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1.
Acta Pharmaceutica Sinica ; (12): 493-502, 2024.
Article in Chinese | WPRIM | ID: wpr-1016636

ABSTRACT

In 2023, drug discovery develops steadily, with improvement of small molecule drugs discovery keeps pace with biological drugs in this year. The Center for Drug Evaluation and Research of U.S. Food and Drug Administration has totally approved 55 kinds of new drugs which have significantly promotion compared to 37 new drugs approval in 2022, including 38 kinds of new molecular entities, 17 kinds of biological drugs, 5 kinds of gene therapeutics and 2 cell therapeutics. The proportion of first-in-class drugs increased steadily, with 13 small molecule first-in-class drugs and 7 biological first-in-class drugs approved this year, mostly in the fields of cancer and rare diseases. Among them, a plurality of first-initiated small molecule drugs exhibits breakthrough significance, such as the first neurokinin 3 (NK3) receptor antagonist fezolinetant, the first retinoic acid receptor (RIG-I) agonist palovarotene, the first protein kinase B (AKT) inhibitor capivasertib, the first complement factor B inhibitor iptacopan, etc. The pioneering drug has huge academic and commercial value, and has become the target of the academic and industrial circles. However, first-in-class drugs not only need new targets, new mechanisms and new molecules, but also need to comprehensively verify the causality between new targets and diseases, study the correlation between new mechanisms and drug efficacy, and explore the balance between new molecules and drug-manufacturing properties. This article analyzed the research background, development process and therapeutic application of three first-initiated small molecule drugs in this year, expecting to provide more research ideas and methods for more first-in-class drugs.

2.
Acta Pharmaceutica Sinica ; (12): 2035-2046, 2023.
Article in Chinese | WPRIM | ID: wpr-999125

ABSTRACT

Molecular chaperone system, which mainly consist of heat shock proteins family and their cochaperones, is crucial for maintaining proteostasis in life. It assists in folding, maturation and ubiquitin-proteasome-mediated degradation of proteins, thus to play a key role in cell proliferation and apoptosis. Functional disorder of molecular chaperone system is highly relevant to occurrence and development of multiple diseases including cancers, autoimmune disease/inflammatory, infective diseases, neurodegenerative disease, etc. Therefore, molecular chaperone system has long been regarded as potential drug targets. In this review, we outline the progress in the design of small molecules targeting molecular chaperone system and analyze the features of small molecules with different mechanisms. Finally, we put forward expects about potential development directions for future drug design in this field.

3.
China Pharmacy ; (12): 2695-2700, 2023.
Article in Chinese | WPRIM | ID: wpr-998551

ABSTRACT

OBJECTIVE To analyze the patents of new target oral drugs for type 2 diabetes mellitus (T2DM), and to provide references for the research and development direction and patent layout of new domestic diabetes drugs. METHODS Based on global patent data in the HimmPat database, from multiple perspectives such as the number of patent applications and authorization, development trend, regional distribution and main applicants, statistics and analysis were performed for the patents related to 3 types of new target oral drugs for T2DM, such as glucokinase activator (GKA), protein tyrosine phosphatase 1B inhibitor (PTP-1B-IN), and 11β-hydroxysteroid dehydrogenase 1 inhibitor (11β-HSD1-IN). RESULTS & CONCLUSIONS A total of 1 649 patents of GKA, 709 patents of PTP-1B-IN, 592 patents of 11β-HSD1-IN were obtained, the main applicants were well-known pharmaceutical companies, which possessed the core patents of pharmaceutical compounds. The research on GKA drugs was more mature, with a larger number of patent applications and a more comprehensive enterprise layout. Domestic enterprises, universities and research institutions had advantages in the field of PTP-1B-IN. Domestic enterprises and research institutions can leverage the advantages of traditional Chinese medicine and resources to enhance their research capabilities and improve technological competitiveness through core technology exploration, the exploration of process route, patent layout, industry- university-research cooperation and the establishment of patent pool.

4.
International Eye Science ; (12): 1935-1942, 2023.
Article in Chinese | WPRIM | ID: wpr-998468

ABSTRACT

AIM: To report 5 cases with drug-induced bilateral acute ciliochoroidal effusion(DBACE)and myopic shift, with or without ocular hypertension(OHT), summarize patients' clinical characteristics and recovery process of DBACE, and investigate the possible pathophysiological mechanism.METHODS:A retrospective observational case study conducted from June 2017 to February 2021. The included patients were subjected to a series of ocular examinations listed as follows: 1)best corrected visual acuity; 2)intraocular pressure(IOP); 3)slit-lamp microscopy; 4)fundus photography; 5)ultrasound biomicroscopy(UBM); 6)subjective optometry; 7)axial length and anterior chamber depth. All patients were followed up every 2d until the diopters were completely restored to the state before the disease onset.RESULTS:In total, 5 patients aged 10-45 years old, including 3 female and 2 male patients, were enrolled in this study. All patients were bilaterally involved(5/5), and had myopic shift(5/5), of whom 3 patients had OHT(3/5). With the increase of age, myopic shift decreased, while OHT increased. Based on OHT, the dynamic aggravation process of DBACE was subdivided into 2 stages, stage 1(myopic shift without OHT)and stage 2(myopic shift with OHT). With the deterioration of DBACE, when myopic shift approached or exceeded the minimum amplitude of accommodation(MAA), IOP gradually rose, and DBACE progressed from stage 1 to stage 2. With the recovery of DBACE after discontinuing the suspicious drugs, DBACE in stage 2 first returned to stage 1, and then returned to normal.CONCLUSION:Pathophysiological mechanism of DBACE was subdivided into 2 stages, including stage 1(myopic shift without OHT)and stage 2(myopic shift with OHT). The transition between the two stages depends on the imbalance between myopic shift and MAA.

5.
Article in Chinese | WPRIM | ID: wpr-998255

ABSTRACT

ObjectiveTo develop a high-quality rehabilitation major curriculum using the World Health Organization rehabilitation competency framework (RCF), to improve the level of traditional Chinese medicine (TCM) rehabilitation major, to meet the requirements of competency-based education development. MethodsThe competence requirements of rehabilitation professionals of higher traditional TCM colleges and universities were analyzed using the theory and method of RCF. ResultsThe competency structure of TCM rehabilitation talents based on RCF was built, and the curriculum setting of TCM rehabilitation based on RCF was proposed. According to the characteristics of the educational environment of colleges and universities, a competency model suitable for undergraduate-level TCM rehabilitation major was established. ConclusionThe theory and methods of RCF are of great significance for the construction of competency-based education system of TCM rehabilitation major. Based on RCF, this study constructs the basic and practical curriculum system of TCM rehabilitation at the undergraduate level to promote the training of applied talents in TCM rehabilitation.

6.
Article in Chinese | WPRIM | ID: wpr-997658

ABSTRACT

ObjectiveTo observe the effects of Dendrobium polysaccharides on the secretion of inflammatory cytokines and Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway in 16HBE cells exposed to cigarette smoke extract (CSE). MethodThe 16HBE cells were classified into the control, CSE, and CSE+ Dendrobium polysaccharides (100, 200, 400 mg·L-1) groups. The cell-counting kit-8 (CCK-8) assay was employed to measure the cell viability, and a microscope was used to observe the cell morphology. The enzyme-linked immunosorbent assay was employed to measure the levels of interleukin (IL)-8, IL-1β, IL-4, IL-13, and transforming growth factor (TGF)-β in cell culture supernatants. Real-time PCR was carried out to determine the mRNA levels of Toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), and IL-4. Western blot was employed to determine the protein levels of interleukin-4 receptor (IL-4R), TLR4, myeloid differentiation primary response protein 88 (MyD88), NF-κB, phosphorylated nuclear factor-κB (p-NF-κB), and nucleoproteins nuclear factor-κB (NEs-NF-κB). The immunofluorescence assay was employed to measure the nuclear translocation of NF-κB. ResultCompared with the control group, the CSE group showed elevated levels of IL-8, IL-1β, IL-4, IL-13, and TGF-β in the cell culture supernatants (P<0.05, P<0.01), up-regulated expression levels of TLR4, MyD88, NF-κB, p-NF-κB, NEs-NF-κB, and IL-4 (P<0.01), and significant nuclear translocation of NF-κB. Compared with the CSE group, Dendrobium polysaccharides increased the cell survival rate, recovered the cell activity, lowered the levels of IL-8, IL-1β, IL-4, IL-13, and TGF-β, down-regulated the expression of TLR4, MyD88, NF-κB, p-NF-κB, NEs-NF-κB, and IL-4 (P<0.05, P<0.01), and reduced the nuclear translocation of NF-κB. ConclusionDendrobium polysaccharides showed significant protective effects on the 16HBE cells exposed to CSE by inhibiting the TLR4/NF-κB signaling pathway.

7.
Article in Chinese | WPRIM | ID: wpr-995522

ABSTRACT

Objective:To investigate the safety and feasibility of Ivor-Lewis procedure under uniportal video-assisted thoracoscopy(VATS) for esophageal cancer and Siewert type I esophago-gastric junction carcinoma.Methods:The patients with middle-lower segment esophageal cancer or Siewert type I esophago-gastric junction carcinoma received minimally invasive esophagectomy between October 2020 and June 2021, and the clinical data was collected and analyzed.Results:26 patients received Ivor-Lewis procedure underwent uniportal VATS, while 45 patients underwent McKeown surgery under multiport VATS. The average operation time of patients in the two groups were(265±110)min and (235±94)min, and the average intraoperative blood loss were(80±57)ml and(105±60)ml. The mean number of lymph nodes removed in the surgery were (19.3±2.9) and 18.6±2.7 respectively in two groups, and the mean length of hospital stay was(7.5±3.5)days and(8.3±2.7)days. The incidence of perioperative complications were not significantly different in two groups. The VAS score of patients received Ivor-Lewis procedure underwent uniportal VATS was lower than that of patients received McKeown surgery in ostoperative day 1, day 3, day 7 and 1 month. The difference was statistically significant in two groups( P<0.05). Conclusion:The Ivor-Lewis procedure under uniportal VATS for esophageal cancer and Siewert type I esophago-gastric junction carcinoma has the advantage of less postoperative pain, and the procedure is feasible in clinical practice.

8.
Article in Chinese | WPRIM | ID: wpr-995400

ABSTRACT

Objective:To compare the histopathological features and treatment efficacy of different methods for metachronous early gastric cancer (MEGC) in the remnant stomach.Methods:A total of 66 patients [38 endoscopic submucosal dissection (ESD) and 28 gastrectomy] with MEGC in the remnant stomach from January 2014 to December 2020 in Drum Tower Hospital were divided into the ESD group and the gastrectomy group. The baseline characteristics, histopathological features, treatment efficacy, and cost differences of the two groups were analyzed.Results:The MEGC in the remnant stomach mostly occurred in elderly male patients, with the mean age of 69.7±8.5 years. The mean interval of the occurrence of MEGC in the remnant stomach was 6 years. As for the tumor location, the gastric body (31.6%) was the main location in the ESD group and gastric cardia (53.6%) in the gastrectomy group with significant difference ( χ2=11.07, P=0.026). The mean operation time, hospital stay, postoperative fasting time, and total treatment cost were 80.0 min, 6.0 d, 1.5 d, ¥19 436 in the ESD group and 215.0 min, 19.0 d, 6.5 d, and ¥68 665 in the gastrectomy group, respectively, with significant differences between the two groups ( P<0.05). The overall survival rate during follow-up was 76.3% in the ESD group and 71.4% in the gastrectomy group with no significant difference between the two groups ( χ2=0.736, P=0.778). In terms of postoperative complications, the incidences of bleeding and infection were 7.9% and 5.3% in the ESD group, and those of obstruction and infection were both 14.3% in the gastrectomy group. There was significant difference in the incidences of postoperative obstruction between the two groups ( P<0.05). Conclusion:ESD is safe and effective for MEGC in the remnant stomach and is better than gastrectomy in terms of the treatment cost and operation time, but the long-term efficacy still needs to be validated by large-scale prospective studies.

9.
Article in Chinese | WPRIM | ID: wpr-995394

ABSTRACT

Objective:To compare the safety and efficacy of endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) for the treatment of biliary obstruction at different locations.Methods:From January 2016 to June 2021 data of 82 patients with obstructive jaundice treated with EUS-HGS in Nanjing Drum Tower Hospital were reviewed in this retrospective cohort study. According to the location of biliary obstruction,patients were divided into hilar biliary obstruction group ( n=30) and distal biliary obstruction group ( n=52). Univariate and multivariate logistic regression analyses were conducted adjusting covariates to compare the technical success rate, the clinical success rate, the adverse reaction incidence, hospital stay and cost of the two groups. Results:The technical success rates were 93.3% (28/30) and 94.2% (49/52) in the hilar biliary obstruction group and the distal biliary obstruction group with no significant difference between the two groups ( P=0.870, OR=1.17, 95% CI: 0.18-7.41). The clinical success rates were 83.3% (25/30) and 88.5% (46/52) in the hilar biliary obstruction group and the distal biliary obstruction group with no significant difference between the two groups ( P=0.514, OR=1.53, 95% CI: 0.43-5.53). The incidence of adverse events in hilar biliary obstruction group was 10.0% (3/30), including cholangitis 3.3% (1/30), biliary fistula 6.7% (2/30), biliary peritonitis 6.7% (2/30). The incidence of adverse events in patients with distal biliary obstruction was 17.3% (9/52), including cholangitis 9.6% (5/52), biliary fistula 7.7% (4/52) and biliary peritonitis 5.8% (3/52). There was no significant difference in the incidence of adverse events between the two groups ( P>0.05). Conclusion:There is no significant difference in safety or efficacy of EUS-HGS for hilar biliary obstruction and distal biliary obstruction.

10.
Article in Chinese | WPRIM | ID: wpr-995324

ABSTRACT

Objective:To investigate the prevalence of Mycoplasma pneumoniae ( Mp) in children undergoing physical examination. Methods:This study randomly enrolled 1 303 children at the age of 6-12 years who underwent physical examination in 2023. Their oral and pharyngeal swabs as well as venous blood samples were collected. The prevalence of Mp in these subjects was detected using isolation and culturing, nucleic acid detection and serological test. Chi-square test was used for statistical analysis. Results:Among the 1 303 children, the detection rate of Mp was 4.1% (53/1 303) by culturing, 7.3% (95/1 303) by nucleic acid detection and 13.6% (177/1 303) by serological test. Statistical analysis showed that there were significant differences in the the detection rates of Mp among children undergoing physical examination between the three methods ( P<0.05). Conclusions:The detection rate of Mp in children undergoing physical examination in 2023 was about 4.1%. Isolation and culturing was more accurate than nucleic acid detection and serological test in the detection of Mp in healthy population as the latter two methods would overestimate the rate.

11.
Article in Chinese | WPRIM | ID: wpr-995189

ABSTRACT

Objective:To observe any effect of long-distance application of Oral Reading for Language with Aphasia (ORLA) training on patients with post-stroke aphasia.Methods:A total of 42 stroke survivors with aphasia were randomly divided into an inpatient group, and two online groups, each of 14. All three groups had their routine rehabilitation treatment supplemented with ordinary multimodal language therapy and ORLA. The inpatient group completed the routine in the rehabilitation treatment room, while the online groups completed it at home using Tencent video conferencing software. The conventional multimodal language therapy was conducted once daily, 5 days a week for 4 weeks. For the inpatient group and online group 2 the daily session lasted 30 minutes, while for the online 1 groups the daily length was doubled. The ORLA therapy was also conducted once daily, 5 days a week for 4 weeks, for the inpatient group and online group 2 the daily session lasted 1h, while for the online 1 groups the daily length was 30min.The speech function, reading ability and life quality of the three groups were evaluated before and after the intervention using the Western Aphasia Battery, the Chinese Standard Aphasia Examination Scale and the Chinese version of the Stroke Aphasia Quality of Life Scale.Results:After treatment, the average aphasia quotient (AQ), reading, naming and quality of life scores in all three groups had improved significantly compared with those before treatment. And related language ability scores (such as retelling, fluency, information volume, listening comprehension, etc.) had also improved significantly in all three groups. However, the average AQ, reading, and oral fluency scores of the inpatient group and online group 2 were significantly higher than those of online group 1. Significant improvement was also observed in the reading aloud and life quality of all three groups, but the average improvement in reading aloud was significantly greater in the inpatient group and in online group 2 compared to online group 1. The average life quality of the online groups was significantly superior to that of the inpatient group.Conclusion:Medium- and high-intensity ORLA synchronous remote speech rehabilitation can significantly improve the speech ability, reading ability and life quality of aphasic stroke survivors.

12.
Acta Physiologica Sinica ; (6): 555-568, 2023.
Article in Chinese | WPRIM | ID: wpr-1007771

ABSTRACT

The development of chronic liver disease can be promoted by excessive fat accumulation, dysbiosis, viral infections and persistent inflammatory responses, which can lead to liver inflammation, fibrosis and carcinogenesis. An in-depth understanding of the etiology leading to chronic liver disease and the underlying mechanisms influencing its development can help identify potential therapeutic targets for targeted treatment. Orphan nuclear receptors (ONRs) are receptors that have no corresponding endogenous ligands to bind to them. The study of these ONRs and their biological properties has facilitated the development of synthetic ligands, which are important for investigating the effective targets for the treatment of a wide range of diseases. In recent years, it has been found that ONRs are essential for maintaining normal liver function and their dysfunction can affect a variety of liver diseases. ONRs can influence pathophysiological activities such as liver lipid metabolism, inflammatory response and cancer cell proliferation by regulating hormones/transcription factors and affecting the biological clock, oxidative stress, etc. This review focuses on the regulation of ONRs, mainly including retinoid related orphan nuclear receptors (RORs), pregnane X receptor (PXR), leukocyte cell derived chemotaxin 2 (LECT2), Nur77, and hepatocyte nuclear factor 4α (HNF4α), on the development of different types of chronic liver diseases in different ways, in order to provide useful references for the therapeutic strategies of chronic liver diseases based on the regulation of ONRs.


Subject(s)
Humans , Orphan Nuclear Receptors/metabolism , Receptors, Steroid/physiology , Ligands , Liver , Liver Diseases , Intercellular Signaling Peptides and Proteins
13.
Chinese Journal of Biotechnology ; (12): 1403-1424, 2023.
Article in Chinese | WPRIM | ID: wpr-981146

ABSTRACT

Malignant tumors are diseases that seriously threaten human health and social development. Traditional tumor therapies such as surgery, radiotherapy, chemotherapy and targeted therapy cannot fully meet the needs of clinical treatment, and emerging immunotherapy has become a research hotspot in the field of tumor treatment. Immune checkpoint inhibitors (ICIs) have been approved as a tumor immunotherapy method for the treatment of various tumors, such as lung cancer, liver cancer, stomach cancer and colorectal cancer, etc. However, during the clinical use of ICIs, only a small number of patients experienced durable responses, which also led to drug resistance and adverse reactions. Therefore, the identification and development of predictive biomarkers is crucial to improve the therapeutic efficacy of ICIs. The predictive biomarkers of tumor ICIs mainly include tumor biomarkers, tumor microenvironment biomarkers, circulation-related biomarkers, host environmental biomarkers and combinatorial biomarkers. They are of great significance for screening, individualized treatment and prognosis evaluation of tumor patients. This article reviews the advances of predictive markers for tumor ICIs therapy.


Subject(s)
Humans , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms , Biomarkers , Immunotherapy/methods , Biomarkers, Tumor/genetics , Prognosis , Tumor Microenvironment
14.
Article in English | WPRIM | ID: wpr-981126

ABSTRACT

OBJECTIVES@#This study aimed to analyze the application value of a modified tragus edge incision and transmasseteric anteroparotid approach to condyle reconstruction.@*METHODS@#Condyle reconstruction was performed in 16 patients (9 females and 7 males) with modified tragus edge incision and transmasseteric anteroparotid approach. After regular follow-up, the function of condyle reconstruction was evaluated by clinical indicators, such as parotid salivary fistula, facial nerve function, mouth opening, occlusal relationship, and facial scar. The morphology of rib graft rib cartilage was evaluated by imaging indicators, such as panoramic radiography, CT, and three-dimensional CT image reconstruction.@*RESULTS@#At 6-36 months postoperative follow-up, all patients had good recovery of facial appearance, concealed incisional scar, no parotid salivary fistula, good mouth opening, and occlusion. One case had temporary facial paralysis and recovered after treatment. Radiographic evaluation further showed that costochondral graft survived in normal anatomic locations.@*CONCLUSIONS@#The modified tragus edge incision and transmasseteric anteroparotid approach can effectively reduce parotid salivary fistula and facial nerve injury in condylar reconstruction. The surgical field was clearly exposed, and the incision scar was concealed without increasing the incidence of other complications. Thus, this approach is worthy of clinical promotion.


Subject(s)
Male , Female , Humans , Mandibular Condyle/surgery , Cicatrix/surgery , Fracture Fixation, Internal/methods , Mandibular Fractures/surgery , Oral Surgical Procedures/methods , Treatment Outcome
15.
Article in English | WPRIM | ID: wpr-981061

ABSTRACT

OBJECTIVE@#This study aimed to evaluate the effects of a mindfulness-based psychosomatic intervention on depression, anxiety, fear of childbirth (FOC), and life satisfaction of pregnant women in China.@*METHODS@#Women experiencing first-time pregnancy ( n = 104) were randomly allocated to the intervention group or a parallel active control group. We collected data at baseline (T0), post-intervention (T1), 3 days after delivery (T2), and 42 days after delivery (T3). The participants completed questionnaires for the assessment of the levels of depression, anxiety, FOC, life satisfaction, and mindfulness. Differences between the two groups and changes within the same group were analyzed at four time points using repeated-measures analysis of variance.@*RESULTS@#Compared with the active control group, the intervention group reported lower depression levels at T2 ( P = 0.038) and T3 ( P = 0.013); reduced anxiety at T1 ( P = 0.001) and T2 ( P = 0.003); reduced FOC at T1 ( P < 0.001) and T2 ( P = 0.04); increased life satisfaction at T1 ( P < 0.001) and T3 ( P = 0.015); and increased mindfulness at T1 ( P = 0.01) and T2 ( P = 0.006).@*CONCLUSION@#The mindfulness-based psychosomatic intervention effectively increased life satisfaction and reduced perinatal depression, anxiety, and FOC.


Subject(s)
Humans , Pregnancy , Female , Mental Health , Mindfulness , Pregnant Women/psychology , Anxiety/prevention & control , China , Depression/prevention & control
16.
International Eye Science ; (12): 1454-1460, 2023.
Article in Chinese | WPRIM | ID: wpr-980532

ABSTRACT

AIM: To investigate the effect of the intravitreal injection of vascular endothelial growth factor-A165(VEGF-A165)on the scleral remodeling of guinea pigs with form-deprivation myopia(FDM).METHODS: A total of 120 tricolor guinea pigs, aged three weeks, were randomly divided into 6 groups, with 20 in each group. The blank group did not undergo any intervention. In the FDM group, only the FDM model was established. In the phosphate buffer saline(PBS)group, 2.5 μL of PBS was injected into the vitreous cavity before establishing the FDM model. In the 1ng group, 5ng group, and 10ng group, VEGF-A165 was injected into the vitreous cavity at concentrations of 1, 5 and 10ng, respectively, before the establishment of the FDM model. The FDM model was established by covering the right eyes of guinea pigs with translucent balloons for 14d. The diopter and axial length of the right eyes were measured before and after covering. After 14d, the content of dopamine(DA)in retina was measured by high performance liquid chromatography. Additionally, the mRNA and protein expression levels of matrix metalloproteinase-2(MMP-2), tissue inhibitor of matrix metalloproteinase-2(TIMP-2), transforming growth factor(TGF)-β1, TGF-β2 and α-smooth muscle actin(α-SMA)in sclera were detected by reverse transcription polymerase chain reaction(RT-PCR)and Western blot.RESULTS: Before covering, there were no significant differences in the diopter and axial length of the right eyes of guinea pigs in all groups(P&#x003E;0.05). After 14d of modeling, when compared with the blank group, FDM group showed an increase in the degree of myopia in the right eye, a prolongation of the axial length, a decrease in the content of DA in the retina, and an increase in the expression of MMP-2, TGF-β2 and α-SMA in the sclera. Conversely, the expression of TIMP-2 and TGF-β1 were decreased(P&#x003C;0.01). However, in comparison to the FDM group, the degree of myopia in the 1ng, 5ng, and 10ng groups of guinea pigs decreased, the growth trend of axial length slowed, the content of DA in the retina increased, and the expression of MMP-2, TGF-β2 and α-SMA in the sclera decreased. Furthermore, the expression of TIMP-2 and TGF-β1 in the sclera increased(P&#x003C;0.01). As the concentration of intravitreal injection of VEGF-A165 increased, the degree of myopia in the right eye of guinea pigs gradually increased, and the axial length gradually prolonged. The content of DA in the retina gradually decreased, the expression of MMP-2, TGF-β2, and α-SMA in the sclera gradually increased, while the expression of TIMP-2 and TGF-β1 decreased gradually.CONCLUSION: Intravitreal injection of VEGF-A165 can increase the content of DA in the retina of FDM guinea pigs, affect the expression of MMP-2, TIMP-2, TGF-β1, TGF-β2 and α-SMA in the sclera, and inhibit scleral remodeling of guinea pigs. Notably, the VEGF-A165 at the concentration of 1ng showed the most significant efficacy.

17.
Acta Pharmaceutica Sinica ; (12): 875-883, 2023.
Article in Chinese | WPRIM | ID: wpr-978775

ABSTRACT

2022 is the third year of the global COVID-19 pandemic, and its troubles on new drug discovery are gradually apparent. 37 new drugs were approved by the FDA's Center for Drug Evaluation and Research (CDER) last year, down from the peak of 50 new drug approvals in 2021. Notably, first-in-class drugs still occupy a dominant position this year, with a total of 21 drugs. Among them, 7 are first-in-class small molecule drugs. Although the total number of new drug approvals in 2022 sharply decreased, some first-in-class small molecule drugs were regarded as significant, including mitapivat, the first oral activator targeting the pyruvate kinase (PK); mavacamten, the first selective allosteric inhibitor targeting the myocardial β myosin ATPase; deucravacitinib, the first deuterated allosteric inhibitor targeting the tyrosine kinase 2 (TYK2); and lenacapavir, the first long-acting inhibitor targeting the HIV capsid. Generally, the research of first-in-class drugs needs to focus on difficult clinical problems and can treat some specific diseases through novel targets and biological mechanisms. There are tremendous challenges in the research processes of new drugs, including biological mechanism research, target selection, molecular screening, lead compound identification and druggability optimization. Therefore, the success of first-in-class drugs development has prominent guidance significance for new drug discovery. This review briefly describes the discovery background, research and development process and therapeutic application of 3 first-in-class small molecule drugs to provide research ideas and methods for more first-in-class drugs.

18.
Article in English | WPRIM | ID: wpr-977150

ABSTRACT

Background@#Irritable bowel syndrome (IBS) is a functional bowel disorder (FBD). @*Objectives@#To assess the therapeutic effects of paeoniflorin (PF) on IBS in rats.Method: Sixty male Sprague–Dawley rats were randomly divided into normal, model, positive drug, low-dose PF, medium-dose PF and high-dose PF groups (n = 10). After gavage for 2 consecutive weeks, the effect of PF on abdominal pain symptoms was assessed based on the abdominal withdrawal reflex (AWR) score, fecal water content and pathological changes in colon tissues. D-lactate, interleukin-1β (IL-1β), transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay, and phosphorylated nuclear factor kappa B (p-NF-κB) p65 was detected by Western blotting. The abundance and diversity changes of intestinal flora were explored using 16S ribosomal RNA sequencing.Result: In PF groups, the mucosal morphology of colon tissues was intact, and the glands were arranged neatly and structured clearly, without obvious inflammatory cell infiltration.Compared with the model group, PF groups had significantly elevated pain threshold, and mRNA and protein levels of zonula occludens-1 (ZO-1) and occludin, decreased AWR score at 20 mmHg pressure, fecal water content, mRNA levels of IL-1β, TGF-β, and TNF-α, protein level of p-NF-κB p65 and level of serum D-lactate, and reduced levels of serum IL-1β, TGF-β, and TNF-α (p < 0.05, p < 0.01). PF groups had higher abundance of Lactobacillus, Akkermansia, Alistipes, and Bacteroides, but lower abundance of Desulfovibrio, Parasutterella, and Enterococcus than those of the model group. @*Conclusions@#PF exerts therapeutic effects on IBS in rats probably by regulating the intestinal flora, and then up-regulating the expressions of ZO-1 and occludin in colon tissue while down-regulating the levels of IL-1β, TGF-β, TNF-α, D-lactate and p-NF-κB p65.

19.
China Pharmacy ; (12): 1468-1472, 2023.
Article in Chinese | WPRIM | ID: wpr-976271

ABSTRACT

OBJECTIVE To study the correlation of novel organic cation transporter 2 (OCTN2) with the chemosensitivity of prostate cancer cells to oxaliplatin. METHODS Tumor samples of patients receiving radical prostatectomy were collected, and OCTN2 protein was detected with immunohistochemistry; the primary cells of the specimen were cultivated to obtain prostate cancer cell line. Inductively coupled plasma mass spectrometry was used to detect the uptake of low concentration (0.1 μmol/L) of oxaliplatin by cancer cells. Real-time PCR and Western blot were used to detect the mRNA and protein expressions of OCTN2 in cancer cells; the prostate cancer cells with the highest and lowest expression of OCTN2 protein were selected, and IC50 of oxaliplatin to prostate cancer cells was analyzed by ATP-TCA method. The inhibitory rate of plasma peak concentration of oxaliplatin (50 μmol/L) to prostate cancer cells was detected by MTT assay. Spearman method was used to analyze the relationship of the uptake of oxaliplatin by prostate cancer cells with inhibitory rate of oxaliplatin to prostate cancer cells and 505916443@qq.com mRNA expressions of OCTN2. RESULTS OCTN2 was located on the membrane of cancer cells, and the uptake of zjdtztougao@163.com oxaliplatin by cancer cells was 0.283±0.264 (n=12)mRNA and protein expression of OCTN2 varied significantly among different cancer cells. The sensitivity of cancer cells with high expression of OCTN2 to oxaliplatin (IC50 of 4.61 μmol/L) was higher than that of cancer cells with lower expression of OCTN2 (IC50 of 26.23 μmol/L). The inhibitory rate of oxaliplatin to cancer cells was (25.4±10.8)% (n=12). There was a correlation between the uptake of oxaliplatin by prostate cancer cells and the inhibition rate of oxaliplatin to prostate cancer cells and mRNA expression of OCTN2 (P<0.05). CONCLUSIONS High-expressed OCTN2 may promote the uptake of oxaliplatin by prostate cancer cells, and its expression can serve as a reference for predicting the sensitivity of prostate cancer cells to oxaliplatin chemotherapy.

20.
Article in Chinese | WPRIM | ID: wpr-993614

ABSTRACT

Objective:To explore the changes of right ventricular myocardial perfusion in pulmonary arterial hypertension (PAH) pig models with a quantitative analysis technique based on dynamic SPECT myocardial perfusion imaging, and analyze the relationship between myocardial blood flow, hemodynamics and right ventricular function.Methods:Eleven Chinese miniature pigs (all males, 6-8 months old) weighing 25-30 kg were selected. The PAH models were established by ligating the main pulmonary artery and embolizing the right lower pulmonary artery. After the models were established, dynamic myocardial perfusion imaging with one-day resting/adenosine stress 99Tc m-methoxyisobutylisonitrile (MIBI) SPECT was performed, and the quantitative parameters of left and right ventricles were obtained, including stress myocardial blood flow (SMBF), rest myocardial blood flow (RMBF) and myocardial flow reserve (MFR: the ratio of stress to rest myocardial blood flow). Right heart catheterization was performed to evaluate the mean pulmonary arterial pressure (mPAP), and the right heart function index tricuspid annular plane systolic excursion (TAPSE) was measured by transthoracic echocardiography. According to TAPSE, animals were divided into right heart function preserved group ( n=5, TAPSE≥17 mm) and right heart dysfunction group ( n=4, TAPSE<17 mm). Pearson correlation analysis and the independent-sample t test were used for data analysis. Results:Nine experimental pig models were established with increased mPAP of (38.1 ± 11.6 ) mmHg (1 mmHg=0.133 kPa). Myocardial perfusion imaging showed clear radiotracer uptake in the right heart and myocardial hypertrophy. There was a significant positive correlation between right ventricular myocardial RMBF ((0.71±0.13) ml·min -1·g -1) and mPAP ( r=0.94, P< 0.001). The SMBF in the decreased right ventricular function group was significantly lower than that in the preserved right ventricular function group ((1.66±0.35) vs (2.24±0.30) ml·min -1·g -1;t=2.68, P=0.032). Conclusion:SPECT myocardial blood flow quantification can be used to evaluate the right ventricular myocardial blood flow in pig models of PAH.

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