Research progress in pharmacokinetics and therapeutic drug monitoring of tyrosine kinase inhibitors in the treatment of gastrointestinal stromal tumors / 中国药房

Tyrosine kinase inhibitors （TKIs） represent a class of small-molecule targeted drugs that improve the survival time of patients with gastrointestinal stromal tumor （GIST）. Imatinib， sunitinib， regorafenib， ripretinib， and avapritinib are commonly used TKIs in the clinical treatment of various types of GIST. This article provides a comprehensive review of the pharmacokinetics and therapeutic drug monitoring （TDM） of these five drugs， finding that there is significant individual variability in the pharmacokinetics of these drugs. Among them， the absorption of imatinib， regorafenib， and avapritinib are influenced by food intake. Imatinib should be taken with meals and 200 mL of water， regorafenib is taken with a low-fat meal， while avapritinib is taken on an empty stomach. TKIs are mainly metabolized by cytochrome P450 3A4 （CYP3A4）， and when used in combination with CYP3A4 inducers or inhibitors， drug exposure levels will significantly change； apart from metabolic enzymes， the exposure levels of TKIs are also influenced by interactions with the transporter proteins P-glycoprotein and breast cancer resistance protein. Currently， research on TDM for TKIs is still in the exploratory stage， with a substantial amount of literature reporting the effective concentrations of imatinib， sunitinib and regorafenib. However， the precise relationship between exposure levels and efficacy/ toxicity needs further exploration. Currently， there is a lack of research on the correlation between exposure levels and efficacy/ toxicity of ripretinib and avapritinib. It is recommended to implement TDM in patients taking these drugs and explore their therapeutic window in combination with pharmacokinetic models. The commonly used methods for clinical TDM of TKIs include immunoassay， chromatography， and surface-enhanced Raman spectroscopy， providing a technical basis for clarifying the therapeutic window of TKIs.

Inhibitory effect and mechanism of total flavonoids from Melicope pteleifolia on transplanted tumor of colorectal cancer in nude mice / 中国药房

OBJECTIVE To study the inhibitory effect and mechanism of total flavonoids from Melicope pteleifolia （TF-MPL） on transplanted tumor of colorectal cancer in nude mice. METHODS The transplanted tumor model of colorectal cancer was induced by injecting 0.2 mL colorectal cancer cell LoVo subcutaneously via the right armpit of nude mice. After successful modeling， nude mice were randomly divided into model group， 5-fluorouracil group （positive control， 10 mg/kg）， TF-MPL high- dose and low-dose groups （25， 12.5 mg/kg）； a normal group （normal saline containing 0.3% carboxymethyl cellulose sodium） without modeling was additionally set up， with 6 mice in each group. Each group was intraperitoneally injected with the corresponding drug solution/solvent for 21 consecutive days. The inhibitory rate of the transplanted tumor， liver and spleen index， and the levels of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in serum were detected after the last medication； the morphological changes of tumor tissue were observed； immunohistochemical staining was used to detect protein expressions of Toll- like receptor 4 （TLR4） and nuclear factor-κB subunit p65 （NF-κB p65） in tumor tissue of nude mice. Western blot assay was used to detect protein expressions of TLR4， myeloid differentiation factor 88 （MyD88）， TNF receptor-associated factor 6 （TRAF6）， interleukin-1 receptor-associated kinase 1 （IRAK-1）， NF-κB p65 and caspase-3 in tumor tissue of nude mice. RESULTS Compared with the model group， TF-MPL high-dose group showed a significant decrease in tumor weight （inhibitory rate of 36.91%）， liver and spleen index， serum levels of TNF-α and IL-6 and protein expressions of TLR4， MyD88， TRAF6，IRAK-1 and NF- κB p65 （P＜0.05 or P＜0.01）； the expression of caspase-3 protein was increased significantly （P＜0.05）， and more tumor cell shrinkage and deformation， nuclear pyknosis and fragmentation were observed. CONCLUSIONS TF-MPL can significantly inhibit the growth of transplanted tumor of colorectal cancer in nude mice， the mechanism of which may be associated with reducing inflammatory response， inhibiting TLR4/MyD88/NF-κB signaling pathway， and promoting apoptosis in colorectal cancer cells.

Current status of AIDS knowledge, attitudes, practices and associated factors of high risk sexual behavior among college students in Tianjin City / 中国学校卫生

Objective@#To understand the current status of acquired immunodeficiency syndrome (AIDS) knowledge, attitudes, and practices of college students in Tianjin City and to further investigate the associated factors of high risk sexual behaviors, so as to provide a scientific and theoretical basis for accurate prevention and treatment of AIDS.@*Methods@#A stratified cluster random sample of 64 697 students in 56 colleges and universities in Tianjin City in November to December 2022 was investigated about the current status of AIDS knowledge, attitudes and practices. Information was collected using online survey via Questionnaire Star. Descriptive analysis was used for the current status of AIDS knowledge, attitudes and practices among college students. Chi square test and multiple Logistic regression analysis were used to analyze the influencing factors of high risk sexual behavior among college students.@*Results@#The AIDS awareness rate of college students in Tianjin City reached 87.33%. The sexual openness rate was 70.73 %. Among the 3 463 students who had sex during the past year, 42.13% of students reported high risk sexual behavior. Multivariate Logistic regression showed that female, having a romantic partner, having received sex education and prevention and treatment knowledge of AIDS were negatively associated with high risk sexual behavior ( OR =0.66, 0.59, 0.81, 0.59, P <0.05). Being in sophomore year, non heterosexuality (homosexuality, bisexuality, not knowing), prejudice against AIDS, and misunderstanding the testing methods for AIDS showed positive correlations with highrisk sexual behavior ( OR =1.22, 2.49, 2.30, 3.17, 1.43, 1.22 , P <0.05).@*Conclusions@#The awareness rate of AIDS in college students in Tianjin is high, but high risk sexual behaviors are still at a high level. Further targeted knowledge education and behavioral interventions are needed to scientifically prevent the spread of AIDS.

Mitochondria-specific near-infrared photoactivation of peroxynitrite upconversion luminescent nanogenerator for precision cancer gas therapy

Gas therapy is emerging as a highly promising therapeutic strategy for cancer treatment. However, there are limitations, including the lack of targeted subcellular organelle accuracy and spatiotemporal release precision, associated with gas therapy. In this study, we developed a series of photoactivatable nitric oxide (NO) donors NRh-R-NO (R = Me, Et, Bn, iPr, and Ph) based on an N-nitrosated upconversion luminescent rhodamine scaffold. Under the irradiation of 808 nm light, only NRh-Ph-NO could effectively release NO and NRh-Ph with a significant turn-on frequency upconversion luminescence (FUCL) signal at 740 nm, ascribed to lower N-N bond dissociation energy. We also investigated the involved multistage near-infrared-controlled cascade release of gas therapy, including the NO released from NRh-Ph-NO along with one NRh-Ph molecule generation, the superoxide anion O2⋅- produced by the photodynamic therapy (PDT) effect of NRh-Ph, and highly toxic peroxynitrite anion (ONOO‒) generated from the co-existence of NO and O2⋅-. After mild nano-modification, the nanogenerator (NRh-Ph-NO NPs) empowered with superior biocompatibility could target mitochondria. Under an 808 nm laser irradiation, NRh-Ph-NO NPs could induce NO/ROS to generate RNS, causing a decrease in the mitochondrial membrane potential and initiating apoptosis by caspase-3 activation, which further induced tumor immunogenic cell death (ICD). In vivo therapeutic results of NRh-Ph-NO NPs showed augmented RNS-potentiated gas therapy, demonstrating excellent biocompatibility and effective tumor inhibition guided by real-time FUCL imaging. Collectively, this versatile strategy defines the targeted RNS-mediated cancer therapy.

Preliminary identification of the cloning， expression， and function of Marmota himalayana type I interferon receptor β subunit / 临床肝胆病杂志

ObjectiveTo clone the gene of Marmota himalayana type ‍Ⅰ interferon receptor β subunit （mhIFNAR2）， and to perform antibody preparation and functional identification. MethodsRT-PCR was used for amplification in the spleen tissue of Marmota himalayana to obtain the sequence， which was cloned to the prokaryotic expression vector pRSET-B to express the recombinant protein. Electrophoresis and Western blot were used for identification. BALB/c mice were immunized with the recombinant protein to prepare the polyclonal antibody of its extracellular domain； immunohistochemistry， immunofluorescence assay， and Western Blot were used for identification， and the method of siRNA blockade was used to investigate its function. An analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for comparison between two groups. ResultsA fragment of mhIFNAR2 （149‍ ‍—‍ ‍1 ‍300 bp） was obtained from spleen tissue， which showed the highest homology of 98.05% in marmot. A prokaryotic expression plasmid was successfully constructed for expression of the extracellular domain of the mhIFNAR2（50-181aa） and was named pRSET-B.mhIFNAR2， and the recombinant protein expressed by this plasmid had a molecular weight of 27 kD， a purity of about 95% after purification， and a concentration of 160 μg/mL. After BALB/c mice were immunized with the purified recombinant protein， 1∶1 000 specific polyclonal antibodies were obtained， and immunohistochemistry and immunofluorescence assay showed the expression in cell membrane and cytoplasm. Among the three siRNAs synthesized， the siRNA starting from the 277 locus （siRNA277） could silence the expression of target genes and weaken the interferon signaling pathway compared with the blank control group and the negative control group （both P<0.05）. ConclusionThe fragment of mhIFNAR2 is obtained， and the polyclonal antibody for the extracellular domain of mhIFNAR2 is successfully prepared， with relatively high titer and specificity， and can be used for immunohistochemistry， immunofluorescence assay， and Western blot.

The Prevention and Treatment of Pulmonary Nodules “Nodule-cancer Transformation” Based on the View of “Disease with Latent Pathogen Induced by a New Pathogen” / 中医杂志

As one of the pathogenic mechanisms contained in The Inner Canon of Yellow Emperor （《黄帝内经》）， “disease with latent pathogen induced by a new pathogen” means that the induced new pathogen resulted to a combination of the latent previous pathogen and the new pathogen， which caused the disease. Based on this， it is believed that the change of “nodule-cancer transformation” of pulmonary nodules is actually based on the deficiency of original qi， and the new pathogen induces the latent pathogens like phlegm coagulation， qi stagnation， blood stasis， toxicity， so healthy qi can not drive the pathogens out， and the long-time detention generated into cancerous turbidity， and deve-loped into cancerous tumour at the end. Therefore， based on the three-stage treatment of unformed cancer， dense cancerous toxin， and developed cancer， the clinical practice applied six methods of clearing， expelling， dissipating， tonifying， harmonizing， and transforming， taking into account both the manifestation and root cause， moving the treatment window of pulmonary nodules forward， attacking the pathogens when the toxin was not yet overbearing， supporting the healthy qi before declining， delaying the process of nodules-cancer transformation， and providing ideas for the prevention and treatment of pulmonary nodules “nodule-cancer transformation” in traditional Chinese medicine.

Research progress in the diagnosis and treatment of neurotrophic keratitis / 国际眼科杂志(Guoji Yanke Zazhi)

Neurotrophic keratitis(NK)is a degenerative corneal disease caused by impairment of trigeminal innervations. It can lead to spontaneous corneal epithelial defects, corneal ulceration and perforation. Early diagnosis of NK is crucial and requires accurate investigation of clinical history and thorough examination of ocular surface to determine clinical stage. Treatment for NK needs to be divided into stages according to disease severity. In addition to conventional treatments including artificial tears, blepharorrhaphy, and amniotic membrane transplantation, there are also emerging treatments such as targeted drug therapy and corneal neurotization. This article summarized the epidemiology, clinical manifestations and classification, etiology, diagnosis, differential diagnosis and treatment of NK, aiming to provide reference for the early diagnosis and treatment of NK in the future.

Treatment of Inflammatory Bowel Disease by Targeting M1/M2 Macrophage Polarization Balance with Traditional Chinese Medicine and Active Components： A Review / 中国实验方剂学杂志

Inflammatory bowel disease （IBD）， consisting of ulcerative colitis and Crohn's disease， is a chronic relapsing inflammatory gastrointestinal disease closely associated with immune dysfunction. The pathogenesis of IBD is closely related to genetic susceptibility， immune system dysfunction， environmental change， and intestinal microbial dysbiosis. Modern research has found that macrophage polarization plays an important role in the development of IBD and can affect the level of inflammatory response， intestinal mucosal repair， and intestinal microbial balance， making it a potential target for IBD treatment. Increasing evidence suggests that traditional Chinese medicine and its active components can regulate macrophage polarization through multiple pathways and balance the M1/M2 macrophage ratio， thus inhibiting inflammatory response， promoting intestinal mucosal repair， and slowing down the progression of IBD. This article summarized the biological processes and targets involved in macrophage polarization and discussed its impact on IBD. It also provided a brief overview of the latest research on how traditional Chinese medicine and its active components can improve IBD by regulating macrophage polarization， so as to provide new directions and strategies for the clinical application of traditional Chinese medicine in IBD treatment.

Mechanism of tyrosine kinase 2 inhibitors in treatment of plaque psoriasis and their progress in clinical trials / 中国临床药理学与治疗学

As a chronic, immune-mediated inflammatory disease, plaque psoriasis has a great burden of disease and influences on patient's physical and mental health. In the past decade, plaque psoriasis treatment with biological agents achieved breakthrough development, while oral drugs with promising efficacy and safety are yet to be met. By cell signal transduction, the Janus kinase-signal transducer and activator of transcription pathway plays an important role in numerous immune-related diseases. Tyrosine kinase 2 (TYK2), a member of the JAK family, can impact on plaque psoriasis by regulating signaling and functional responses downstream of IL-12, IL-23, IFN. Deucravacitinib, a highly selective TYK2 inhibitor, has finished its phase 3 clinical trials and shown its efficacy and safety in treatment of plaque psoriasis. Several kinds of TYK2 inhibitors are under research and development at the moment. In this review, we demonstrate roles of JAK-STAT pathway and TYK2 in plaque psoriasis as well as updates on ongoing and recently completed trials of TYK2 inhibitors.

Research progress of endothelial-mesenchymal transdifferentiation in fibrotic diseases / 中国药理学通报

Fibrosis is a repair response initiated by tissues and organs after injury, and is a self-protection mechanism of the body. It has been found that endothelium-to-interstitial transdifferentiation (EndMT) is involved in the physiological and pathological processes of various organ fibrosis, which has become a focus of the research on fibrotic diseases. In recent years, the study has found that EndMT plays an important role in many pathological processes in cardiovascular system, lungs, kidneys, liver, pancreas fibrosis, and so on. This article summarizes EndMT regulatory mechanism and its role in each organ fibrosis, as well as the related treatment progress of EndMT targets, so as to provide new targets for prevention and control of organ fibrosis.

Mechanism of Buyang Huanwu Decoction alleviating inflammatory response after cerebral ischemia/reperfusion injury by activating SIRT1 in hippocampus of rats / 中国药理学通报

Aim To explore the inhibitory effect of Buyang Huanwu Decoction on the inflammatory response in the hippocampus of brain tissues of CIRI rats by regulating SIRT1 and the underlying mechanism. Methods The middle cerebral artery embolization (MCAO) model was prepared in rats and divided into sham operation group (Sham), model group (MCAO/R), Buyang Huanwu Decoction group (BYHWT),and BYHWT + SIRT1 inhibitor group (BYHWT + EX527). Zea Longa was used to detect the neurological function score of rats in each group; TTC staining was used to determine the volume of cerebral infarction; HE staining was used to observe the pathological damage of the hippocampus; Western blot was used to detect the expression levels of SIRT1 and IL-6; immunohistochemistry was used to detect TNF-α, IL-1β expression level. Results Compared with the sham group,the neurological function score of the MCAO/R group increased (P < 0.05); the volume of cerebral infarction increased (P < 0.05); the nerve cells in hippocampus were severely damaged, arranged disorderly, and the nucleus was broken; Western blot showed that the expression of SIRT1 decreased, IL-6 expression increased (P <0.05); immunohistochemistry showed that TNF-α,IL-1β expression increased (P < 0.05). Compared with the MCAO/R group, the neurological function score of the BYHWT group decreased (P <0.05); the volume of cerebral infarction decreased (P < 0.05); the damage of nerve cells in hippocampus was reduced; Western blot showed that the expression of SIRT1 increased and IL-6 expression decreased (P < 0.05); immunohistochemistry showed that TNF-α, IL-1β expression decreased (P < 0.05). Compared with the BYHWT group, the neurological function score of the BYHWT + EX527 group increased (P < 0.05); the volume of cerebral infarction was raised (P <0.05); the damage of nerve cells in hippocampus was aggravated; Western blot showed that the expression of SIRT1 decreased and IL-6 expression increased (P < 0.05); immunohistochemistry showed that TNF-α, IL-1β expression increased (P < 0.05). Conclusions Preliminary discussion of Buyang Huanwu Decoction can activate SIRT1 in hippocampus of rat brain tissues to reduce the inflammatory response after CIRI and play a role in brain protection.

Auranofin reverses acquired resistance to osimertinib in non-small cell lung cancer / 中国药理学通报

Aim To investigate the role of auranofin in reversing acquired resistance to osimertinib in non-small cell lung cancer. Methods Osimertinib-sensi-tive NSCLC cell lines HI975 and PC9 were used to establish osimertinib-resistant NSCLC cell lines HI975/OR and PC9/OR. An FDA approved library of 1470 FDA drugs was used to high-throughput screen the reversal agents of acquired resistant of osimertinib by CCK-8. Compusyn was used to calculate the combination index of osimertinib and auranofin to determine the optimal dose of drug combination. CCK-8, EdU, flow cytometry and Transwell experiments were used to detect osimertinib, auranofin and the combination drug effect on proliferation, apoptosis, migration and invasion of osimertinib acquired NSCLC cell lines. RNA-sequencing was applied to screen differentially expressed mRNAs in osimertinib treatment alone and osimertinib combined with auranofin treatment group. qRT-PCR and western blot were employed to validate the selected gene expression and protein expression. Results Compared with osimertinib sensitive cell lines H1975 and PC9, H1975/OR and PC9/OR showed significantly higher cell viability and lower apoptosis rate after osimertinib treatment. The resistance index was 70. 31 and 136. 99, respectively. In FDA approved 1470 drug library, only auranofin could enhance the sensitivity of osimertinib in H1975/OR and PC9/OR. When 1 μmol • L

Purpurolide C-based microneedle promotes macrophage-mediated diabetic wound healing via inhibiting TLR4-MD2 dimerization and MYD88 phosphorylation

Delayed wound healing in diabetes is a global challenge, and the development of related drugs is a clinical problem to be solved. In this study, purpurolide C (PC), a small-molecule secondary metabolite of the endophytic fungus Penicillium purpurogenum, was found to promote diabetic wound healing. To investigate the key regulation targets of PC, in vitro RNA-seq, molecular docking calculations, TLR4-MD2 dimerization SDS-PAGE detection, and surface plasmon resonance (SPR) were performed, indicating that PC inhibited inflammatory macrophage activation by inhibiting both TLR4-MD2 dimerization and MYD88 phosphorylation. Tlr4 knockout in vivo attenuated the promotion effect of PC on wound healing. Furthermore, a delivery system consisting of macrophage liposome and GelMA-based microneedle patches combined with PC (PC@MLIP MN) was developed, which overcame the poor water solubility and weak skin permeability of PC, so that successfully punctured the skin and delivered PC to local tissues, and accurately regulated macrophage polarization in diabetic wound management. Overall, PC is an anti-inflammatory small molecule compound with a well-defined structure and dual-target regulation, and the PC@MLIP MN is a promising novel biomaterial for the management of diabetic wound.

Gut microbiota-derived short-chain fatty acids ameliorate methamphetamine-induced depression- and anxiety-like behaviors in a Sigmar-1 receptor-dependent manner

Methamphetamine (Meth) abuse can cause serious mental disorders, including anxiety and depression. The gut microbiota is a crucial contributor to maintaining host mental health. Here, we aim to investigate if microbiota participate in Meth-induced mental disorders, and the potential mechanisms involved. Here, 15 mg/kg Meth resulted in anxiety- and depression-like behaviors of mice successfully and suppressed the Sigma-1 receptor (SIGMAR1)/BDNF/TRKB pathway in the hippocampus. Meanwhile, Meth impaired gut homeostasis by arousing the Toll-like receptor 4 (TLR4)-related colonic inflammation, disturbing the gut microbiome and reducing the microbiota-derived short-chain fatty acids (SCFAs). Moreover, fecal microbiota from Meth-administrated mice mediated the colonic inflammation and reproduced anxiety- and depression-like behaviors in recipients. Further, SCFAs supplementation optimized Meth-induced microbial dysbiosis, ameliorated colonic inflammation, and repressed anxiety- and depression-like behaviors. Finally, Sigmar1 knockout (Sigmar1-/-) repressed the BDNF/TRKB pathway and produced similar behavioral phenotypes with Meth exposure, and eliminated the anti-anxiety and -depression effects of SCFAs. The activation of SIGMAR1 with fluvoxamine attenuated Meth-induced anxiety- and depression-like behaviors. Our findings indicated that gut microbiota-derived SCFAs could optimize gut homeostasis, and ameliorate Meth-induced mental disorders in a SIGMAR1-dependent manner. This study confirms the crucial role of microbiota in Meth-related mental disorders and provides a potential preemptive therapy.

Azvudine reduces the in-hospital mortality of COVID-19 patients: A retrospective cohort study

In our retrospective cohort study, we aim to explore whether Azvudine modifies the risk of death in COVID-19 patients. It was conducted on the medical records of patients, consecutively admitted for COVID-19 pneumonia to two hospitals in Chongqing, China. Based on Azvudine treatment exposure, the patients were divided into Azvudine group and non-Azvudine group. We used 1:2 ratio propensity score matching (PSM) in our study to adjust for confounding factors and differences between Azvudine and non-Azvudine groups. There were 1072 patients included in our original cohort. With 1:2 ratio PSM, the Azvudine group included 195 patients and non-Azvudine group included 390 patients. The results showed that Azvudine treatment was associated with improved in-hospital mortality in overall population (OR 0.375, 95% CI 0.225-0.623, P < 0.001), severe subgroup (OR 0.239, 95% CI 0.107-0.535, P = 0.001), critical subgroup (OR 0.091, 95% CI 0.011-0.769, P = 0.028) in matched cohort with univariate analysis. And there was a significantly lower in-hospital mortality in overall population (11% vs. 24%, P＜0.001), severe sub-group (10% vs. 32%, P < 0.001) and critical sub-group (5% vs. 34%, P = 0.017) in matched cohort. These results suggest Azvudine can reduce in-hospital mortality in overall COVID-19 patients, severe, and critical subgroup population.

Pharmacological inhibition of BAP1 recruits HERC2 to competitively dissociate BRCA1-BARD1, suppresses DNA repair and sensitizes CRC to radiotherapy

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

Mesenchymal stem cell-derived apoptotic bodies alleviate alveolar bone destruction by regulating osteoclast differentiation and function / 国际口腔科学杂志·英文版

Periodontitis is caused by overactive osteoclast activity that results in the loss of periodontal supporting tissue and mesenchymal stem cells (MSCs) are essential for periodontal regeneration. However, the hypoxic periodontal microenvironment during periodontitis induces the apoptosis of MSCs. Apoptotic bodies (ABs) are the major product of apoptotic cells and have been attracting increased attention as potential mediators for periodontitis treatment, thus we investigated the effects of ABs derived from MSCs on periodontitis. MSCs were derived from bone marrows of mice and were cultured under hypoxic conditions for 72 h, after which ABs were isolated from the culture supernatant using a multi-filtration system. The results demonstrate that ABs derived from MSCs inhibited osteoclast differentiation and alveolar bone resorption. miRNA array analysis showed that miR-223-3p is highly enriched in those ABs and is critical for their therapeutic effects. Targetscan and luciferase activity results confirmed that Itgb1 is targeted by miR-223-3p, which interferes with the function of osteoclasts. Additionally, DC-STAMP is a key regulator that mediates membrane infusion. ABs and pre-osteoclasts expressed high levels of DC-STAMP on their membranes, which mediates the engulfment of ABs by pre-osteoclasts. ABs with knock-down of DC-STAMP failed to be engulfed by pre-osteoclasts. Collectively, MSC-derived ABs are targeted to be engulfed by pre-osteoclasts via DC-STAMP, which rescued alveolar bone loss by transferring miR-223-3p to osteoclasts, which in turn led to the attenuation of their differentiation and bone resorption. These results suggest that MSC-derived ABs are promising therapeutic agents for the treatment of periodontitis.

Efficacy, safety, and mechanism of Huangkui Capsules in treating chronic kidney disease: Meta-analysis and integrative bioinformatics / 中国中药杂志

Meta-analysis and integrative bioinformatics were employed to comprehensively study the efficacy, safety, and mechanism of Huangkui Capsules in treating chronic kidney disease(CKD). CNKI, Wanfang, VIP, SinoMed, Cochrane Library, PubMed, EMbase, and Web of Science were searched for randomized controlled trial(RCT) of Huangkui Capsules for CKD from inception to January 3, 2023. The outcome indicators included urine protein, serum creatinine(Scr), and blood urea nitrogen(BUN) levels, and Cochrane Handbook 5.1 and RevMan 5.3 were employed to perform the Meta-analysis of the included RCT. The active ingredients of Huangkui Capsules were retrieved from CNKI, and the targets of CKD from GeneCards, OMIM, and TTD. Cytoscape 3.8.0 was used to build a "component-disease" network and a protein-protein interaction(PPI) network for the screening of core components and targets. Next, a differential analysis of the core targets of Huangkui Capsules for treating CKD was conducted with the clinical samples from GEO to identify the differentially expressed core targets, and correlation analysis and immune cell infiltration analysis were then performed for these targets. A total of 13 RCTs were included for the Meta-analysis, involving 2 372 patients(1 185 in the observation group and 1 187 in the control group). Meta-analysis showed that the Huangkui Capsules group and the losartan potassium group had no significant differences in reducing the urinary protein levels after 12(MD=19.60, 95%CI[-58.66, 97.86], P=0.62) and 24 weeks(MD=-66.00, 95%CI[-264.10, 132.11], P=0.51) of treatment. Huangkui Capsules in combination with conventional treatment was superior to conventional treatment alone(MD=-0.55, 95%CI[-0.86,-0.23], P=0.000 6). Huangkui Capsules combined with conventional treatment was superior to conventional treatment alone in recovering Scr(MD=-9.21, 95%CI[-15.85,-2.58], P=0.006) and BUN(MD=-1.02, 95%CI[-1.83,-0.21], P=0.01). Five patients showed clear adverse reactions, with abdominal or gastrointestinal discomfort. Huangkui Capsules had 43 active ingredients and 393 targets, and the core ingredients were myricetin, quercetin, gossypin, elaidic acid, dihydromyricetin, isochlorogenic acid B, and caffeic acid. CKD and Huangkui Capsules shared 247 common targets, including 25 core targets. The GEO differential analysis predicted 18 differentially expressed core targets, which were mainly positively correlated with immune cell expression and involved in immune inflammation, oxidative stress, pyroptosis, lipid metabolism, sex hormone metabolism, and cell repair. Conclusively, Huangkui Capsules combined with conventional treatment significantly reduced urine protein, Scr, and BUN. Huangkui Capsules alone and losartan potassium had no significant difference in reducing urine protein. This efficacy of Huangkui Capsules may be associated with the multi-component, multi-target, and multi-pathway responses to immune inflammation and oxidative stress. The included RCT had small sample sizes and general quality. More clinical trial protocols with large sample sizes and rigorous design and in line with international norms are needed to improve the evidence quality, and the results of bioinformatics analysis remain to be confirmed by further studies.

Network Meta-analysis of oral Chinese patent medicines in treating type 2 diabetes mellitus complicated with angina pectoris of coronary heart disease / 中国中药杂志

Bayesian network Meta-analysis was employed to compare the efficacy of different oral Chinese patent medicines in treating type 2 diabetes mellitus with angina pectoris of coronary heart disease. Randomized controlled trial(RCT) of oral Chinese patent medicines in treating type 2 diabetes mellitus complicated with angina pectoris of coronary heart disease were retrieved from 8 Chinese and English databases including CNKI, Wanfang, VIP, SinoMed, EMbase, PubMed, Cochrane Library, and Web of Science with the time interval from inception to November 2022. The BUGSnet package in R 4.2.1 was used to conduct Meta-analysis. A total of 45 RCTs were included, involving 4 727 patients and 7 oral Chinese patent medicines. Network Meta-analysis showed that the conventio-nal western medicine combined with Chinese patent medicines improved the outcome indicators. Shexiang Baoxin Pills + conventional western medicine had the best effect on reducing the incidence of adverse cardiovascular events, and Yixinshu Capsules + conventional western medicine on reducing the frequency and duration of angina pectoris. The conventional western medicine combined with oral Chinese patent medicines can reduce blood glucose indicators. Yindan Xinnaotong Soft Capsules + conventional western medicine had the best effect on reducing fasting blood glucose(FBG), 2 hours postprandial blood glucose(PBG), and glycosylated hemoglobin(HbA1c). The conventional western medicine combined with oral Chinese patent medicines can reduce blood lipid indicators. Yixinshu Capsules + conventional western medicine had the best effect on reducing total cholesterol(TC) and low density lipoprotein-cholesterol(LDL-C), and Yindan Xinnaotong Soft Capsules + conventional western medicine on reducing triglyceride(TG). Current evidence suggests that the patients with type 2 diabetes mellitus complicated with angina pectoris of coronary heart disease could reasonably choose oral Chinese patent medicines on the basis of routine antiplatelet, anticoagulant, hypoglycemic, and antihypertensive therapies, which could reduce the incidence of adverse cardiovascular events, alleviate the symptoms of angina pectoris, and reduce the glucose and lipid metabolism indicators. Shexiang Baoxin Pills + conventional treatment and Yixinshu Capsules + conventional western medicine have better effect on angina pectoris, Yindan Xinnaotong Soft Capsules + conventional western medicine on lowering blood glucose, and Yindan Xinnaotong Soft Capsules + conventional western medicine and Yixinshu Capsules + conventional western medicine on reducing blood lipid. Due to the lack of direct comparative results between Chinese patent medicines and other factors, high-quality studies remain to be carried out for further verification.

Identification of mixed medicinal powder of Epimedii Folium with different origins based on pyrosequencing technology / 药学学报

There are many multi-original medicinal materials in Chinese Pharmacopoeia, and the mixed use of medicinal materials from different sources is common, which has certain influence on the stability of clinical medication. In this study, pyrosequencing technology was used to screen species-specific single nucleotide polymorphisms (SNP) from commonly used DNA barcode sequences, and a rapid and accurate molecular identification method for original species in mixed medicinal powder of Epimedii Folium was established. Multiple sequence alignment analysis showed that the 176th (C/T) mutation and the 196th (A/G) mutation of ITS, the 123rd (C/G) mutation of matK and the 892nd (A/C) mutation of rbcL could be used as the unique SNPs of E. sagittatum, E. koreanum, E. brevicornu and E. pubescens, respectively. In this study, the applicability of pyrosequencing and Sanger sequencing methods in the sequencing of mixture samples was investigated from the perspective of sensitivity and stability. Pyrosequencing method has higher detection sensitivity than Sanger sequencing method for low content samples in the mixed samples. Stability analysis showed that pyrosequencing technology could still obtain effective sequencing results for the amplified products of template DNA after 45 min of 95 ℃ high temperature water bath, while the critical point of Sanger sequencing method was 30 min. In this study, a new identification technology of Epimedii Folium mixed powder primordial species based on pyrosequencing and specific SNP was developed, which can quickly and accurately identify the mixed use of Epimedii Folium with high sensitivity and stability, and can also support the identification of different primordial species and mixed powder primordial herbs, which is conducive to ensuring the consistency and stability of clinical medication.