ArchiveGlutamine （Gln） is the key carbon and nitrogen donor and energy source of the body. It is not only a critical player in tumorigenesis but also involved in regulating the development and activation of immune cells. Rapidly proliferating tumor cells will obtain a large amount of nutrients from the tumor microenvironment, leading to depletion of Gln, which significantly inhibits the activity and function of T cells and induces T cell exhaustion. The proliferation of tumor cells was suppressed by Gln metabolism inhibitors, including Gln mimetics, glutaminase inhibitors，and Gln transporter inhibitors. Meanwhile, T cell depletion was not further aggravated. Instead, the tumor microenvironment was improved to enhance the antitumor immune response by regulating multiple mechanisms such as immune checkpoint molecule expression,extracellular matrix structure remodeling, and tumor-associated macrophage polarization. Combining Gln metabolic inhibitors with immune checkpoint inhibitors can also exert synergistic effects.
Glaucoma, a leading cause of irreversible blindness worldwide, primarily involves pathological elevation of intraocular pressure （IOP）, which is its main risk factor, so the clinical goal in treating glaucoma is to reduce IOP to individual target levels. Currently, the classical local anti-glaucoma drugs include five categories: prostaglandin analogues（PGAs）, β-adrenergic receptor blockers, α2- adrenergic receptor agonists, carbonic anhydrase inhibitors, and cholinergic receptor agonists. These drugs mainly work by reducing aqueous humor production, increasing aqueous outflow through the trabecular pathway and the uveal scleral pathway, and contracting the pupil sphincter to open the chamber angle. Among these, PGAs have become the preferred choice for controlling IOP in primary open-angle glaucoma patients due to their efficacy and safety. In recent years, the introduction of novel glaucoma medications, including Rho kinase inhibitors and nitric oxide-donating anti-glaucoma drugs, along with the development of related drug-releasing formulations （intraocular and extraocular drug delivery systems）, offers new options for glaucoma treatment.
In order to establish a technical evaluation system in line with the characteristics of traditional Chinese medicine （TCM） and promote the inheritance and innovative development of TCM, China is building a TCM registration and evaluation evidence system combining TCM theory, human experience, and clinical trials. Human experience is of great significance to support the registration and evaluation of new drugs of TCM. Based on the survey of 20 medical institutions in Shanghai, this paper analyzed the current situation and common problems of human experience collection of TCM. It was found that medical institutions had been aware of carrying out human experience collection for the development of TCM preparations or new drugs. However, the hardware conditions, personnel capabilities, and the importance of medical institutions in collecting human experience were still not optimistic. There were difficulties in the collection process. 90%of institutions believed that the quality of collected data did not meet the requirements of drug registration. Regulators and medical institutions should work together to improve and standardize the collection of human experience of TCM by improving collection methods, increasing research capabilities, strengthening the construction of information systems, and enhancing research quality management according to GCP principles, so as to ultimately obtain high-quality evidence materials to support the innovation and transformation of TCM.
Risk minimisation measure （RMM） is a critical step to maximize the benefit-risk ratio of a medicinal product in pharmacovigilance activities. Through literature review and consulting the websites of major healthcare authorities in Europe Union, the USA, and Japan, this paper reviewed the RMM regulatory requirements and implementation status of these countries and regions. It was found that Europe, the USA, and Japan established relevant regulations earlier and accumulated valuable experience, and the specific implementation and supervision intensity of RMM varied among regions due to differences in medical systems. For example, additional risk minimization measures in Japan and the European Union are presented as risk evaluation and mitigation strategies in the USA. It is suggested that RMM-related regulations and supervision system should be continuously improved, and the marketing authorization holders in China should develop RMM implementation plans that conform to the actual conditions of China based on foreign experience and combined with the current situation of local medical system, and conduct feasible and efficient RMM effectiveness assessment to ensure patient medication safety.
To observe the influences of ginsenoside Rb1 （GsRb1） on the proliferation and osteogenic differentiation of human periodontal ligament stem cells （hPDLSCs）, and its molecular mechanism related to stromal cell-derived factor-1 （SDF-1）/CXC chemokine receptor 4 （CXCR4） pathway.
hPDLSCs were isolated and cultured by enzyme digestion method. Cell morphology was observed under an inverted microscope. Flow cytometry was used to detect the proportion of stromal cell antigen 1 （STRO-1） and cluster of differentiation 146 （CD146） positive cells. hPDLSCs were treated with 0, 0.5, 1.0, 2.0, 4.0, 6.0 μmol·L-1 GsRb1, respectively, and the optimal concentration was screened by CCK-8 method. hPDLSCs were divided into control group, GsRb1 （4.0 μmol·L-1） group, AMD3100 （5 μg·mL-1） group, and GsRb1+AMD3100 group, the cell proliferation and alkaline phosphatase （ALP） activity of each group were compared, the mRNA expression of Runt-related gene 2 （Runx2）, oxterix, and osteopontin （OPN） were detected by qRT-PCR, and the formation of mineralized nodules in hPDLSCs was detected by alizarin red staining and quantitative analysis. Western blot was used to detect the expression of SDF-1/CXCR4 signaling pathway-related proteins.
hPDLSCs were arranged radially, with long spindles, and the growth was relatively dense. The proportions of STRO-1 and CD146 positive cells were 97.19% and 98.01%, respectively. With the increase of GsRb1 concentration, the proliferation activity of hPDLSCs was enhanced in a dose-dependent manner （P<0.05）. Compared with the control group, the cell viability and ALP activity in the GsRb1 group were enhanced, and the mRNA expression of Runx2, oxterix, OPN, the amount of mineralized nodules, and the protein expression of SDF-1 and CXCR4 were increased （P<0.05）, while the AMD3100 group was the opposite （P<0.05）.Compared with the GsRb1 group, the cell viability and ALP activity in the GsRb1+AMD3100 group were decreased, and the mRNA expression of Runx2, oxterix, OPN, the amount of mineralized nodules, and the protein expression of SDF-1 and CXCR4 were decreased （P<0.05）.
GsRb1 can promote the proliferation and osteogenic differentiation of hPDLSCs, which may be related to the increased protein expression of SDF-1/CXCR4 signaling pathway.
To study the anti-tumor effect of icotinib combined with metformin on non-small cell lung cancer （NSCLC） H1975 cells and its possible mechanism.
CCK-8 assay was used to detect the proliferation inhibitory effect and combination index （CI） of icotinib monotherapy （0, 0.1, 1, 5, 10, 20, 40 μmol·mL-1）, metformin monotherapy （0, 2, 4, 8, 16, 32, 64 mmol·mL-1）, and icotinib （0, 0.125, 0.25, 0.5, 1 times of IC50） combined with metformin （0.5 times of IC50） on the H1975 cells. The migratory ability of the cells was detected by scratch test，and the invasive ability of the cells was detected by invasion test. Annexin V-FITC/PI flow cytometry was used to detect the rate of apoptosis. Western blot was used to detect the expression level of related proteins.
The IC50 of icotinib and metformin for the inhibition on H1975 cells after 48 h were （49.90±4.84） μmol·mL-1 and （13.20±1.27）mmol·mL-1, respectively. Icotinib and metformin produced a synergistic effect in H1975 cells（CI<1）. Compared with the metformin group and the icotinib group, the migration rate and invasion ability of combination group were significantly decreased, and the apoptosis rate was significantly increased （P<0.05）；the expression of p-Akt, p-mTOR and Bcl-2 were significantly decreased, while the expression of p-AMPK and Bax were significantly increased （P<0.05）.
Icotinib and metformin have significant synergic antitumor effects and proapoptotic effects on non-small cell lung cancer H1975 cells, and the underlying mechanism may be related to enhancing activation of AMPK and inhibition of Akt/mTOR signaling pathway.
To observe the anesthetic effect of ciprofol in intracranial aneurysm embolization.
One hundred and twenty patients undergoing intracranial aneurysm embolization, ASA Ⅰor Ⅱ, were randomly divided into control group and experimental group （n=60, each group）. During anesthesia induction, patients were given with midazolam 0.04 mg·kg-1, sufentanil 0.25 μg·kg-1, ciprofol 0.4 mg·kg-1 （experimental group） or propofol 2.0 mg·kg-1 （control group）, and rocuronium 0.6 mg·kg-1. During anesthesia maintenance, all patients were maintained with remifentanil 1 μg·kg-1·h-1 and cisatracurium 0.1 mg·kg-1·h-1, combined with ciprofol 0.8 mg·kg-1·h-1 （experimental group） or propofol 5 mg·kg-1·h-1 （control group）. The bispectral index （BIS） was maintained between 40 and 60 by adjusting the pumping speed during the operation. The changes of vital signs and BIS were observed. The anesthesia induction time,awakening time, and Ramsay sedation score after extubation were recorded. And the occurrence of adverse reactions was also observed.
There was no significant difference in systolic blood pressure （SBP）, diastolic blood pressure （DBP）,and heart rate （HR） between the two groups before anesthesia, after anesthesia induction, after tracheal intubation, at the end of operation, and after tracheal extubation. The BIS at the end of operation in the experimental group was lower than that in the control group （P<0.05）. The fluctuation value of SBP, DBP, and HR during anesthesia induction in the control group was significantly greater than that in the experimental group （P<0.05）. The recovery time of the experimental group was slightly longer while the use of sedatives was less than that of the control group （P<0.05）. The incidences of post-induced hypotension, hypertension after intubation, and injection pain in the experimental group were lower than those in the control group （P<0.05）.
Ciprofol can be used in intracranial aneurysm embolization with outstanding sedative efficacy. The hemodynamics of patient is more stable, and the incidence of postoperative adverse reaction is low.
To observe the difference of clinical efficacy and safety between regular hemodialysis （HD）and peritoneal dialysis （PD） uremic patients treated with roxadustat for renal anemia.
From December 2019 to March 2023, 102 renal anemia patients treated with roxadustat for uremic dialysis were selected. The initial dose of roxadustat was chosen based on weight, with 100 mg orally for patients weighing 45 to 60 kg and 120 mg for those weighing ≥60 kg. The medication was administered three times a week for 12 consecutive weeks, with dosage adjustments according to hemoglobin （Hb） levels. According to the dialysis method, there were 50 cases in the PD group and 52 cases in the HD group. Within the groups, those with high sensitive C-reactive protein （hs-CRP） ≥6 mg·L-1 were classified as high hs-CRP subgroup, while those with <6 mg·L-1 were considered the normal hs-CRP subgroup.Changes in anemia-related indicators, iron metabolism, lipid metabolism, and adverse reactions before and after roxadustat treatment were observed in both groups.
After 12 weeks of treatment with roxadustat, the levels of Hb, red blood cell count （RBC）, hematocrit （HCT）, and serum iron （SI） in the both groups all increased compared with before the treatment （P<0.05）, while the levels of serum ferritin （SF）, total cholesterol （TC）,triglyceride （TG）, and low-density lipoprotein cholesterol （LDL-C） all decreased （P<0.05）. After treatment, the levels of Hb, RBC, HCT, SI, TC, and LDL-C in the PD group were significantly higher than those in the HD group（P<0.05）. There were no significant differences in transferrin saturation （TSAT）, total iron-binding capacity （TIBC）,and high-density lipoprotein cholesterol （HDL-C） levels within and between the groups before and after the treatment（P>0.05）. There were no significant differences in TG and SF levels and the occurrence of adverse reactions between the two groups （P>0.05）. After 12 weeks of treatment, the average Hb level of the high hs-CRP subgroup and normal hs-CRP subgroup of the two groups significantly increased compared with before treatment （P<0.05）, and there was no significant difference between the two subgroups （P>0.05）.
Roxadustat is effective in improving renal anemia in uremia patients with HD or PD, and the short-term safety is good. Compared with HD patients, anemia is more significantly improved in PD patients.
To study the protective effect of cerebroprotein hydrolysate and its related mechanism of regulating endoplasmic reticulum stress in ischemic stroke based on network pharmacology and animal experiments.
GeneCards and OMIM databases were used to screen the targets related to ischemic stroke and endoplasmic reticulum stress, and Wayne diagram was drawn to get the intersection genes. The protein-protein interaction network diagram was downloaded from String database and visualized by Cytoscape software, and the top 10 genes were screened by cytoHubba plug-in. Finally, Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） were enriched and analyzed. Mouse models of ischemic stroke were made by the suture-occluded method, and randomly divided into sham group, model group, cerebroprotein hydrolysate 0.2 g·kg-1 group and 0.5 g·kg-1 group, and edaravone 8 mg·kg-1 group,with 11 mice in each group. The drug was administered continuously for 5 days after operation. The volume of cerebral infarction was measured by TTC staining, the contents of interleukin （IL）-6, IL-1β, γ-interferon （IFN-γ） and brain-derived neurotrophic factor （BDNF） in cerebral ischemic penumbra and serum were measured by ELISA, and the expression of Caspase-3 and AKT protein in brain tissue was observed by immunohistochemistry.
According to the results of network pharmacology, 41 intersection genes of ischemic stroke and endoplasmic reticulum stress were screened, and the top 10 genes screened were IL-6, ALB, INS, TNF, AKT1, CASP3, MAPK3, TP53, SIRT1 and VEGFA, respectively. GO enrichment resulted in 515 related entries. KEGG pathway enrichment involved lipid and atherosclerosis pathway, human cytomegalovirus infection, Alzheimer’s disease, phosphatidylinositol -3- kinase/ protein kinase B （PI3K/AKT） signaling pathway and so on. Compared with the model group, the cerebral infarction volume was significantly reduced （P<0.01）; the contents of IL-6, IL-1β and IFN-γ in serum and penumbra were decreased significantly （P<0.05）, and the contents of BDNF in serum and penumbra were increased significantly （P<0.05）; the expression of Caspase-3 in brain tissue was decreased significantly （P<0.05）, and the expression of AKT was increased significantly （P<0.05） in the two groups of cerebroprotein hydrolysate.
Based on the analysis of network pharmacology, the endoplasmic reticulum stress mechanism of ischemic stroke may be related to inflammation and apoptosis. The neuroprotective mechanism of cerebroprotein hydrolysate may be related to activating BDNF/PI3K/AKT pathway and inhibiting inflammation and apoptosis.
To study the antibacterial mechanism of palmatine based on network pharmacology, molecular docking, and molecular dynamics.
The drug targets of palmatine were predicted through the Swiss Target Prediction website, and the potential antibacterial targets of palmatine were obtained by mapping them with the antibacterial targets retrieved from GeneCards and OMIM databases. Protein-protein interaction network was constructed using STRING database and Cytoscape software and key targets were screened. The DAVID database was used to carry out Gene Ontology（GO） functional analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis of potential targets, and visual processing was performed to build the “Component-Target-Pathway” network of palmatine. The binding of palmatine to key targets was validated through molecular docking and molecular dynamics simulations. In vitro antibacterial experiments were conducted to verify the antibacterial activity of palmatine.
A total of 28 critical anti-bacterial targets of palmatine were screened and enriched to 199 GO entries and 105 related pathways. “Ingredients-Target-Pathway”network showed that MAPK8, RAC1, and STAT3 were key anti-bacterial targets.The molecular docking results indicated that palmatine had an excellent binding effect with key targets MAPK8 and RAC1. Molecular dynamics studies found that there were hydrogen bonds and hydrophobic interactions between palmatine and proteins, enabling stable binding of palmatine to target proteins. In vitro antibacterial experiments showed that palmatine had strong inhibitory activity against Staphylococcus aureus and Candida albicans, and it had synergistic effects when combined with positive drugs.
Palmatine may exert its antibacterial effects by inhibiting the gene expression of MAPK8 and RAC1 through endocrine resistance and signaling pathways such as PI3K-Akt and FoxO.
To analyze the general patterns and characteristics of osimertinib related interstitial lung disease（ILD）.
The case reports of osimertinib related ILD from CNKI, VIP, Wanfang and PubMed database between November 2015 to June 2023 were searched and analyzed.
A total of 25 case reports were enrolled,involving 28 cases with ILD, 14 male and 14 female cases, aged 32 to 86 years old. PD-1 inhibitors were used sequentially in 4 patients before administering osimertinib, 21 patients developed ILD in 3 months, 25 patients experienced symptom relief after discontinuation reduction medication, and 3 patients died.
ILD should be closely guarded in 3 months of the application of osimertinib, especially these patients who received the sequence treatment of PD-1 inhibitors.The key to improving the prognosis is to stop using osimertinib immediately after ILD.
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