This study investigated the mechanism of Gegen Qinlian Decoction(GQD) in improving glucose metabolism in vitro and in vivo by alleviating endoplasmic reticulum stress(ERS). Molecular docking was used to predict the binding affinity between the main effective plasma components of GQD and ERS-related targets. Liver tissue samples were obtained from normal rats, high-fat-induced diabetic rats, rats treated with metformin, and rats treated with GQD. RNA and protein were extracted. qPCR was used to measure the mRNA expression of ERS marker glucose-regulated protein 78(GRP78), and unfolded protein response(UPR) genes inositol requiring enzyme 1(Ire1), activating transcription factor 6(Atf6), Atf4, C/EBP-homologous protein(Chop), and caspase-12. Western blot was used to detect the protein expression of GRP78, IRE1, protein kinase R-like ER kinase(PERK), ATF6, X-box binding protein 1(XBP1), ATF4, CHOP, caspase-12, caspase-9, and caspase-3. The calcium ion content in liver tissues was determined by the colorimetric assay. The ERS-HepG2 cell model was established in vitro by inducing with tunicamycin for 6 hours, and 2.5%, 5%, and 10% GQD-containing serum were administered for 9 hours. The glucose oxidase method was used to measure extracellular glucose levels, flow cytometry to detect cell apoptosis, glycogen staining to measure cellular glycogen content, and immunofluorescence to detect the expression of GRP78. The intracellular calcium ion content was measured by the colorimetric assay. Whereas Western blot was used to detect GRP78 and ERS-induced IRE1, PERK, ATF6, and eukaryotic translation initiation factor 2α(eIF2α) phosphorylation. Additionally, the phosphorylation levels of insulin receptor substrate 1(IRS1), phosphatidylinositol 3-kinase regulatory subunit p85(PI3Kp85), and protein kinase B(Akt), which were involved in the insulin signaling pathway, were also measured. In addition, the phosphorylation levels of c-Jun N-terminal kinases(JNKs), which were involved in both the ERS and insulin signaling pathways, were measured by Western blot. Molecular docking results showed that GRP78, IRE1, PERK, ATF4, and various compounds such as baicalein, berberine, daidzein, jateorhizine, liquiritin, palmatine, puerarin and wogonoside had strong binding affinities, indicating that GQD might interfere with ERS-induced UPR. In vivo results showed that GQD down-regulated the mRNA transcription of Ire1, Atf6, Atf4, Grp78, caspase-12, and Chop in diabetic rats, and down-regulated GRP78, IRE1, PERK, as well as ERS-induced apoptotic factors ATF4 and CHOP, caspase-12, caspase-9, and caspase-3, while up-regulating XBP1 to enhance adaptive UPR. In addition, GQD increased the calcium ion content in liver tissues, which facilitated correct protein folding. In vitro results showed that GQD increased glucose consumption in ERS-induced HepG2 cells without significantly affecting cell viability, increased liver glycogen synthesis, down-regulated ATF6 and p-eIF2α(Ser51), and down-regulated IRE1, PERK, and GRP78, as well as p-IRS1(Ser312) and p-JNKs(Thr183/Tyr185), while up-regulating p-PI3Kp85(Tyr607) and p-Akt(Ser473). These findings suggested that GQD alleviates excessive ERS in the liver, reduces insulin resistance, and improves hepatic glucose metabolism in vivo and in vitro.
Rats ; Animals ; Proto-Oncogene Proteins c-akt ; Endoplasmic Reticulum Chaperone BiP ; Caspase 3 ; Caspase 9 ; Diabetes Mellitus, Experimental ; Caspase 12 ; Calcium/pharmacology* ; Molecular Docking Simulation ; Endoplasmic Reticulum Stress ; Protein Serine-Threonine Kinases/genetics* ; Liver ; Apoptosis ; Insulin ; Glucose ; Glycogen/pharmacology* ; RNA, Messenger

Early colorectal cancers refer to invasive cancers that have infiltrated into the submucosa without invading muscularis propria, and approximately 10% of these patients have lymph node metastases that cannot be detected by conventional imaging. According to the guidelines of Chinese Society of Clinical Oncology (CSCO) Colorectal Cancer, early colorectal cancer cases with risk factors for lymph node metastasis (poor tumor differentiation, lymphovascular invasion, deep submucosal invasion and high-grade tumor budding) should receive salvage radical surgical resection; however, the specificity of this risk-stratification is inadequate, making most patients undergo unnecessary surgery. Firstly, this review focuses on the definition, oncological impact importance and controversy of the above "risk factors". Then, we introduce the progress of the risk stratification system for lymph node metastasis in early colorectal cancer, including the identification of new pathological risk factors, the construction of new risk quantitative models based on pathological risk factors, artificial intelligence and machine learning technology and the discovery of novel molecular markers associated with lymph node metastasis based on gene test or liquid biopsy. Aim to enhance clinicians' understanding of the risk assessment of lymph node metastasis in early colorectal cancer; we suggest to take the patient's personal situation, tumor location, anti-cancer intention and other factors into account to make individualized treatment strategies.
Humans ; Lymphatic Metastasis/pathology* ; Artificial Intelligence ; Colorectal Neoplasms/surgery* ; Risk Factors ; Risk Assessment ; Neoplasm Invasiveness ; Lymph Nodes/pathology*

During coronavirus disease 2019 epidemic, the treatment of severe trauma has been impacted. The Consensus on emergency surgery and infection prevention and control for severe trauma patients with 2019 novel corona virus pneumonia was published online on February 12, 2020, providing a strong guidance for the emergency treatment of severe trauma and the self-protection of medical staffs in the early stage of the epidemic. With the Joint Prevention and Control Mechanism of the State Council renaming "novel coronavirus pneumonia" to "novel coronavirus infection" and the infection being managed with measures against class B infectious diseases since January 8, 2023, the consensus published in 2020 is no longer applicable to the emergency treatment of severe trauma in the new stage of epidemic prevention and control. In this context, led by the Chinese Traumatology Association, Chinese Trauma Surgeon Association, Trauma Medicine Branch of Chinese International Exchange and Promotive Association for Medical and Health Care, and Editorial Board of Chinese Journal of Traumatology, the Chinese expert consensus on emergency surgery for severe trauma and infection prevention during coronavirus disease 2019 epidemic ( version 2023) is formulated to ensure the effectiveness and safety in the treatment of severe trauma in the new stage. Based on the policy of the Joint Prevention and Control Mechanism of the State Council and by using evidence-based medical evidence as well as Delphi expert consultation and voting, 16 recommendations are put forward from the four aspects of the related definitions, infection prevention, preoperative assessment and preparation, emergency operation and postoperative management, hoping to provide a reference for severe trauma care in the new stage of the epidemic prevention and control.

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.
Female ; Humans ; Male ; Aged ; Middle Aged ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy* ; Prognosis ; Lymphoma, B-Cell ; Immunohistochemistry ; Immunoglobulin Heavy Chains/therapeutic use*

Aristolochic acid (AA), extracted from Aristolochiaceae plants, plays an essential role in traditional herbal medicines and is used for different diseases. However, AA has been found to be nephrotoxic and is known to cause aristolochic acid nephropathy (AAN).AA-induced acute kidney injury (AKI) is a syndrome in AAN with a high morbidity that manifests mitochondrial damage as a key part of its pathological progression. Melatonin primarily serves as a mitochondria-targeted antioxidant. However, its mitochondrial protective role in AA-induced AKI is barely reported. In this study, mice were administrated 2.5 mg/kg AA to induce AKI. Melatonin reduced the increase in Upro and Scr and attenuated the necrosis and atrophy of renal proximal tubules in mice exposed to AA. Melatonin suppressed ROS generation, MDA levels and iNOS expression and increased SOD activities in vivo and in vitro. Intriguingly, the in vivo study revealed that melatonin decreased mitochondrial fragmentation in renal proximal tubular cells and increased ATP levels in kidney tissues in response to AA. In vitro, melatonin restored the mitochondrial membrane potential (MMP) in NRK-52E and HK-2 cells and led to an elevation in ATP levels. Confocal immunofluorescence data showed that puncta containing Mito-tracker and GFP-LC3A/B were reduced, thereby impeding the mitophagy of tubular epithelial cells. Furthermore, melatonin decreased LC3A/B-II expression and increased p62 expression. The apoptosis of tubular epithelial cells induced by AA was decreased. Therefore, our findings revealed that melatonin could prevent AA-induced AKI by attenuating mitochondrial damage, which may provide a potential therapeutic method for renal AA toxicity.

According to the taste analysis of Pudilan Xiaoyan Oral Liquid, the unpleasant taste of the oral liquid is mainly caused by the inherent taste of Chinese medicine and the taste introduced in the preparation process, which leads to its unpopularity among children. Therefore, aiming at the special children patient group, Xiaoer Pudilan Xiaoyan Syrup was developed via technology optimization and dosage form improvement to improve the unpleasant taste and enhance the medication compliance among children. Based on the material properties of Pudilan Xiaoyan Oral Liquid and Xiaoer Pudilan Xiaoyan Syrup extracts, the authors compared the properties(pH, density, turbidity, viscosity, chromaticity, particle size), taste, content of five quality markers and in vivo pharmacokinetic characteristics of these two preparations, to evaluate the suitability of Xiaoer Pudilan Xiaoyan Syrup. The results showed that compared with those of Pudilan Xiaoyan Oral Liquid, the pH, density, turbidity, viscosity and chromaticity of Xiaoer Pudilan Xiaoyan Syrup were significantly changed, and the unpleasant taste was reduced by 26%; the transfer rate of the main active ingredients chicoric acid was increased, while the transfer rate of baicalin had small difference from that of the oral liquid. In addition, pharmacokinetics revealed that the total absorption amount of baicalin in vivo was higher, and the time to peak T_(max) of baicalin and oroxindin in the syrup and the mean residence time MRT_(last )of corynoline in vivo were significantly prolonged. The absorption degree of Xiaoer Pudilan Xiaoyan Syrup and Pudilan Xiaoyan Oral Liquid in the body was the same: baicalin>oroxindin>corynoline. The new dosage form process was simpler than that of the original dosage form, safe, environmentally friendly, reasonable and feasible, meeting the mass production demand. This provided a basis for the reasonable and scientific optimization of Xiaoer Pudilan Xiaoyan Syrup, and also laid a foundation for its further safe and rational use, so as to expand the clinical application in children.
Child ; Humans ; Drugs, Chinese Herbal ; Glucuronates

Objective:To explore the effect of play-based communication and behavior intervention (PCBI) on internalizing and externalizing behaviors in children with autism spectrum disorder (ASD).Methods:From November 2018 to November 2021, 90 ASD children aged 8-30 months who registered in the Child Mental Health Research Center of the Affiliated Brain Hospital of Nanjing Medical University for PCBI ultra-early intervention training were selected and randomly assigned to the intervention group( n=60) and the waiting group( n=30) according to the ratio of 2∶1.Behavioral videos of free play between children and caregivers were collected before and after the 12-week intervention and the behavioral observation and analysis system (Observer XT) was used to code the parent-child interaction status and children's internalizing and externalizing behaviors.SPSS 23.0 statistical software were used and the data were analyzed by t-test, chi-square test, Pearson correlation analysis and multiple linear stepwise regression analysis. Results:After the intervention, the children in the intervention group had improved internalizing and externalizing behaviors (2.43±2.22, 1.88±1.91) compared with those before the intervention (4.82±3.37, 3.68±5.68), and the difference was statistically significant ( t=4.66, 2.60, both P<0.05). The children in the waiting group had no significant difference in internalizing and externalizing behaviors before (4.23±2.47, 4.00±2.18) and after intervention (4.37±2.57, 4.67±3.72) ( t=-0.23, -0.83, both P>0.05). After intervention, the children in the intervention group had fewer internalizing and externalizing behaviors than those in the waiting group, and the difference was statistically significant ( t=-3.70, -4.71, both P<0.05). The differences in internalizing behaviors (2.38±3.96, 1.80±5.37) and externalizing behaviors (1.80±5.37, -0.67±4.38) between the two groups before and after the intervention were statistically significant ( t=3.03, 2.18, both P<0.05). The results of multiple linear stepwise regression showed that the negative interaction of caregivers ( β=0.29, P<0.01) was a risk factor for internalizing behaviors.The negative interaction of children ( β=0.45, P<0.01) was a risk factor for externalizing behaviors, and the child's object status ( β=-0.30, P<0.01) and binary interaction ( β=-0.39, P<0.01) were protective factors for externalizing behaviors.In the intervention group, active child interaction, active caregiver interaction, and binary interaction increased after the intervention ( t=-6.77, -4.58, -7.72, all P<0.05), while the child's object status and the caregiver's negative interaction decreased ( t=3.37, 4.30, both P<0.05). Conclusion:The PCBI ultra-early intervention can effectively improve the internalizing and externalizing behaviors of ASD children.Improvements in internalizing behaviors may work by reducing negative caregiver interactions, and improvements in externalizing behaviors may work by increasing parent-child binary interactions.

Objective: To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development (DSD). Methods: A retrospective study of 1 235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021. After capturing 277 DSD-related candidate genes, second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes. Results: Among 1 235 children with clinically proposed DSD, 980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years. A total of 443 children with pathogenic variants were detected through molecular genetic studies, with a positive detection rate of 35.9%. The most common clinical phenotypes were micropenis (455 cases), hypospadias (321 cases), and cryptorchidism (172 cases) and common mutations detected were in SRD5A2 gene (80 cases), AR gene (53 cases) and CYP21A2 gene (44 cases). Among them, the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias, while the AMH mutation is the most common in children with simple cryptorchidism. Conclusions: The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD, and micropenis, cryptorchidism, and hypospadias are the most common clinical phenotypes. Molecular diagnosis can provide clues about the biological basis of DSD, and can also guide clinicians to perform specific clinical examinations. Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics* ; Child ; China/epidemiology* ; Cryptorchidism/genetics* ; Disorders of Sex Development/genetics* ; Female ; Genital Diseases, Male ; Genotype ; Humans ; Hypospadias/genetics* ; Male ; Membrane Proteins/genetics* ; Penis/abnormalities* ; Phenotype ; Retrospective Studies ; Steroid 21-Hydroxylase/genetics*

Haining City and Jiashan County in Zhejiang Province are the first areas to carry out colorectal cancer screening in China, which started in the early 1970s and has been going on for more than 40 years. Meanwhile, Haining and Jiashan have also become the first batch of National Demonstration Bases for Early Diagnosis and Treatment of Colorectal Cancer. In the past 40 years, owing to Professor Zheng Shu who is brave and innovative, with an indomitable spirit, as well as the unremitting efforts and active exploration of all the team members, colorectal cancer screening which was unknown by the public and implemented with difficulties, has gradually been widely accepted and benefited the population. Today, remarkable achievements have been fulfilled in the colorectal cancer screening of Haining and Jiashan which has become the pioneer power in promoting the progress of colorectal cancer prevention and control in China and has certain influence both on China and the world. Meanwhile, a set of colorectal cancer screening strategies suitable for China has been explored and further promoted to be used nationwide, which is of great significance to the prevention and control of colorectal cancer in China. Looking forward to the future, the prevention and control of colorectal cancer in China is still difficult. We will continue to give full play to our existing advantages, not forget our original intention, move forward, explore innovation, and create greater glories!
China/epidemiology* ; Colonic Neoplasms/diagnosis* ; Colorectal Neoplasms/diagnosis* ; Early Detection of Cancer/statistics & numerical data* ; History, 20th Century ; Humans ; Mass Screening/methods* ; Rural Population/statistics & numerical data*

Objective To evaluate the association between diabetic retinopathy (DR) and mean ocular perfusion pressure (MOPP) in patients with type 2 diabetes mellitus (T2DM).Methods Patients from the Fushun Diabetic Retinopathy Cohort Study (FS-DIRECT), a communitybased prospective cohort study conducted in northeast China, were included in this study. The presence and severity of DR were determined by grading fundus photographs according to the Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy scale. Systolic and diastolic blood pressure (SBP and DBP) were recorded using an electronic sphygmomanometer. Intraocular pressure (IOP) was measured using an iCare rebound tonometer. MOPP was calculated using the formula MOPP = 2/3 [DBP + 1/3(SBP ? DBP)] ? IOP.Results In total, 1,857 patients who had gradable fundus photography and MOPP data were enrolled in this study. Male patients had a higher MOPP than female patients (52.25 ± 8.75 vs. 50.96 ± 8.74mmHg, P = 0.002). Overall, both male and female patients with any type of DR, non-proliferative DR (NPDR), or non-sight-threatening DR (non-STDR) had significantly higher MOPP relative to patients without DR. Increased MOPP (per 1 mmHg) was in turn associated with the presence of any type of DR [odds ratio (OR) = 1.03, 95％ confidence interval (CI) : 1.02–1.04], NPDR (OR = 1.0395％ CI: 1.02–1.04),and non-STDR (OR = 1.03, 95％ CI: 1.01–1.04) after adjusting for confounders. Increased MOPP (per 1 mmHg) was also associated with an increased likelihood of macular edema (OR = 1.02, 95％ CI:1.01–1.04).Conclusions The results suggest that increased MOPP was associated with DR and macular edema in northeastern Chinese patients with T2DM.