OBJECTIVE: To identify the underlying molecular mechanism of Modified Hu-Lu-Ba-Wan (MHW) in alleviating renal lesions in mice with diabetic kidney disease (DKD). METHODS: The db/db mice were divided into model group and MHW group according to a random number table, while db/m mice were settled as the control group (n=8 per group). The control and model groups were gavaged daily with distilled water [10 mL/(kg·d)], and the MHW group was treated with MHW [17.8 g/(kg·d)] for 6 weeks. After MHW administration for 6 weeks, indicators associated with glucolipid metabolism and urinary albumin were tested. Podocytes were observed by transmission electron microscopy. Kidney transcriptomics was performed after confirming therapeutic effects of MHW on DKD mice. The relevant target of MHW' effect in DKD was further determined by enzyme-linked immunosorbent assay, Western blot analysis, immunohistochemistry, and immunofluorescence staining. RESULTS: Compared with the model group, MHW improved glucose and lipid metabolism (P<0.05), and reduced lipid deposition in the kidney. Meanwhile, MHW reduced the excretion of urinary albumin (P<0.05) and ameliorated renal damage. Transcriptomic analysis revealed that the inflammation response, particularly the interleukin-17 (IL-17) signaling pathway, may be responsible for the effect of MHW on DKD. Furtherly, our results found that MHW inhibited IL-17A and alleviated early fibrosis in the diabetic kidney. CONCLUSION MHW ameliorated renal damage in DKD via inhibiting IL-17A, suggesting a potential strategy for DKD therapy.
Animals ; Diabetic Nephropathies/genetics* ; Interleukin-17/antagonists & inhibitors* ; Drugs, Chinese Herbal/therapeutic use* ; Male ; Kidney/ultrastructure* ; Podocytes/metabolism* ; Mice ; Albuminuria ; Lipid Metabolism/drug effects* ; Mice, Inbred C57BL

Cells not only contain membrane-bound organelles (MBOs), but also membraneless organelles (MLOs) formed by condensation of many biomacromolecules. Examples include RNA-protein granules such as nucleoli and PML nuclear bodies (PML-NBs) in the nucleus, as well as stress granules and P-bodies in the cytoplasm. Phase separation is the basic organizing principle of the form of the condensates or membraneless organelles (MLOs) of biomacromolecules including proteins and nucleic acids. In particular, liquid-liquid phase separation (LLPS) compartmentalises and concentrates biological macromolecules into liquid condensates. It has been found that phase separation of biomacromolecules requires some typical intrinsic characteristics, such as intrinsically disordered regions, modular domains and multivalent interactions. The phase separation of biomacromolecules plays a key role in many important cell activities. In recent years, the phase separation of biomacromolecules phase has become a focus of research in gene transcriptional regulation. Transcriptional regulatory elements such as RNA polymerases, transcription factors (TFs), and super enhancers (SEs) all play important roles through phase separation. Our group has previously reported for the first time that long-term inactivation or absence of assembly factors leads to the formation of condensates of RNA polymerase II (RNAPII) subunits in the cytoplasm, and this process is reversible, suggesting a novel regulatory model of eukaryotic transcription machinery. The phase separation of biomacromolecules provides a biophysical understanding for the rapid transmission of transcriptional signals by a large number of TFs. Moreover, phase separation during transcriptional regulation is closely related to the occurrence of cancer. For example, the activation of oncogenes is usually associated with the formation of phase separation condensates at the SEs. In this review, the intrinsic characteristics of the formation of biomacromolecules phase separation and the important role of phase separation in transcriptional regulation are reviewed, which will provide reference for understanding basic cell activities and gene regulation in cancer.

Tripterifordin and neotripterifordin are important ent-kaurane diterpenoids in the Chinese medicinal herb Tripterygium wilfordii, possessing significant anti-HIV(human immunodeficiency virus) activity. On the basis of elucidating the natural biosynthetic pathways of these compounds, heterologous production with microbial cell factories can help to alleviate the reliance on plant resources and provide abundant raw materials for sustainable production. TwKO is the first CYP450 enzyme involved in the biosynthesis of tripterifordin and neotripterifordin. This study aimed to enhance the catalytic activity of TwKO by site-directed mutagenesis to benefit the production of tripterifordin and neotripterifordin in yeast. The AlphaFold DB established based on the AlphaFold 2 was employed to obtain the protein model of TwKO. According to multiple sequence alignments and principles of natural evolution, the key residues influencing the binding of TwKO to the substrate were identified. Subsequently, functional characterization of the mutants were conducted in Saccharomyces cerevisiae. A total of 71 mutants were obtained, among which 11 and 11 mutants had the abilities of enhancing the production of 16α-hydroxy-ent-kaurenol and 16α-hydroxy-ent-kaurenoic acid, respectively. In addition, 10 mutants could increase the proportion of the oxidation product of 16α-hydroxy-ent-kaurenol. In particular, R304 was identified as a key residue affecting the catalytic specificity of TwKO, the mutation of which led to the specific prodiction of 16α-hydroxy-ent-kaurenol. This study was the first to reveal the key residue affecting the catalytic activity of TwKO and obtained the mutants with increased TwKO activity, lay a foundation for the biosynthesis of tripterifordin and neotripterifordin.
Tripterygium/chemistry* ; Mutagenesis, Site-Directed ; Diterpenes, Kaurane/chemistry* ; Plant Proteins/chemistry* ; Cytochrome P-450 Enzyme System/chemistry* ; Saccharomyces cerevisiae/metabolism*

OBJECTIVE: To explore the association between depressive symptoms and the risks of rapid decline in renal function and chronic kidney disease (CKD) in middle-aged and elderly with normal kidney function. METHODS: The residents aged 40- 75 years with eGFR≥60 mL·min^-1·1.73 m^-2 without proteinuria in Lanzhou region, who participated in the "REACTION" study carried out in 2011, were selected and followed up in 2014. A total of 4961 individuals with complete and qualified data from the two surveys were included in the subsequent analysis. Based on PHQ-9 questionnaire scores, the baseline population was divided into two groups with and without depressive symptoms. Cox proportional hazard analysis was used to compare the incidences of rapid renal function decline and CKD between the two groups and study the association of depressive symptoms with the risk of these renal conditions. RESULTS: PHQ-9 questionnaire scores were not found to correlate with baseline SCr, ALB, UACR or eGFR levels among the participarts (P>0.05). After a mean follow-up time of 3.4±0.6 years, 33.9% of the participants with depressive symptoms at baseline experienced a rapid decline in renal function and 3.6% progressed to CKD. During the follow-up, the incidence of rapid decline in renal function and the risk of developing CKD were not found to correlate with depressive symptoms in these participants (P>0.05) regardless of the type of the depressive syndromes. CONCLUSION Depressive symptoms are not associated with the risks of rapid renal function decline or progression to CKD in middle-aged and elderly with normal kidney function.
Aged ; Middle Aged ; Humans ; Cohort Studies ; Depression ; Glomerular Filtration Rate ; Disease Progression ; Renal Insufficiency, Chronic/epidemiology* ; Kidney/physiology* ; Risk Factors

Objective:Bibliometric analysis of SCI papers in Shanghai tertiary obstetrics and gynecology specialized hospitals from 2017 to 2021 was conducted to provide reference for further improving management measures and optimizing the quality of SCI papers in specialized hospitals.Methods:The Web of Science database was used to retrieve SCI papers published by tertiary obstetrics and gynecology specialized hospitals in Shanghai from 2017 to 2021. Based on bibliometric methods VOSviwer 1.6.17 and Scimago Graphica 1.0.23 was adopted to analyze the number, journals, domestic and international cooperation, and hot research areas.Results:2 721 papers were published by Shanghai Tertiary A obstetrics and Gynecology hospitals from 2017 to 2021. These papers published in 765 journals. The number of papers published and publication journals increased year by year. The number of papers and journals with an impact factor of 3~5 is the largest, accounting for 37.96% and 35.95% of the total number of papers and journals respectively. However, papers and journals with more than 10 points accounted for only 7.98% and 10.20% respectively. Scientific Reports, a comprehensive journal, published the largest number of papers. International cooperation is concentrated in the United States. Domestic cooperation is concentrated in universities and research institutions in Jiangsu, Zhejiang and Shanghai. The hot research areas focused on Oncology, Obstetrics & Gynecology, Genetics, Reproductive Biology and other basic medical fields.Conclusions:The number of papers published by Shanghai's tertiary obstetrics and gynecology specialized hospitals has increased year by year, but there are fewer highly influential journals. Domestic and international scientific research cooperation is limited to several institutions. The achievements in the field of basic research are far more than those in clinical research.

Tigliane type macrocyclic diterpenoids with special structures and diverse bioactivities are mainly extracted from plants of Euphorbiaceae and Thymelaeaceae. According to the different functional groups, they can be classified into types of phorbol esters, C-4 deoxyphorbol esters, C-12 deoxyphorbol esters, C-16 or C-17 substituted phorbol esters and others. Most of them present promising antiviral activities and cytotoxic activities and are expected to be developed as candidates for anti-AIDS, anti-tuberculosis, and anti-tumor clinical trials, demonstrating great potential for the application in healthcare. This paper reviews 115 novel tigliane-type diterpenoids discovered since 2013 and summarize their chemical structures and bioactivities, aiming to lay a foundation for further development and utilization of these compounds and provide new ideas for the development of clinical drugs.
Phorbols ; Molecular Structure ; Diterpenes/chemistry* ; Antiviral Agents ; Phorbol Esters

Humans ; Heart Failure/therapy* ; Stroke Volume ; Consensus ; Ventricular Function, Left

Humans ; Heart Failure/therapy* ; Stroke Volume ; Consensus ; Ventricular Function, Left

ObjectiveTo observe the regulatory effect of Xiao Qinglongtang and its ingredients on lung water transport-related proteins， and to explain the biological connotation of lung governing water movement， based on which the regulatory mechanism of Xiao Qinglongtang will be explored. MethodAccording to the composition rules of classical formula， Xiao Qinglongtang （11.22 g·kg^-1）， Guizhi Gancao （2.70 g·kg^-1）， Shaoyao Gancao （2.70 g·kg^-1）， Jiangxinwei （3.90 g·kg^-1）and Banxia Muahuang （0.032 7 g·kg^-1） were prepared. The pathological model of syndrome of cold fluid accumulated in lung of rats was established by the "coldness of body + drinking cold + cold bath" method， and Xiao Qinglongtang and its ingredients were administrated to intervene with the model rats. Lung function parameters of forced vital capacity （FVC）， functional residual capacity （FRC）， mean mid-expiratory flow （MMEF）， inspiratory time （tI）， and inspiratory time （tE） were determined by lung function analyzer. Hematoxylin and eosin （HE） staining was used to observe the changes in pathological morphology. The expression of aquaporin （AQP）1， AQP5， epithelial sodium channel α subunit（α-ENaC） and Na⁺-K⁺-ATPase in lung tissues of rats， the content of tumor necrosis factor -α（TNF-α）， the mRNA expression of cyclic adenosine monophosphate （cAMP）， protein kinase A （PKA） and cAMP-response element binding protein （CREB）， and the protein expression of cAMP， PKA， CREB， and phosphorylated-CREB （p-CREB） were detected by immunohistochemistry （IHC）， enzyme-linked immunosorbent assay （ELISA）， Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）， and Western blot， respectively. ResultCompared with normal group， functions of FVC， FRC and MMEF in model group were significantly decreased (P<0.01)， and the time of tI and tE was significantly prolonged （P<0.05，P<0.01）. The content of TNF-α in lung tissue was significantly increased （P<0.01）. The mRNA and protein expressions of cAMP， PKA and CREB in lung tissue were significantly decreased （P<0.01）. The expression of AQP5 and α-ENAC in lung tissue decreased significantly. The alveolar cavity of rats was filled with edema fluid， surrounding tissue hyperemia， inflammatory cell infiltration, bronchial mucosa epithelial adhesion. Compared with model group， Xiao Qinglongtang and its fangyuan group could significantly enhance the FVC, FRC and MMEF functions of model rats （P<0.05，P<0.01）， and tI and tE time were shortened （P<0.05，P<0.01）. The content of TNF-α in lung tissues of Xiao Qinglongtang group， Guizhi Gancao group and Banxia Mahuang group was significantly decreased （P<0.01）. The mRNA expressions of cAMP， PKA and CREB in Xiao Qinglongtang group were significantly up-regulated （P<0.01）， and the mRNA expressions of cAMP and PKA in Guizhi Gancao， Jiangxinwei and Banxia Mahuang groups were significantly up-regulated （P<0.01）. The protein expressions of cAMP， PKA and CREB in Xiao Qinglongtang group， Guizhi Gancao group， Jiangxinwei group and Banxia Mahuang group were significantly up-regulated （P<0.01）， and the protein expression of CREB in Shaoyao Gancao group was significantly up-regulated（P<0.05）. Xiao Qinglongtang could up-regulate the positive expression of AQP5 and α-ENAC， and Guizhi Gancao group could up-regulate the positive expression of α-ENAC. Xiao Qinglongtang and its fangyuan can reduce the lung edema， inflammatory cell infiltration and bronchial mucosal adhesion of model rats. ConclusionXiao Qinglongtang and its ingredients can reduce lung edema and inhibit inflammation by improving the expression of lung water transport-related proteins AQP1， AQP5， and α-ENaC through cAMP/PKA pathway， thereby restoring the lung functions in rats with syndrome of cold fluid accumulated in lung. Na⁺-K⁺-ATPase may play an auxiliary role in the regulation of lung water transport. This provides a certain objective basis for preliminarily elucidating the connotation of lung governing water movement from the perspective of lung water transport-related proteins.

Interaction exists in lung cancer and microbiota. Lung microecological homeostasis can improve the immune tolerance, enhance immune suppression, and inhibit inflammatory responses, to reduce the lung cancer; while lung cancer can lead to pulmonary microecological imbalance, change the lung environment, and promote tumor cell proliferation. Therefore, modulating microbial flora and microecological immunotherapy may be a potential and preventive treatment for lung cancer, to restore tumor immunosuppression and improve patient survival. However, the individual differences in the lung microecology, because of different genetics, ethnic characteristics, and dietary habits, increasing the difficulty of precise diagnosis and treatment, which is also the current bottleneck in the application of microecological immunotherapy. Otherwise, the effectiveness of regulatory measures such as probiotics, prebiotics or antimicrobials is questionable. The research on microbial flora is still in its infancy, and further exploration is needed to form a standardized, effective, and precise treatment plan. So, standardized, effective, and precise microbial flora treatment strategies need to be further explored.
Humans ; Probiotics ; Prebiotics ; Microbiota ; Lung Neoplasms