chemistry* ; Disease Models, Animal ; Tumor Necrosis Factor-alpha/blood* ; Plant Extracts/pharmacology* ; Interleukin-6/blood* ; HSP90 Heat-Shock Proteins/metabolism* ; Male ; Drugs, Chinese Herbal/pharmacology*

Shock is the clinical manifestation of acute circulatory failure, which results in inadequate utilization of cellular oxygen. It is a common condition with high mortality rates in intensive care units. The intravenous administration of Shenfu Injection (SFI) may attenuate inflammation, regulate hemodynamics and oxygen metabolism; inhibit ischemia-reperfusion responses; and have adaptogenic and antiapoptotic effects. In this review, we have discussed the clinical applications and antishock pharmacological effects of SFI. Further in-depth and large-scale multicenter clinical studies are warranted to determine the therapeutic effects of SFI on shock.
Humans ; Drugs, Chinese Herbal/therapeutic use* ; Shock/drug therapy* ; Injections ; Oxygen ; Multicenter Studies as Topic

Severe pneumonia is one of the most common infectious diseases and the leading cause of sepsis and septic shock. Preventing infection, balancing the patient's immune status, and anti-coagulation therapy are all important elements in the treatment of severe pneumonia. As multi-target agents, Xuebijing injection (XBJ) has shown unique advantages in targeting complex conditions and saving the lives of patients with severe pneumonia. This review outlines progress in the understanding of XBJ's anti-inflammatory, endotoxin antagonism, and anticoagulation effects. From the hundreds of publications released over the past few years, the key results from representative clinical studies of XBJ in the treatment of severe pneumonia were selected and summarized. XBJ was observed to effectively suppress the release of pro-inflammatory cytokines, counter the effects of endotoxin, and assert an anticoagulation effect in most clinical trials, which are consistent with experimental studies. Collectively, this evidence suggests that XBJ could play an important and expanding role in clinical medicine, especially for sepsis, septic shock and severe pneumonia. Please cite this article as: Zhang M, Zheng R, Liu WJ, Hou JL, Yang YL, Shang HC. Xuebijing injection, a Chinese patent medicine, against severe pneumonia: Current research progress and future perspectives. J Integr Med. 2023; 21(5): 413-422.
Humans ; Nonprescription Drugs ; Shock, Septic/drug therapy* ; Sepsis/drug therapy* ; Endotoxins ; Anticoagulants/therapeutic use*

OBJECTIVE: To investigate the value of maximal rate of left ventricular pressure (dp/dtmax) in evaluating the changes of cardiac function before and after heart rate reduction in patients with sepsis-induced cardiomyopathy (SIC). METHODS: A single-center, prospective randomized controlled study was conducted. Adult patients with sepsis/septic shock admitted to the department of intensive care unit (ICU) of Tianjin Third Central Hospital from April 1, 2020 to February 28, 2022 were enrolled. Speckle tracking echocardiography (STE) and pulse indication continuous cardiac output (PiCCO) monitoring were performed immediately after the completion of the 1 h-Bundle therapy. The patients with heart rate over 100 beats/minutes were selected and randomly divided into esmolol group and regular treatment group, 55 cases in each group. All patients underwent STE and PiCCO monitoring at 6, 24 and 48 hours after admission in ICU and calculated acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA). Primary outcome measure: change in dp/dtmax after reducing heart rate by esmolol. Secondary outcome measures: correlation between dp/dtmax and global longitudinal strain (GLS); changes of vasoactive drug dosage, oxygen delivery (DO₂), oxygen consumption (VO₂) and stroke volume (SV) after the administration of esmolol; proportion of heart rate reaching the target after the administration of esmolol; 28-day and 90-day mortality in two groups. RESULTS: Baseline data on age, gender, body mass index, SOFA score, APACHE II score, heart rate, mean arterial pressure, lactic acid, 24-hour fluid balance, sepsis etiology and prior comorbidities were similar between esmolol group and regular treatment group, there were no significant differences between the two groups. All SIC patients achieved the target heart rate after 24 hours of esmolol treatment. Compared with regular treatment group, parameters reflecting myocardial contraction such as GLS, global ejection fraction (GEF) and dp/dtmax were significantly increased in esmolol group [GLS: (-12.55±4.61)% vs. (-10.73±4.82)%, GEF: (27.33±4.62)% vs. (24.18±5.35)%, dp/dtmax (mmHg/s): 1 312.1±312.4 vs. 1 140.9±301.0, all P < 0.05], and N-terminal pro-brain natriuretic peptide (NT-proBNP) significantly decreased [μg/L: 1 364.52 (754.18, 2 389.17) vs. 3 508.85 (1 433.21, 6 988.12), P < 0.05], DO₂ and SV were significantly increased [DO₂ (mL×min^-1×m^-2): 647.69±100.89 vs. 610.31±78.56, SV (mL): 49.97±14.71 vs. 42.79±15.77, both P < 0.05]. The system vascular resistance index (SVRI) in esmolol group was significantly higher than that in regular treatment group (kPa×s×L^-1: 287.71±66.32 vs. 251.17±78.21, P < 0.05), even when the dosage of norepinephrine was similar between the two groups. Pearson correlation analysis showed that dp/dtmax was negatively correlated with GLS in SIC patients at 24 hours and 48 hours after ICU admission (r values were -0.916 and -0.935, respectively, both P < 0.05). Although there was no significant difference in 28-day mortality between esmolol group and regular treatment group [30.9% (17/55) vs. 49.1% (27/55), χ² = 3.788, P = 0.052], the rate of esmolol use in patients who died within 28 days was lower than that in patients who survived [38.6% (17/44) vs. 57.6% (38/66), χ² = 3.788, P = 0.040]. In addition, esmolol has no effect on the 90-day mortality of patients. Logistic regression analysis showed that after adjusting for SOFA score and DO₂ factors, patients who used esmolol had a significantly lower risk of 28-day mortality compared with patients who did not use esmolol [odds ratio (OR) = 2.700, 95% confidence interval (95%CI) was 1.038-7.023, P = 0.042]. CONCLUSIONS dp/dtmax in PiCCO parameter can be used as a bedside indicator to evaluate cardiac function in SIC patients due to its simplicity and ease of operation. Esmolol control of heart rate in SIC patients can improve cardiac function and reduce short-term mortality.
Adult ; Humans ; Prospective Studies ; Ventricular Pressure ; Sepsis/complications* ; Shock, Septic/drug therapy* ; Cardiomyopathies/etiology* ; Prognosis

Objective: To analyze the eligibility of empirical antibiotic therapy in culture positive sepsis in the pediatric intensive care unit (PICU), and to explore the application of antibiotic de-escalation (ADE) in children with sepsis and its impact on prognosis. Methods: A total of 123 children with sepsis-associated organ dysfunction or septic shock admitted to the PICU of Shengjing Hospital of China Medical University from January 2018 to December 2020 were retrospectively analyzed. The general information, laboratory tests, the use of empirical anti-bacterial drugs and the application of ADE were collected. According to the adjustment of anti-bacterial drugs, these children were divided into ADE group and non-ADE group. Comparisons between groups were performed with unpaired Student t test, or Mann-Whitney U test, or chi-square test or Fisher exact test. Results: In these 123 children, 70 were males and 53 were females, the age was 11.4 (2.8, 56.5) months. Body fluid culture was detected positive in 41 children including 3 children (7.3%) who received inadequate empirical antibiotic therapy and 38 children (92.7%) who received adequate empirical antibiotic therapy. Excluding 10 children who received appropriate therapy, 28 received unnecessary broad-spectrum antibiotics. There were no significant differences regarding the PICU all-cause mortality rates, length of PICU stay, hospitalization cost, duration of mechanical ventilation, as well as incidences of re-infection between the ADE group (n=46) and non-ADE group (n=77) (all P>0.05). However, among the 101 children who have used antibiotics against multidrug-resistant organism, the duration of such antibiotics use in ADE group (n=43) was shorter than that in non-ADE group (n=58) (5.0 (4.0, 12.0) vs. 9.5 (7.0, 13.0) d, Z=-3.14, P=0.002). Conclusions: Overuse of unnecessary broad-spectrum empirical antibiotics is very common, but the application of ADE is rather disappointing. ADE can reduce the use of anti-bacterial drugs against multi-drug resistant bacteria without significant adverse effects on prognosis in children with sepsis.
Anti-Bacterial Agents/therapeutic use* ; Child ; Female ; Humans ; Infant ; Male ; Prognosis ; Retrospective Studies ; Sepsis/drug therapy* ; Shock, Septic

This paper clarified the scientific connotation of the changes in cold and heat properties of Arisaematis Rhizoma and Arisaema Cum Bile through investigating the changes of substance and energy metabolism after drug intervention in the rats with normal and cold/heat syndrome, so as to improve the method of evaluating the drug properties of Chinese medicine. After one week of adaptive feeding, healthy male SD rats were randomly divided into three parts: normal rats, heat syndrome rat models, and cold syndrome rat models. Through ice water bath and oral euthyrox(120 μg·kg~(-1)), the models of cold syndrome and heat syndrome were induced, respectively. The models were made at 9:00 am. and administrated by gavage at 3:00 pm. every day. All administration groups were administrated with Arisaematis Rhizoma and Arisaema Cum Bile decoction, respectively, and the blank group was given the same dose of normal saline. After continuous administration for 15 d, the rats were anesthetized by chloral hydrate, blood was taken from abdominal aorta, and the hearts and livers were removed and stored at-80 ℃. The changes in the body weight and anal temperature of rats during administration were detected, and the liver coefficient of rats was detected after removing the liver. Enzyme-linked immunosorbent assay(ELISA) was adopted to detect the expression level of the indexes related to substance and energy metabolism in liver and heart of rat, and Western blot was used to detect the expression of key proteins in AMPK/mTOR signaling pathway for further verification. The results showed that Arisaematis Rhizoma enhanced the expression level of enzymes related to substance and energy metabolism in the normal and cold and heat syndrome rat models, and increased anal temperature, which exhibited warm(hot) drug property. Arisaema Cum Bile inhibited the level of substance and energy metabolism in rats, and reduced anal temperature, which showed cold(cool) drug property. Chinese Pharmacopoeia has recorded "Arisaematis Rhizoma has warm property and Arisaema Cum Bile has cool property", which is consistent with the phenomenon in this study. Therefore, it is feasible to evaluate the drug properties of Chinese medicine based on the substance and energy metabolism of normal and cold/heat syndrome model rats, which completes the method of evaluating drug properties of Chinese medicine.
AMP-Activated Protein Kinases ; Animals ; Arisaema/chemistry* ; Bile ; Chloral Hydrate ; Cold-Shock Response/drug effects* ; Drugs, Chinese Herbal/therapeutic use* ; Energy Metabolism ; Heat Stroke/therapy* ; Hot Temperature ; Male ; Rats ; Rats, Sprague-Dawley ; Saline Solution ; Syndrome ; TOR Serine-Threonine Kinases ; Thyroxine ; Water

OBJECTIVE: To investigate the effects of Shenfu Injection (, SFI) on endothelial damage in a porcine model of hemorrhagic shock (HS). METHODS: After being bled to a mean arterial pressure of 40±3 mm Hg and held for 60 min, 32 pigs were treated with a venous injection of either shed blood (transfusion group), shed blood and saline (saline group), shed blood and SFI (SFI group) or without resuscitation (sham group). Venous blood samples were collected and analyzed at baseline and 0, 1, 2, 4, and 6 h after HS. Tumor necrosis factor-α (TNF-α), serum interleuking (IL)-6, and IL-10 levels were measured by enzyme-linked immunosorbent assay (ELISA); expressions of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM -1), von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1) and Bcl-2, Bax, and caspase-3 proteins were determined by Western blot. RESULTS: The serum level of TNF-α in the SFI group was significantly lower than in the other groups at 0, 1, and 2 h after HS, while the level of IL-6 was lower at 4 and 6 h compared with the saline group (P<0.01 or P<0.05). The concentration of serum IL-10 was significantly higher in the SFI group than in the other groups at 0, 1, 4, and 6 h after HS (P<0.01). Western blot and immunohistochemistry of vascular tissue showed that the expression of caspase-3 was downregulated, and that of Bcl-2 and Bax was upregulated in the SFI group compared to other groups (P<0.05). CONCLUSION SFI attenuated endothelial injury in the porcine model of HS by inhibiting cell apoptosis, suppressing the formation of proinflammatory cytokines, and reducing endothelial activation.
Animals ; Caspase 3/metabolism* ; Drugs, Chinese Herbal ; Interleukin-10 ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Shock, Hemorrhagic/drug therapy* ; Swine ; Tumor Necrosis Factor-alpha/metabolism* ; bcl-2-Associated X Protein/metabolism*

Objective: To investigate the pathogen composition, initial anti-infectives and pathogen coverage, and trends over the last 5 years in children with septic shock in pediatric intensive care unit (PICU). Methods: The single-center retrospective study included 257 children with septic shock who were admitted to PICU of Beijing Children's Hospital, Capital Medical University from 2017 to 2021. The causitive pathogen composition, initial use of anti-infective drugs, pathogen coverage, and changes in recent years were analyzed. The children were divided into sufficient and insufficient coverage groups according to whether the pathogen were sufficiently covered by initial anti-infectives; community-and hospital-acquired groups; and with and without underlying disease groups. T test, rank-sum test and Chi-square test were used for comparison between the groups to investigate the differences in pathogen, treatment and prognosis. Results: A total of 257 septic shock children were included, with 162 males and 95 females, aged 36 (12, 117) months. The pathogen positive rate was 64.6% (166/257) and the in-hospital mortality was 27.6% (71/257). In the 208 pathogen-positive samples, bacteria was the most common (57.7%, 120/208) with G-negative bacteria predominating (55.8%, 67/120), followed by viruses (26.0%, 54/208). Nearly 99.2% (255/257) of the children were treated with antibacterial at the beginning, of whom 47.1% (121/257) were treated with carbapenems combined with vancomycin or linezolid. The proportion of 3 or more antibacterial combinations was higher in children with underlying diseases and hospital-acquired septic shock than in those without underlying disease or community-acquired septic shock (27.4% (49/179) vs. 14.1% (11/78), 29.4% (52/177) vs. 10.0% (8/80), χ²=5.35,11.56,all P<0.05). The proportion of initial combination of carbapenem and vancomycin or linezolid reduced from 52.5% (21/40) to 41.3% (19/46), and of adequate pathogen coverage increased from 40.0% (16/40) to 58.7% (27/46) in the last five years. Conclusions: The initial use of antibacterial drugs is common in children with septic shock in PICU, especially in those with hospital-acquired septic shock and underlying diseases. In recent years, antimicrobial combinations have decreased, but the pathogen coverage has improved, indicating that drug selection is more reasonable and accurate.
Child ; Female ; Male ; Humans ; Shock, Septic/drug therapy* ; Linezolid ; Vancomycin ; Retrospective Studies ; Anti-Infective Agents/therapeutic use* ; Anti-Bacterial Agents/therapeutic use* ; Carbapenems

Objective: To analyze the status of early use of oral β-blocker and its relationship with in-hospital outcomes in eligible patients with acute coronary syndrome (ACS). Methods: The study was based on the Improving Care for Cardiovascular Disease in China (CCC)-ACS project. The data of ACS patients that collected during 2014 to 2019 from 230 collaborating hospitals across China were analyzed. Propensity score matching method and Cox multivariate regression analysis were used to analyze the association between early use of oral β-blocker and in-hospital outcomes within 15 days. Results: A total of 38 663 eligible ACS patients were included in this study. The mean age was (57.0±9.0), and 78.8% of the ACS patients (30 470/38 663) were male. The proportion of early use of oral β-blockers was 64.9% (25 112/38 663), but varied substantially, in the 230 hospitals with a range from 0 to 100%. Compared with the patients no early use of oral β-blocker, the patients receiving early oral β-blocker had significantly lower incidence of major cardiovascular adverse events (MACEs) (3.4% (395/11 536) vs. 2.9%(339/11 536), P=0.036)and less occurrences of heart failure (2.7% (316/11 536) vs. 2.1% (248/11 536), P=0.004). Multivariate Cox regression analyses showed the patients receiving early oral β-blocker had 15.5%, 23.1%, and 35.3% lower risks of MACEs, heart failure and cardiogenic shock respectively than the patients no early oral β-blocker. Conclusions: Compared with the patients no early oral β-blocker, the patients receiving early oral β-blocker had lower risks of MACEs events, heart failure and cardiogenic shock. However, the early use of oral β-blocker in ACS patients was generally insufficient with huge differences among different hospitals in China.
Acute Coronary Syndrome/drug therapy* ; Adrenergic beta-Antagonists/therapeutic use* ; Heart Failure ; Hospitals ; Humans ; Male ; Shock, Cardiogenic