Pyloric gland adenoma:a clinicopathological analysis of 16 cases / 临床与实验病理学杂志

Purpose To investigate the clinical feature and histopathology of pyloric gland adenoma.Methods Clinical da-ta of 16 cases of pyloric adenomas were collected.The expres-sion of Pepsinogen I,p53,MUC6,MUC5AC,CgA,Syn,CD56,Ki67,CDX-2,MUC2,β-catenin,and CD10 was detec-ted by immunohistochemistry EnVision method.The relationship with clinicopathological features and prognosis was analyzed.Results There were 7 males and 9 females,aged from 26 to 81 years with an average of 58 years.Tumor diameters ranged from 0.2 to 4 centimeter with a mean of 1.3 centimeter.The anatomi-cal sites of the 16 PGA were stomach(6 cases),including 3 ca-ses in body,3 cases in fundus and duodenum(3 cases).7 ca-ses of low-grade PGAs were composed of closely packed pyloric-type glands,lined by cuboidal/low columnar epithelia.The nu-clei(round to ovoid)were basally located,with inconspicuous nucleoli.Neoplastic cells characterized by a defined ground-glass appearance,with clear or eosinophilic cytoplasm.The cell was lack of a well-defined apical mucin cap.1 case of high-grade PGAs consistently exhibited architecture,crowded nuclei,and loss of nuclear polarity.The remaining 8 cases had both low-and high-grade components.Squamous morula was found in 5 cases.According to immunohistochemical characteristics,8 of 16 cases were mixed pattern(MUC5AC+,MUC6+).Others were pure pyloric type(MUC5AC-,MUC6+).No foveolar-dominant type(MUC5AC+,MUC6-)was found.Conclusion PGA is a rare tumor of the digestive system,with characteristic morpholog-ical characteristics and immunophenotype.Clinicians and pathol-ogists need to strengthen their understanding and better manage patients because of the risk of malignant transformation.Early detection,early diagnosis and early treatment are needed.

Progress of non-pharmacological treatments for treatment-resistant depression / 实用医学杂志

Depression,with its characteristics of high prevalence,younger onset age,and high suicide rate,has repeatedly become the focus of societal discussion.It severely impairs the quality of life of patients and affects the development of the economy.Currently,treatments for depression are limited and vary in effectiveness.An increasing number of patients are classified as having treatment-resistant depression.In order to improve the cure rate further,numerous non-pharmacological treatments have been explored,among which physical therapies have garnered significant attention.This article provides a brief overview and discussion of recent physical treatments for treatment-resistant depression,offering new prospects for the field and inspiring readers with fresh ideas.

Characterization of temporal and intensity parameters of early postural adjustment phase during gait initiation in stroke patients / 中国组织工程研究

BACKGROUND:Early postural adjustments serve as preparatory measures for forthcoming actions or potential disruptions in posture,thereby facilitating improved movement execution and mitigating destabilizing effects caused by posture interference. OBJECTIVE:To investigate the characteristics of temporal and intensity parameters of key lower limb muscles during early postural adjustment phase when stroke patients with varying levels of balance initiate walking at a self-selected comfortable pace. METHODS:The characteristics of early postural adjustments in 16 stroke patients were observed.Sixteen patients were divided into a non-fall group(n=8)and a fall group(n=8)based on the history of falls and Berg Balance Scale scores.Noraxon inertial sensors and Noraxon Ultium EMG wireless surface electromyography were utilized to collect body kinematic data and surface electromyography data during gait initiation.Muscle activation time and activation sequence of six key muscles in the lower limbs(tibialis anterior,medial and lateral gastrocnemius,rectus femoris,lateral femoris and biceps femoris muscles)during the early postural adjustment phase,as well as normalized electromyography integral values for the four time windows(each 150 ms)before gait initiation,were analyzed. RESULTS AND CONCLUSION:Stroke patients with a history of falls exhibited earlier activation times for the six key muscles in the lower limbs during gait initiation compared with those in the non-fall group.The fall group demonstrated significantly earlier activation times for tibialis anterior,lateral head of gastrocnemius,and vastus lateralis(P<0.01,P<0.05).In contrast,the non-fall group displayed a consistent pattern of activating extensor muscles before flexor muscles,with thigh muscle activation preceding calf muscle activation.However,in the fall group,calf extensor muscle activation occurred prior to thigh extensor muscle activation,and the vastus lateralis was activated even earlier.The tibialis anterior was the last activated muscle in both groups.Specifically during T3(>-300 to-150 ms),the tibialis anterior exhibited significantly higher activity in the fall group compared with the non-fall group(P<0.05),while the lateral head of gastrocnemius demonstrated significant inhibition during T3(P<0.05)and the medial head of gastrocnemius showed significant inhibition during both T3 and T4(>-150 to 0 ms)stages compared with the non-fall group(P<0.01,P<0.05).To conclude,stroke patients with varying balance abilities employ distinct early postural adjustment strategies prior to stepping,as evidenced by differences in muscle activation timing,recruitment order,and muscle activity amplitude.Patients at a high risk of falling exhibit prolonged duration of early postural adjustment and delayed initiation of gait,indicating earlier activation of the tibialis anterior muscle and inhibition of gastrocnemius muscle activity.These delays in gait initiation and variations in muscle recruitment strategies may contribute to unstable posture and an increased susceptibility to falls.

Effect and mechanism of short-chain fatty acids in aged rats with sarcopenia / 中国组织工程研究

BACKGROUND:Studies have shown that short-chain fatty acids(SCFAs)are a potential regulator of skeletal muscle energy metabolism,but the exact mechanism is unclear. OBJECTIVE:To observe the effect of SCFAs on aged rats with sarcopenia and to explore the underlying mechanism. METHODS:Sprague-Dawley rats were randomly divided into control group,sarcopenia group,and sarcopenia+SCFAs group(SCFAs group).In the latter two groups,rat models of sarcopenia were established using ovariectomized rats injected with 5 mg/kg dexamethasone for 7 days.In the control group,the abdominal cavity was only exposed but not removed,and then sutured.Rats in the SCFAs group were administered drinking water containing 150 mmol/L short-chain fatty acids,600 mg/kg sodium acetate,200 mg/kg sodium propionate,and 200 mg/kg sodium butyrate for 4 weeks.Rats in the control and sarcopenia groups were given the same volume of normal saline.Successful modeling was assessed by measuring the bilateral gastrocnemius muscle mass and body mass to calculate the gastrocnemius index after modeling.Food intake,body mass and grip strength of rats were measured at 0,1,2 and 4 weeks after successful modeling;morphological changes of gastrocnemius muscle were observed by hematoxylin-eosin staining;and the expression of p-AMPK and p-ULK1 proteins in gastrocnemius muscle was detected by western blot. RESULTS AND CONCLUSION:Compared with the control group,the sarcopenia group showed significantly decreased body mass,food intake,forelimb grip strength(P<0.05),wet mass of gastrocnemius muscle(P<0.05),and protein levels of p-AMPK and p-ULK1(P<0.05).Compared with the sarcopenia group,the SCFAs group showed a significant increase in food intake,body mass,grip strength,wet mass of gastrocnemius muscle,and protein levels of p-AMPK and p-ULK1 in gastrocnemius muscle(P<0.05).All these findings indicate that SCFAs improve symptoms of sarcopenia in the elderly and may be associated with the upregulation of AMPK and ULK1 proteins in skeletal muscle.

Challenges in the study of self-assembled aggregates in decoction of traditional Chinese medicine: A preliminary review / 药学学报

Decoction is the most commonly used dosage form in the clinical treatment of traditional Chinese medicine (TCM). During boiling, the violent movement of various active ingredients in TCM creates molecular forces such as hydrogen bonding, π-π stacking, hydrophobic interactions and electrostatic interactions, which results in the formation of self-assembled aggregates in decoction (SADs), including particles, gels, fibers, etc. It was found that SADs widely existed in decoction with biological activities superior to both effective monomers and their physical mixtures, providing a new idea to reveal the pharmacodynamic material basis of Chinese herbal medicine from the perspective of component interactions-phase structure. Recently, SADs have become a novel focus of research in TCM. This paper reviewed their relevant studies in recent years and found some issues to be concerned in the research, such as the polydispersity of decoction system, instability of active ingredient interactions during boiling, uncertainty of the aggregates self-assembly rules, and stability, purity, yield of the products. In this regard, some solutions and new ideas were presented for the integrated development and clinical application of SADs.

Opportunities, challenges and suggestions for the development of plastic degradation and recycling under the context of circular bioeconomy / 生物工程学报

At present, the negative impact caused by white pollution has spread to all aspects of human society economy, ecosystem, and health, which causes severe challenges for developing the circular bioeconomy. As the largest plastic production and consumption country in the world, China has shouldered an important responsibility in plastic pollution control. In this context, this paper analyzed the relevant strategies of plastic degradation and recycling in the United States, Europe, Japan and China, measured the literature and patents in this field, analyzed the status quo of technology from the perspective of research and development trends, major countries, major institutions, and discussed the opportunities and challenges faced by the development of plastic degradation and recycling in China. Finally, we put forward future development suggestions which include the integration of policy system, technology path, industry development and public cognition.

Metabolomics study of Berberidis Radix in intervening ulcerative colitis based on UPLC-Q-TOF-MS / 中国中药杂志

The effect of Tujia medicine Berberidis Radix on endogenous metabolites in the serum and feces of mice with ulcerative colitis(UC) induced by dextran sulfate sodium(DSS) was analyzed by metabolomics technology to explore the metabolic pathway and underlying mechanism of Berberidis Radix in the intervention of UC. The UC model was induced in mice by DSS. Body weight, disease activity index(DAI), and colon length were recorded. The levels of tumor necrosis factor-α(TNF-α) and interleukin-10(IL-10) in colon tissues were determined by ELISA. The levels of endogenous metabolites in the serum and feces were detected by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS). Principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA) were employed to characterize and screen differential metabolites. The potential metabolic pathways were analyzed by MetaboAnalyst 5.0. The results showed that Berberidis Radix could significantly improve the symptoms of UC mice and increase the level of the anti-inflammatory factor IL-10. A total of 56 and 43 differential metabolites were identified in the serum and feces, respectively, belonging to lipids, amino acids, fatty acids, etc. After the intervention by Berberidis Radix, the metabolic disorder gradually recovered. The involved metabolic pathways included biosynthesis of phenylalanine, tyrosine, and tryptophan, linoleic acid metabolism, phenylalanine metabolism, and glycerophospholipid metabolism. Berberidis Radix can alleviate the symptoms of mice with DSS-induced UC, and the mechanism may be closely related to the re-gulation of lipid metabolism, amino acid metabolism, and energy metabolism.

Complete chloroplast genome sequencing and phylogeny of wild Atractylodes lancea from Yuexi, Anhui province / 中国中药杂志

This study investigated the choroplast genome sequence of wild Atractylodes lancea from Yuexi in Anhui province by high-throughput sequencing, followed by characterization of the genome structure, which laid a foundation for the species identification, analysis of genetic diversity, and resource conservation of A. lancea. To be specific, the total genomic DNA was extracted from the leaves of A. lancea with the improved CTAB method. The chloroplast genome of A. lancea was sequenced by the high-throughput sequencing technology, followed by assembling by metaSPAdes and annotation by CPGAVAS2. Bioiformatics methods were employed for the analysis of simple sequence repeats(SSRs), inverted repeat(IR) border, codon bias, and phylogeny. The results showed that the whole chloroplast genome of A. lancea was 153 178 bp, with an 84 226 bp large single copy(LSC) and a 18 658 bp small single copy(SSC) separated by a pair of IRs(25 147 bp). The genome had the GC content of 37.7% and 124 genes: 87 protein-coding genes, 8 rRNA genes, and 29 tRNA genes. It had 26 287 codons and encoded 20 amino acids. Phylogenetic analysis showed that Atractylodes species clustered into one clade and that A. lancea had close genetic relationship with A. koreana. This study established a method for sequencing the chloroplast genome of A. lancea and enriched the genetic resources of Compositae. The findings are expected to lay a foundation for species identification, analysis of genetic diversity, and resource conservation of A. lancea.

Pathological features of early gastric cancer and its background mucosa after eradication of Helicobacter pylori and their implications for biopsy diagnosis / 中华病理学杂志

Objective: To investigate the clinicopathological changes of early gastric cancer, especially its background mucosa, after the eradication of Helicobacter pylori (H. pylori), and to investigate the causes of underdiagnosis in preoperative biopsy pathology. Methods: Ninety cases of early gastric cancer after H. pylori eradication and 120 cases of endoscopic submucosal dissection (ESD) specimens without H. pylori eradication and their corresponding biopsy specimens were collected from Beijing Friendship Hospital Affiliated to Capital Medical University during 2016-2021. The clinicopathological data of the patients were analyzed, and the histopathological characteristics and immunophenotypic results compared. Results: Compared with the early gastric cancer without H. pylori eradication history, the histopathological type of early gastric cancer after H. pylori eradication was differentiated adenocarcinoma, with staggered distribution of cancerous and non-cancerous epithelium in the tumor area. The morphologic characteristics of gastric mucosa in the background of early gastric cancer after H. pylori eradication, were distinctive, including widening of the opening of enterosylated glandular ducts, serrated change of luminal margin, eosinophilic and microvesicular cytoplasm of enterosylated epithelium. Low-grade atypia existed in gastric cancer epithelial cells after sterilization, which might lead to underdiagnosis or missed diagnosis in biopsy pathology. Conclusions: Early gastric cancer and its background mucosa after H. pylori eradication have unique morphological characteristics, which can be used as a clue for pathological diagnosis, improve the accuracy of biopsy pathology and reduce the underdiagnosis.

PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats / 药物分析学报

Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease(PD).However,the mechanisms underlying this association remain unclear.In the present study,we found that high glucose(HG)levels in the cerebrospinal fluid(CSF)of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine(6-OHDA)on the development of motor disorders,and the damage to the nigrostriatal dopaminergic neuronal pathway.In vitro,HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor(NGF)(NGF-PC12).Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle(TCA cycle)activity,which was closely related to abnormal mito-chondrial fusion,thus resulting in mitochondrial loss.Interestingly,HG-induced upregulation of pyruvate kinase M2(PKM2)combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 cells.In addition,we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HG+6-OHDA.Furthermore,we found that shikonin(SK),an inhibitor of PKM2,restored the mito-chondrial number,promoted TCA cycle activity,reversed hyperglycolysis,enhanced the tolerance of cultured neurons to 6-OHDA,and reduced the risk of PD in diabetic rats.Overall,our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upre-gulation of PKM2,leading to an increase in the vulnerability of dopaminergic neurons to 6-OHDA.Thus,the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.

Effect of remnant cholesterol levels on carotid intima thickness in patients with type 2 diabetes mellitus evaluated by ultra-high frequency ultrasound / 中华超声影像学杂志

Objective:To discuss the effect of remnant cholesterol (RC) levels on carotid intima thickness (CIT) in patients with type 2 diabetes mellitus (T2DM) by ultra-high frequency ultrasound.Methods:A total of 60 patients with T2DM who received treatment in Henan Provincial People′s Hospital from May 2021 to July 2022 were prospectively recruited, and they were divided into a higher RC group (31 cases) and a lower RC group (29 cases) according to the RC levels. Thirty-one age, sex and body mass index(BMI)-matched healthy volunteers were selected as control group. Carotid CIT, carotid media thickness(CMT) and intima-media thickness(CIMT) were measured by 24 MHz ultra-high frequency ultrasound probe. The difference of general clinical data, laboratory indicators and CIMT, CIT, CMT among the three groups were compared, and the influencing factors of CIT in T2DM patients were explored by multivariate regression analysis.Results:①There were no statistical significances in gender, age, BMI, high-density lipoprotein cholesterol (HDL-C) and CMT among the three groups (all P>0.05). There were no statistical significances in duration of diabetes, fasting blood-glucose and glycated haemoglobin between the two subgroups of T2DM (all P>0.05). ②Compared with the control group, CIMT and CIT were thicker in the T2DM group (both P<0.05). ③CIT was thicker in the higher RC group than in the lower RC group ( P<0.05), while the difference of CIMT was not statistically significant the two groups ( P>0.05). ④Multivariate regression analysis showed that RC was the influence factor of CIT in patients with T2DM(β=0.610, P=0.005). Conclusions:CIT is significantly thicker in T2DM patients with higher RC than in those with lower RC, and RC is the influence factor of CIT, which suggests that more attention should be paid to the detection of RC in T2DM patients.

Change in expression of tumor necrosis factor receptor-associated factor 6 in lung tissues of rats with pulmonary hypertension / 中华麻醉学杂志

Objective:To determine the change in the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) in lung tissues of rats with pulmonary hypertension (PH).Methods:Sixteen SPF-grade healthy male Sprague-Dawley rats, aged 8 weeks, weighing 200-220 g, were divided into 2 groups ( n=8 each) by the random number table method: control group (group C1) and PH group (group PH1). The model of PH was prepared by subcutaneous injection of monocrotaline. On day 28 after developing the model, the mean pulmonary arterial pressure (mPAP) was measured, and the Fulton index was calculated, and the percentage of media wall thickness of the small and medium pulmonary arteries and percentage of muscularized vessels were also calculated. The expression of TRAF6, transcription-3 (STAT3), phosphorylated STAT3 (p-STAT3) and Cyclin D1 in lung tissues was detected by Western blot, and p-STAT3/STAT3 ratio was calculated. The interaction between TRAF6 and STAT3 was determined by immunoprecipitation assay. Primarily cultured pulmonary artery smooth muscle cells of normal rats (group C2) and pulmonary artery smooth muscle cells of rats with PH (group PH2) were inoculated in 6-well plates ( n=3 each). The expression of TRAF6 mRNA was detected by quantitative polymerase chain reaction. The expression of TRAF6, STAT3, p-STAT3 and Cyclin D1 was detected by Western blot. Results:Compared with group C1, the mPAP, Fulton index, percentage of media wall thickness of the small and medium pulmonary arteries and percentage of muscularized vessels were significantly increased, the expression of TRAF6 and Cyclin D1 in lung tissues was up-regulated, the p-STAT3/STAT3 ratio was increased ( P<0.05 or 0.01), and the results of immunoprecipitation showed that TRAF6 interacted with STAT3 in group PH1. Compared with group C2, the expression of TRAF6 protein and mRNA and Cyclin D1 was significantly up-regulated, and the p-STAT3/STAT3 ratio was increased in group PH2 ( P<0.05 or 0.01). Conclusions:The expression of TRAF6 in the lung tissue is up-regulated in rats with PH, which may be related to pulmonary vascular remodeling by promoting the activation of STAT3.

Advances in research on small molecule regulators targeting HBV cccDNA generation and transcription / 药学学报

Hepatitis B virus (HBV) represents a significant global public health challenge. Despite the availability of several approved drugs for hepatitis B treatment, the persistence of covalently closed circular DNA (cccDNA) renders HBV eradication elusive, thereby leading to disease relapse after drug withdrawal. This paper reviews the regulatory mechanisms of cccDNA formation, transcription and replication, and summarizes the research progress of related small molecule regulators from the perspective of medicinal chemistry.

Recent advances of small molecule inhibitors directly targeting HBV / 药学学报

Hepatitis B virus infection is a serious threat to human life and health. The approved anti-HBV drugs including interferons and nucleos(t)ide analogues have serious adverse effect, rebound phenomena after drug withdrawal, and drug resistance. And the cccDNA cannot be completely eliminated by both of them, which is the reason why a complete cure for hepatitis B cannot be achieved. Therefore, developing anti-HBV drugs directly targeting protein or nucleic acid of HBV remains a current public health priority. Based on the analysis of representative literature from the last decade, this article reviews recent developments in small molecule inhibitors directly targeting HBV from a medicinal chemistry perspective.

Study on the Emotional Status and Rights Protection of Participants in Drug Clinical Trials during Epidemic Prevention and Control / 中国医学伦理学

【Objective:】 To analyze the emotional status and follow-up status of the participants in the drug clinical trials in a hospital during the epidemic prevention and control, with a view to maximizing the protection of participants’ rights and interests under special circumstances. 【Methods:】 The general information, depression screening scale (PHQ-9), anxiety screening scale (GAD-7) and subject compliance assessment scale were completed online by participants with gold data questionnaire. At the same time, the status of drug clinical trials under study and the follow-up status of participants under study were collected from November 1, 2021 to December 8, 2021 and from December 9, 2021 to January 24, 2022. Excel software and SPSS18.0 software were used for data statistics and analysis. 【Results:】 During the epidemic prevention and control, there were 20 drug clinical trial projects under way in the hospital. From December 9, 2021 to January 24, 2022, the planned number of visits was 161, and the actual number of visits to the hospital was 84 (52.2%). Plus 24 participants who mailed drugs, the overall visit rate was 67.1%, among which the visit rates of oral drugs, non-oral drugs, and oral drugs combined with non-oral drugs were 79.3%, 71.9%, and 41.0% respectively. From November 1, 2021 to December 8, 2021, the planned number of visits was 166, the actual number of visits to the hospital was 157 (94.6%), and the number of telephone visits accounted for 1.8% of the total planned number of visits. The number of participants who did not take the drug and those who delayed taking the drug were both 0. The total compliance of participants was as high as 80.0%. A total of 40 valid questionnaires were retrieved, and the detection rates of depression and anxiety were 42.5% and 30.0% respectively. 【Conclusion:】 The epidemic prevention and control has a large short-term impact on the follow-up of the participants under study. The formulation of relevant follow-up measures and the conduction of classification management can not only improve the emotions of the participants to a certain extent, but also protect the rights and interests of participants, providing suggestions for the follow-up of participants under emergencies in the future.

Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma

The well-known insulin-like growth factor 1 (IGF1)/IGF-1 receptor (IGF-1R) signaling pathway is overexpressed in many tumors, and is thus an attractive target for cancer treatment. However, results have often been disappointing due to crosstalk with other signals. Here, we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma (HCC) cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) activity. In response to ligand binding, IGF-1Rβ is translocated into the ER by β-arrestin2 (β-arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ. SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβ levels. ER IGF-1Rβ phosphorylates SERCA2 on Tyr990 to enhance its activity. Mutation of SERCA2-Tyr990 disrupted the interaction of ER IGF-1Rβ with SERCA2, and therefore ER IGF-1Rβ failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca2+ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rβ and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca2+ER perturbation by enhancing SERCA2 activity through phosphorylating Tyr990 in HCC.

Recent advances in small molecule inhibitors of interleukin‑1 receptor-associated kinase / 药学学报

Interleukin-1 receptor associated kinase 4 (IRAK-4), acting as a serine threonine kinase, is considered as a key signal node for the transduction of IL-1R family and TLRs signal pathway. Studies have found that IRAK-4 has a hand in many signal pathways, involving the inflammatory response of human joints, intestines, liver and nervous system, as well as other autoimmune diseases. It is also one of the causes of drug resistance of some cancer cells. Therefore, IRAK-4 tends to be an effective therapeutic target for inflammatory diseases and cancer. The prospects for the development of drugs in this pathway is to develop novel IRAK-4 small molecule inhibitors and investigate their safety and effectiveness, enrich the clinical treatment of inflammatory and cancer diseases finally. This paper classified and summarized the latest research progress on small molecule inhibitors of IRAK-4 signaling pathway according to structures of the compounds, in order to provide assistances and references for the research and development of related drugs.

Comprehensive identification of metabolites and metabolic characteristics of luteolin and kaempferol in Simiao Yong'an Decoction in rats by UHPLC-LTQ-Orbitrap MS/MS / 中国中药杂志

Simiao Yong'an Decoction is a classic prescription for treating gangrene. Modern medical evidence has proven that Si-miao Yong'an Decoction has therapeutic effects on atherosclerosis(AS), vascular occlusion angeitides, and hypertension, while its pharmacodynamic mechanism remains unclear. The evidence of network pharmacology, molecular docking, literature review, and our previous study suggests that luteolin and kaempferol are two major flavonoids in Simiao Yong'an Decoction and can inhibit macrophage inflammation and exert anti-AS effects. However, due to lack of the metabolism studies in vivo, little is known about the metabolic characteristics of luteolin and kaempferol. This study employed ultra-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry(UHPLC-LTQ-Orbitrap MS/MS) and relevant software to identify the metabolites and metabolic pathways of luteolin and kaempferol in rat plasma, urine, and feces, after oral administration of luteolin and kaempferol, respectively. After the administration of luteolin, 10, 11, and 3 metabolites of luteolin were detected in the plasma, urine, and feces, respectively. After the administration of kaempferol, 9, 3, and 1 metabolites of kaempferol were detected in the plasma, urine, and feces, respectively. The metabolic pathways mainly involved methylation, glucuronidation, and sulfation. This study enriches the knowledge about the pharmacological mechanism of luteolin and kaempferol and supplies a reference for revealing the metabolic process of other flavonoids in Simiao Yong'an Decoction, which is of great significance for elucidating the pharmacological effects and effective substances of this decoction in vivo.

Challenges and Perspectives in Target Identification and Mechanism Illustration for Chinese Medicine / 中国结合医学杂志

Chinese medicine (CM) is an important resource for human life understanding and discovery of drugs. However, due to the unclear pharmacological mechanism caused by unclear target, research and international promotion of many active components have made little progress in the past decades of years. CM is mainly composed of multi-ingredients with multi-targets. The identification of targets of multiple active components and the weight analysis of multiple targets in a specific pathological environment, that is, the determination of the most important target is the main obstacle to the mechanism clarification and thus hinders its internationalization. In this review, the main approach to target identification and network pharmacology were summarized. And BIBm (Bayesian inference modeling), a powerful method for drug target identification and key pathway determination was introduced. We aim to provide a new scientific basis and ideas for the development and international promotion of new drugs based on CM.

Activation of insulin-like growth factor-1 receptor (IGF-1R) promotes growth of colorectal cancer through triggering the MEX3A-mediated degradation of RIG-I

Insulin-like growth factor-1 receptor (IGF-1R) has been made an attractive anticancer target due to its overexpression in cancers. However, targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream signalings. Here, we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of RIG-I. The active β-arrestin-2 scaffolds this disobliging signaling to talk with MEX3A. In response to ligands, IGF-1Rβ activated the basal βarr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250, opening the middle loop (Leu130‒Cys141) to the RING domain of MEX3A through the conformational changes of βarr2. The models of βarr2/IGF-1Rβ and βarr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of RIG-I. The assay of the mutants βarr2Y64A and βarr2Y250A further confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1Rβ and the RING domain of MEX3A. The truncated-βarr2 and the peptide ATQAIRIF, which mimicked the RING domain of MEX3A could prevent the formation of βarr2/IGF-1Rβ and βarr2/MEX3A complexes, thus blocking the IGF-1R-triggered RIG-I degradation. Degradation of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I pathway. Poly(I:C) could reverse anti-PD-L1 insensitivity by recovery of RIG-I. In summary, we revealed a disobliging IGF-1R signaling by which IGF-1Rβ promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.