ObjectiveTo investigate the chemical constituents of Chuanxiong Rhizoma-Paeoniae Radix Rubra（CRPRR） that cross the blood-brain barrier in rats with ischemic stroke， their brain-protective effects， and their impact on inflammatory factors including tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and interleukin-18 （IL-18） based on ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF-MS） and pharmacodynamic experiments. MethodsA focal cerebral ischemia-reperfusion injury model was established in rats via the middle cerebral artery occlusion/reperfusion （MCAO/R） method using intraluminal suture. Neurological function was evaluated using behavioral scoring. UPLC-Q-TOF-MS was employed to identify the chemical constituents of CRPRR that crossed the blood-brain barrier and entered the cerebrospinal fluid in MCAO/R model rats. Male Sprague-Dawley rats were randomly divided into six groups： sham operation group， model group， low-， medium-， and high-dose CRPRR groups （1.35， 2.7， 5.4 g·kg^-1， respectively）， and an edaravone group （5 mg·kg^-1）， with 12 rats in each group. The sham and model groups received normal saline， while the treatment groups received the respective doses of CRPRR once daily by gavage for three consecutive weeks. The brain-protective effects of CRPRR were assessed using the Longa five-point scoring method， open field test， Morris water maze， 2，3，5-triphenyltetrazolium chloride （TTC） staining， hematoxylin and eosin （HE） staining， and transmission electron microscopy. ResultsNine chemical constituents were identified in the cerebrospinal fluid containing CRPRR， namely paeoniflorin， senkyunolide F， senkyunolide G， paeonimetabolin Ⅰ， paeoniflorin derivative， senkyunolide H， benzoylpaeoniflorin， senkyunolide A， and ligustilide. Animal experiment results showed that compared with the sham operation group， the model group exhibited disordered neuronal arrangement， severe vacuolation， nuclear pyknosis， and evident mitochondrial swelling. Chromatin aggregation and peripheralization were also observed. Neurological scores and the number of crossings in the central region were significantly increased （P<0.01）， while platform crossings were significantly decreased （P<0.01）， and clear infarct areas were present （P<0.01）. Serum levels and protein expression of TNF-α， IL-1β， and IL-18 were significantly elevated （P<0.01）. Compared with the model group， all dose groups of CRPRR showed marked improvement in neuronal morphology which was close to the normal level， with mitochondrial swelling alleviated and chromatin distribution more uniform. The medium- and high-dose groups significantly reduced neurological scores （P<0.01）， while the low-， medium-， and high-dose groups significantly reduced the number of central crossings （P<0.01） and infarct volume （P<0.01）， and decreased TNF-α， IL-1β， and IL-18 levels （P<0.05， P<0.01） compared with the model group. Furthermore， the medium- and high-dose groups significantly reduced TNF-α protein expression （P<0.05，P<0.01）， and the high-dose group significantly reduced IL-1β and IL-18 protein expression （P<0.01）. ConclusionThis study confirmed that CRPRR improves neurological function and alleviates brain tissue damage in MCAO/R rats. Its mechanism may be associated with the downregulation of inflammatory factors TNF-α， IL-1β， and IL-18， as well as the presence of nine active chemical constituents in cerebrospinal fluid， namely paeoniflorin， senkyunolide F， senkyunolide G， paeonimetabolin Ⅰ， paeoniflorin derivative， senkyunolide H， benzoylpaeoniflorin， senkyunolide A， and ligustilide， which are closely related to their brain-protective effects.

ObjectiveTo investigate the chemical constituents of Chuanxiong Rhizoma-Paeoniae Radix Rubra（CRPRR） that cross the blood-brain barrier in rats with ischemic stroke， their brain-protective effects， and their impact on inflammatory factors including tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and interleukin-18 （IL-18） based on ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF-MS） and pharmacodynamic experiments. MethodsA focal cerebral ischemia-reperfusion injury model was established in rats via the middle cerebral artery occlusion/reperfusion （MCAO/R） method using intraluminal suture. Neurological function was evaluated using behavioral scoring. UPLC-Q-TOF-MS was employed to identify the chemical constituents of CRPRR that crossed the blood-brain barrier and entered the cerebrospinal fluid in MCAO/R model rats. Male Sprague-Dawley rats were randomly divided into six groups： sham operation group， model group， low-， medium-， and high-dose CRPRR groups （1.35， 2.7， 5.4 g·kg^-1， respectively）， and an edaravone group （5 mg·kg^-1）， with 12 rats in each group. The sham and model groups received normal saline， while the treatment groups received the respective doses of CRPRR once daily by gavage for three consecutive weeks. The brain-protective effects of CRPRR were assessed using the Longa five-point scoring method， open field test， Morris water maze， 2，3，5-triphenyltetrazolium chloride （TTC） staining， hematoxylin and eosin （HE） staining， and transmission electron microscopy. ResultsNine chemical constituents were identified in the cerebrospinal fluid containing CRPRR， namely paeoniflorin， senkyunolide F， senkyunolide G， paeonimetabolin Ⅰ， paeoniflorin derivative， senkyunolide H， benzoylpaeoniflorin， senkyunolide A， and ligustilide. Animal experiment results showed that compared with the sham operation group， the model group exhibited disordered neuronal arrangement， severe vacuolation， nuclear pyknosis， and evident mitochondrial swelling. Chromatin aggregation and peripheralization were also observed. Neurological scores and the number of crossings in the central region were significantly increased （P<0.01）， while platform crossings were significantly decreased （P<0.01）， and clear infarct areas were present （P<0.01）. Serum levels and protein expression of TNF-α， IL-1β， and IL-18 were significantly elevated （P<0.01）. Compared with the model group， all dose groups of CRPRR showed marked improvement in neuronal morphology which was close to the normal level， with mitochondrial swelling alleviated and chromatin distribution more uniform. The medium- and high-dose groups significantly reduced neurological scores （P<0.01）， while the low-， medium-， and high-dose groups significantly reduced the number of central crossings （P<0.01） and infarct volume （P<0.01）， and decreased TNF-α， IL-1β， and IL-18 levels （P<0.05， P<0.01） compared with the model group. Furthermore， the medium- and high-dose groups significantly reduced TNF-α protein expression （P<0.05，P<0.01）， and the high-dose group significantly reduced IL-1β and IL-18 protein expression （P<0.01）. ConclusionThis study confirmed that CRPRR improves neurological function and alleviates brain tissue damage in MCAO/R rats. Its mechanism may be associated with the downregulation of inflammatory factors TNF-α， IL-1β， and IL-18， as well as the presence of nine active chemical constituents in cerebrospinal fluid， namely paeoniflorin， senkyunolide F， senkyunolide G， paeonimetabolin Ⅰ， paeoniflorin derivative， senkyunolide H， benzoylpaeoniflorin， senkyunolide A， and ligustilide， which are closely related to their brain-protective effects.

Non-small cell lung cancer (NSCLC), as the predominant histological subtype of lung cancer, accounts for approximately 85% of all lung cancer cases. In recent years, immune checkpoint inhibitors (ICIs), represented by programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors, have achieved breakthrough advancements in patients with driver gene-negative NSCLC. They have been established as a key component of first-line treatment regimens and have significantly improved clinical outcomes. However, limited clinical evidence has emerged showing the phenomenon of histological transformation from NSCLC to small cell lung cancer (SCLC) in patients experiencing disease progression after ICIs monotherapy or combination therapy. Systematic research data on the clinical characteristics, molecular biological basis, and subsequent treatment strategies for such transformation events are currently lacking. This article reports a case of SCLC transformation occurring in a patient with KRAS-mutated lung adenocarcinoma after 16 months of ICIs combination therapy and provides a systematic review of 22 similar published cases. The study demonstrates that small cell transformation is a critical mechanism of immunotherapy resistance, and transformed patients exhibit poor prognosis. The research emphasizes the importance of dynamic monitoring of neuron-specific enolase (NSE) and standardized repeat biopsies during treatment, providing a basis for clinical practice. This aids in enhancing the recognition and management capabilities for this rare histological transformation, ultimately improving patient outcomes.
Humans ; Immune Checkpoint Inhibitors/therapeutic use* ; Lung Neoplasms/immunology* ; Carcinoma, Non-Small-Cell Lung/immunology* ; Small Cell Lung Carcinoma/genetics* ; Male ; Middle Aged ; Female

Andrographolide sulfonate (AS) is a sulfonated derivative of andrographolide extracted from Andrographis paniculata (Burm.f.) Nees, and has been approved for several decades in China. The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis. Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling, improved body weights, and attenuated pathological changes in joints of rats with adjuvant-induced arthritis. Additionally, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in the serum and ankle joints were reduced. Bioinformatics analysis, along with the spleen index and measurements of IL-17 and IL-10 levels, suggested a potential relationship between AS and Th17 cells under arthritic conditions. In vitro, AS was shown to block Th17 cell differentiation, as evidenced by the reduced percentages of CD4⁺ IL-17A⁺ T cells and decreased expression levels of RORγt, IL-17A, IL-17F, IL-21, and IL-22, without affecting the cell viability and apoptosis. This effect was attributed to the limited glycolysis, as indicated by metabolomics analysis, reduced glucose uptake, and pH measurements. Further investigation revealed that AS might bind to hexokinase2 (HK2) to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or pyruvate kinase M2 (PKM2), and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation. Furthermore, AS impaired the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signals in vivo and in vitro, which was abolished by the addition of lactate. In conclusion, AS significantly improved adjuvant-induced arthritis (AIA) in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
Animals ; Th17 Cells/immunology* ; Diterpenes/pharmacology* ; Arthritis, Rheumatoid/metabolism* ; Proto-Oncogene Proteins c-akt/immunology* ; Glycolysis/drug effects* ; Cell Differentiation/drug effects* ; Phosphatidylinositol 3-Kinases/genetics* ; Rats ; Male ; Rats, Sprague-Dawley ; Humans ; Andrographis paniculata/chemistry* ; Arthritis, Experimental/drug therapy* ; Interleukin-17/immunology* ; Signal Transduction/drug effects*

With the process of China’s aging population intensifying， palliative care， as an important guarantee for improving the quality of life of terminally ill patients， is receiving more and more social attention， and the demand is constantly increasing. Palliative care needs versatile professionals， and general education can enhance people’s awareness and understanding of it， enabling more people to understand， accept， and participate in palliative care. With the advancement of knowledge and technology in palliative care， the traditional cramming education models are no longer able to meet the actual needs. Therefore， there is an urgent need to innovate palliative care education strategies. By analyzing the current problems in the general education of palliative care in China， this paper proposed thoughts and suggestions for general and innovative education of palliative care in several aspects， such as establishing general and innovative education systems and evaluation systems of palliative care， diversifying educational contents and methods， strengthening medical staffs training， promoting diversified student groups， and strengthening the popularization of palliative care knowledge among the public.

BACKGROUND:Plastic as a durable,inexpensive,easy to manufacture organic synthetic polymer materials are widely used.At the same time,plastic resistance to high temperatures,acid and alkali resistance,corrosion-resistant properties make it difficult to degrade in nature,and ultimately forming a huge number of microplastic pollution threatening human health. OBJECTIVE:To investigate the effects of microplastic exposure on growth and development and hepatic lipid metabolism in mice. METHODS:Twenty C57BL/6J male mice were adaptively fed for one week,and then randomly divided into normal and microplastic groups(n=10 per group).Mice in the normal group were given a normal diet and water,for 4 weeks.Mice in the microplastic group were given a normal diet and free drinking of microplastic(polystyrene)water with a concentration of 1 000 μg/L,for 4 weeks.At 2 and 4 weeks of drinking,body mass and grip strength,blood lipids and liver and kidney function,ultrasonic morphology and pathological morphology of liver and lipid deposition were detected. RESULTS AND CONCLUSION:(1)With the extension of time,the body mass of mice in the two groups gradually increased,and the body mass of mice in the microplastic group was greater than that in the normal group after 2,4 weeks of drinking water(P<0.05).With the extension of time,the grip strength of mice in the normal group gradually increased,and the grip strength of mice in the microplastic group first decreased and then increased,and the grip strength of mice in the microplastic group was lower than that in the normal group after drinking water for 4 weeks(P<0.05).(2)Liver ultrasound examination showed that compared with the normal group,the ultrasonic echo signal of the liver in the microplastic group was enhanced after 2 and 4 weeks of drinking water.(3)Hematoxylin-eosin staining showed that the morphology of liver cells in the microplastic group did not change significantly after 2 and 4 weeks of drinking water,but inflammatory cell infiltration could be seen.Oil red O staining showed that obvious lipid deposition was observed in the liver of microplastic group after 2 and 4 weeks of drinking water.(4)Compared with the normal group,the levels of serum high density lipoprotein cholesterol,triacylglycerol,and aspartate aminotransferase in the microplastic group were decreased after 2 weeks of drinking water(P<0.05),and the serum triacylglycerol concentration was decreased after 4 weeks of drinking water(P<0.05).(5)These findings confirm that microplastics may cause weight gain,loss of physical strength,and abnormal hepatic lipid metabolism in mice.

Objective:To improve understanding of acute promyelocytic leukemia (APL) with STAT3::RARA fusion gene positive.Methods:The clinical data, gene detection, diagnosis and treatment of 1 APL patient with STAT3::RARA fusion gene positive admitted to General Hospital of Ningxia Medical University in July 2020 were retrospectively analyzed, and the related literatures were reviewed.Results:The patient was a 70-year-old elderly male who was admitted to the hospital due to bleeding hemorrhoids accompanied with recurrent oral ulcers for 2 months. Physical examination showed anemic appearance and no obvious positive signs were detected. Admission blood routine examination: white blood cell count was 4.36×10 9/L, neutrophil ratio was 56.5%, lymphocyte ratio was 22.7%, hemoglobin was 67 g/L, and platelet count was 37.0×10 9/L. Bone marrow smear of ilium puncture: myeloproliferative hyperplasia was hyperactive, granular dysplasia was abnormal and pathological promyelocytes could be predominantly seen. The results of real-time quantitative polymerase chain reaction showed that PML::RARA L (bcr1), PML::RARA V (bcr2) and PML::RARA S (bcr3) were not detected. PML::RARA fusion gene probe fluorescence in situ hybridization showed positive for partial deletion of RARA gene locus and negative for fusion of PML::RARA gene locus. Blood tumor panoramic gene variation test showed STAT3::RARA fusion gene was positive, and no gene variation associated with blood tumors was detected. Finally, the patient was diagnosed as atypical APL (STAT::RARA fusion gene positive). The patient did not respond to the combination treatment of all-trans retinoic acid and arsenic trioxide. And then he received symptomatic supportive treatment rather than the combined chemotherapy, and was discharged after remission of fatigue symptoms. Conclusions:STAT::RARA fusion gene positive APL is clinically rare and lacks effective treatment compared with classical APL. Its insensitivity to all-trans retinoic acid and arsenic trioxide may be related to this fusion gene.

Objective:To investigate the clinical efficacy and adverse reactions of pemetrexed disodium in the maintenance treatment of advanced lung adenocarcinoma after chemotherapy with pemetrexed disodium and platinum.Methods:The clinical data of 35 patients with stage Ⅳ lung adenocarcinoma who received chemotherapy with pemetrexed disodium and platinum and were well treated in Beijing Huairou Hospital from January 2013 to August 2020 were retrospectively analyzed. Maintenance therapy with pemetrexed disodium was initiated after the completion of combination chemotherapy until disease progression. The clinical characteristics, therapeutic effects, adverse reactions, progression-free survival, and overall survival of the 35 patients were evaluated.Results:Among the 35 patients, no patients had complete remission, 11 patients had partial remission, 22 patients had stable disease, and 2 patients had progressive disease. The objective remission rate was 31.4%, disease control rate was 94.3%, median progression-free survival was 9.53 months, median overall survival was 18.21 months, 1-year survival rate was 68.6%, 2-year survival rate was 31.4%, and 3-year survival rate was 11.4%. Gender, age, smoking, and the baseline characteristics of patients undergoing first-line pemetrexed disodium or second-line pemetrexed disodium treatment had no effects on progression-free survival (all P > 0.05). Positive gene mutation and receiving four or more chemotherapy cycles had a protective effect on progression-free survival (both P < 0.05). Chemotherapy-related adverse reactions mainly included myelosuppression, nausea, elevated transaminase, and nephrotoxicity, all of which were mild and were relieved after symptomatic treatment. Conclusion:Pemetrexed disodium is effective and safe in the maintenance treatment of advanced lung adenocarcinoma. The results of this study are scientific.

Objective:To evaluate the role of the sodium leak channel (NALCN) in the hippocampal dentate gyrus (DG) in the social behavior of mice.Methods:Thirty-nine male wild-type C57BL/6 mice, aged 6-8 weeks, weighing 18-22 g, were used in this study. Three mice were sacrificed to verify the expression and co-expression of NALCN with neuronal nuclear antigen (NeuN) in the hippocampal DG using the immunofluorescent staining. The remaining 36 mice were divided into 2 groups ( n=18 each) by the random number table method: control group (group C) and NALCN gene knockdown group (group KO). NALCN-shRNA virus was injected in group KO, and scrambled-shRNA virus was injected in group C. The three box social test and open field test were performed at 3 weeks after the virus injection. Mice were sacrificed under anesthesia after the behavioral test, hippocampal tissues were collected, and the injection location of the virus was verified with a fluorescence microscope, and the NALCN protein and mRNA expression in the hippocampal DG was detected by Western blot and real-time polymerase chain reaction, respectively. Results:NALCN and NeuN co-expressed a lot on the same neuron in the hippocampal DG of mice, indicating that NALCN was widely expressed on the neurons in the hippocampal DG. Compared with group C, the expression of NALCN and mRNA in the hippocampal DG was significantly down-regulated, and the social novelty preference disappeared ( P<0.05), and no significant change was found in the social ability and each parameter in the open field test in group KO ( P>0.05). Conclusions:NALCN in the hippocampal DG is involved in the regulation of social memory in mice, and the down-regulated expression of NALCN can lead to the loss of social novelty preference in mice.

OBJECTIVE To compare the efficacy， safety and economy of tacrolimus （TAC）， cyclosporin A （CsA）， cyclophosphamide （CTX） and rituximab （RTX） in the treatment of membranous nephropathy （MN）. METHODS Retrieved from Pubmed， the Cochrane Library， Wanfang data， CNKI and health technology assessment （HTA） official website， HTA reports， systematic reviews/meta-analysis and pharmacoeconomic studies about TAC， CsA， CTX and RTX combined with glucocorticoid in the treatment of MN were collected during the inception and Mar. 2022. After data extraction and quality evaluation， descriptive analysis was performed on the results of the included studies. RESULTS A total of 15 articles were included， involving 13 systematic reviews/meta-analysis and 2 pharmacoeconomic studies. In terms of efficacy， TAC and CsA showed significant advantages in increasing the response rate， and could improve the levels of urine protein， serum albumin， serum creatinine and serum total cholesterol. In terms of safety， the incidence of adverse reaction induced by TAC， CsA and RTX was low and the symptoms were mild. In terms of economics， CTX cost lower but caused severe adverse reaction； TAC cost higher but showed higher remission rate and good safety. CONCLUSIONS TAC combined with glucocorticoid may be the recommended scheme for MN.