ObjectiveTo characterize the changes of metabolites of Blumea balsamifera in the process of sweating by non-targeted metabolomics， and to investigate the influence of sweating processing on the constituents of B. balsamifera. MethodsUltra performance liquid chromatography-quadrupole/electrostatic field orbitrap high resolution mass spectrometry（UPLC-Q-Exactive Orbitrap-MS） metabolomics was used to identify the metabolites in no sweating group（F1）， sweating 2 d group（F2） and sweating 4 d group（F3）， the differences of metabolites between the groups were compared by principal component analysis（PCA） and orthogonal partial least squares-discriminant analysis（OPLS-DA）， and differential metabolites were screened according to the variable importance in the projection（VIP） value>1 and P<0.05， and the pathway enrichment of the differential metabolites was analyzed by Kyoto Encyclopedia of Genes and Genomes（KEGG）. ResultsThe results of PCA and OPLS-DA showed a clear distinction between the three groups of samples， indicating significant differences in the compositions of the three groups of samples. A total of 433 differential metabolites were screened between the F1 and F2， with 154 up-regulated and 279 down-regulated， the significant up-regulated metabolites were tangeritin， 5-O-demethylnobiletin and so on， while the metabolites with significant down-regulation included alternariol， fortunellin， etc. A total of 379 differential metabolites were screened between the F2 and F3， with 150 up-regulated and 229 down-regulated， the significant up-regulated metabolites were isoimperatorin， helianyl octanoate and so on， and the significant down-regulated metabolites were hovenoside I， goyasaponin Ⅲ， etc. KEGG pathway enrichment analysis showed that tyrosine metabolism， isoquinoline alkaloid biosynthesis， phenylalanine， tyrosine and tryptophan biosynthesis， tryptophan metabolism， valine， leucine and isoleucine biosynthesis， pantothenate and coenzyme A biosynthesis may be the key pathways affecting metabolite differences of B. balsamifera after sweating treatment. ConclusionSweating can reduce the content of endophytic mycotoxins in B. balsamifera and has a great impact on the synthesis and metabolic pathways of total flavonoids and auxin. This study can provide a reference for the process research on the sweating conditions of B. balsamifera.

Huangqintang， with its accurate efficacy， is a classic formula specialized in treating dysentery recommended and promoted by medical experts from successive generations， and it was included in the Catalogue of Ancient Classic Prescriptions （the Second Batch， Han Chinese medicine prescriptions） published by the National Administration of Traditional Chinses Medicine （TCM） in 2023. The method of bibliometrics was applied in this study to conduct textual research on the classic formula Huangqintang and provide a literature reference for the development of modern preparations of Huangqintang. A total of 2 026 pieces of ancient literature were searched with "Huangqintang" as the key word， and 23 pieces of effective data were selected， involving 15 ancient TCM books. The historic evolution， composition， dosage， origin， processing methods， preparation and decocting methods， efficiency， and application of Huangqintang were carefully reviewed. The results showed that Huangqintang was first recorded in the Treatise on Febrile Diseases written by ZHANG Zhongjing. It has the effect of clearing heat， stopping dysentery， regulating the middle， and downbearing counterflow and has become one of the classic formulas widely used in clinical practice. Because of its accurate efficacy， medical experts from later generations have modified it from its original composition. Though many prescriptions have different names， it is the manifestation of physicians' inheritance and development of the thought of ZHANG Zhongjing. Ancient literature showed this prescription had wide indications yet centered on digestive system diseases such as dysentery and abdominal pain. Modern applications of Huangqintang involve digestive， respiratory， ophthalmology and otolaryngology， gynecological， skin， musculoskeletal system， and connective tissue， and this prescription has great potential in treating ulcerative colitis， diarrhea， acute enteritis， and damp-heat dysentery. Through a systematic textual excavation and review of the ancient literature about Huangqintang， the paper has confirmed its key information， so as to provide a scientific basis for the clinical application and new drug development of classic formulas.

OBJECTIVE To optimize the simmering technology of Rheum palmatum from Menghe Medical School and compare the difference of chemical components before and after processing. METHODS Using appearance score， the contents of gallic acid， 5-hydroxymethylfurfural （5-HMF）， sennoside A+sennoside B， combined anthraquinone and free anthraquinone as indexes， analytic hierarchy process （AHP）-entropy weight method was used to calculate the comprehensive score of evaluation indicators； the orthogonal experiment was designed to optimize the processing technology of simmering R. palmatum with fire temperature， simmering time， paper layer number and paper wrapping time as factors； validation test was conducted. The changes in the contents of five anthraquinones （aloe-emodin， rhein， emodin， chrysophanol， physcion）， five anthraquinone glycosides （barbaloin， rheinoside， rhubarb glycoside， emodin glycoside， and emodin methyl ether glycoside）， two sennosides （sennoside A， sennoside B）， gallic acid and 5-HMF were compared between simmered R. palmatum prepared by optimized technology and R. palmatum. RESULTS The optimal processing conditions of R. palmatum was as follows: each 80 g R. palmatum was wrapped with a layer of wet paper for 0.5 h， simmered on high heat for 20 min and then simmered at 140 ℃， the total simmering time was 2.5 h. The average comprehensive score of 3 validation tests was 94.10 （RSD＜1.0%）. After simmering， the contents of five anthraquinones and two sennosides were decreased significantly， while those of 5 free anthraquinones and gallic acid were increased to different extents； a new component 5-HMF was formed. CONCLUSIONS This study successfully optimizes the simmering technology of R. palmatum. There is a significant difference in the chemical components before and after processing， which can explain that simmering technology slows down the relase of R. palmatum and beneficiate it.

Sinisan is a classical prescription developed and applied by ancient medical experts and it is first recorded in the Treatise on Cold Damage written by ZHANG Zhongjing in the Eastern Han Dynasty. Later physicians have modified this prescription based on this original one. The bibliometrics methods were used to analyze the key information and research trend of Sinisan. According to the inclusion and exclusion criteria， 69 pieces of effective data were extracted， involving 67 ancient traditional Chinese medicine （TCM） books. The results showed that the name， composition， and decocting methods of Sinisan in later generations were inherited from the original record in the Treatise on Cold Damage. The original plants of medicinal materials used in Sinisan are basically clear. We recommend Bupleuri Radix as the dried root of Bupleurem scorzonerifolium， Paeoniae Radix Alba as the dried root of Paeonia lactiflora， Aurantii Fructus as the dried fruit of Citrus aurantium， Glycyrrhizae Radix et Rhizoma as the dry root and rhizome of Glycyrrhiza uralensis. Raw materials of Bupleuri Radix and Paeoniae Radix Alba， Aurantii Fructus stir-fried with bran， and stir-fried Glycyrrhizae Radix et Rhizoma should be used for preparation of Sinisan. According to measurement system in the Han Dynasty， a bag of Sinisan is composed of 1.25 g Bupleuri Radix， 1.25 g Paeoniae Radix Alba， 1.25 g Aurantii Fructus， and 1.25 g Glycyrrhizae Radix et Rhizoma. The materials should be grounded into coarse powder and taken with a proper amount of rice soup， 3 times a day. Sinisan has the effects of regulating qi movement and harmonizing the liver and spleen. It can be used for treating reversal cold in limbs and cold damage. In modern clinical practice， Sinisan can be used to treat chronic gastritis， irritable bowel syndrome， and dyspepsia. The above research results provide scientific reference for the future research and development of Sinisan.

OBJECTIVE To analyze the impact of intergenerational substitution effect of the drugs with the same indication on fund expenditures for national medical insurance for this indication in China， taking national medical insurance negotiated drugs for non-small cell lung cancer （hereinafter referred to as “NSCLC national negotiation drugs”） as an example. METHODS The sales amounts of 15 types of NSCLC national negotiated drugs in secondary and tertiary public hospitals across seven sample provinces from 2017 to 2023 were collected from the Pharmaceutical Drug Database of the China National Pharmaceutical Industry Information Center. A sliding t-test and Mann-Kendall trend test were used to evaluate the trends in sales amounts and DDDs. Taking epidermal growth factor receptor（EGFR）-tyrosine kinase inhibitors （TKIs） and anaplastic lymphoma kinase （ALK）-TKIs as examples， the generational substitution characteristics of these drugs were analyzed. RESULTS The change points of sales amounts and DDDs differed slightly across provinces； the change points of sales amount were mostly concentrated between the first quarter of 2019 and the second quarter of 2020， while those for DDDs were primarily concentrated in the first to second quarters of 2021. In five provinces， i.e. Beijing， Heilongjiang， Jiangsu， Sichuan and Shaanxi， sales amounts showed no significant upward trend after the breakpoints （P＞0.05）， whereas in Guangdong and Hubei， both sales amounts and DDDs continued to rise significantly following the breakpoints （P＜0.05）. Since 2020， the growth in sales amounts of EGFR-TKIs had slowed. After 2021， the sales amounts and DDDs of first- and second-generation EGFR-TKIs declined， while third-generation EGFR-TKIs showed clear substitution effects. The sales amounts of ALK-TKIs continuedto grow. However， the sales amounts and DDDs of first-generation ALK-TKIs had declined year by year， with second-generation ALK-TKIs demonstrating a significant substitution effect on first-generation ones， while third-generation ALK-TKIs had not yet shown a clear substitution trend. CONCLUSIONS With the annual access to and renewal of drugs in national medical insurance negotiations， the overall expenditure trend for NSCLC negotiated drugs comes to a plateau. The intergenerational substitution relationships of drugs with the same indication achieve a relative balance in fund expenditures for negotiated drugs with the same indication. It is recommended that pharmaceutical companies carefully consider their research pipelines， and that medical insurance authorities， during the renewal management process， pay attention to the impact of drug substitution effects on the overall actual expenditure of medical insurance funds for that specific target or the same indication， and scientifically evaluate the extent of price reductions during contract renewals.

Diabetic cataract, a prevalent ocular complication of diabetes mellitus, arises from a complex interplay of pathological mechanisms, with oxidative stress and glycation stress playing central roles. Autophagy, a critical cellular self-protection mechanism, sustains intracellular homeostasis by selectively degrading damaged organelles and misfolded proteins, thereby counteracting the detrimental effects of oxidative and glycation stress under hyperglycemic conditions. Emerging evidence indicates a synergistic interaction between glycation stress and oxidative stress, which may exacerbate autophagic dysfunction and accelerate the onset and progression of diabetic cataract. However, the precise molecular mechanisms underlying this relationship remain incompletely understood. This review systematically examines the regulatory role of autophagy inthe pathogenesis of diabetic cataract, with a particular focus on how autophagic impairment influences disease progression under the combined effects of glycation and oxidative stress. By elucidating these mechanisms, the paper aims to provide novel insights into molecular diagnostic approaches and targeted therapeutic strategies for diabetic cataract.

Tissue-resident memory T (TRM) cells are a recently defined subtype of non-recirculating memory T cells with longevity and protective functions in peripheral tissues. As an essential frontline defense against infections, TRM cells have been reported to robustly patrol the tissue microenvironment in malignancies. Accumulating evidence also implicates that TRM cells in the relapse of chronic inflammatory skin diseases such as psoriasis and vitiligo. In light of these developments, this review aims to synthesize these recent findings to enhance our understanding of TRM cell characteristics and actions. Therefore, after providing a brief overview of the general features of the TRM cells, including precursors, homing, retention, and maintenance, we discuss recent insights gained into their heterogeneous functions in skin diseases. Specifically, we explore their involvement in conditions such as psoriasis, vitiligo, fixed drug eruption - dermatological manifestations of drug reactions at the same spot, cutaneous T cell lymphoma, and melanoma. By integrating these diverse perspectives, this review develops a comprehensive model of TRM cell behavior in various skin-related pathologies. In conclusion, our review emphasizes that deciphering the characteristics and mechanisms of TRM cell actions holds potential not only for discovering methods to slow cancer growth but also for reducing the frequency of recurrent chronic inflammation in skin tissue.
Humans ; Skin Diseases/immunology* ; Memory T Cells/immunology* ; Animals ; Vitiligo/immunology* ; Psoriasis/immunology* ; Immunologic Memory

Membrane protein degradation is a cutting-edge field in targeted protein degradation (TPD). Herein, we developed glypican-3 (GPC3)-mediated lysosome-targeting chimeras (GLTACs) as a novel strategy for the targeted degradation of tumor-specific membrane proteins. GLTACs utilize tumor-specific expression and endocytosis properties of GPC3 to degrade membrane proteins. By conjugating a GPC3-targeting peptide with the ligand of protein of interest (POI), GLTACs induce the formation of a ternary complex that is internalized into lysosomes, leading to the degradation of the POI. The effectiveness and specificity of GLTACs were validated by designing PD-L1, c-Met, and FGFR1 degraders. In particular, GLTAC WP0 potently degraded PD-L1 and induced T-cell-mediated tumor killing against HepG2 cells, highlighting the potential therapeutic applications. The development of GLTAC technology expands the scope of TPD strategies and opens new avenues for discovering novel therapeutic modalities against challenging protein targets.

OBJECTIVE: The investigation of the correlation between ecological factors and the genetic characteristics or metabolites of plants offers valuable insights into the regional causes of genetic and metabolic diversity. Here, Gastrodia elata, a medicinal plant, is employed as a model to explore the environmental factors that influence its genetic characteristics and metabolic accumulations. METHODS: A total of 23 G. elata populations from six cultispecies and 11 cultivated regions were selected based on the predictions of the global geographic information system. The genetic characteristics of these populations were evaluated using highly polymorphic simple sequence repeat markers. Additionally, the metabolic accumulations and antioxidant capacity of mature tubers were measured employing colorimetry and high performance liquid chromatography (HPLC). Ecological data of each region were obtained from the WorldClim-global climate database and harmonized world soil database. To assess the influence of ecological factors on the genetic characteristics and metabolic profiles of G. elata, Pearson's correlation analysis was conducted. RESULTS: Genetic variation among G. elata populations exceeded that within populations. Genetic diverisity, distance and structure manifested regional and species-specific patterns. Metabolic profiling and antioxidant capacity exhibited regional variations. Notably, the Lueyang region demonstrated that a content range of total polysaccharide, total protein, and phenolic glycosides was 9.34%-189.67% higher than the average. Similarly, in the Hubei region, total phenolic content, p-hydroxybenzyl alcohol content, and antioxidant indicators were observed to be higher than the average levels, by 106.57%, 136.47% and 12.50%-91.14%, respectively. Furthermore, ecological factors had a significant comprehensive impact on G. elata genetic characteristics (r > 0.256 and P < 0.05). Multivariate metabolite accumulations in G. elata were influenced by dominant ecological factors. Temperature notably impacted the accumulation of total protein (|r| > 0.528 and P < 0.05). Moisture, encompassing precipitation and soil content, significantly affected the production of phenolic glycosides (|r| > 0.503 and P < 0.05). CONCLUSION The genetic characteristics of G. elata manifested regional and species-specific patterns, with the metabolic accumulations and antioxidant capacity of mature tubers exhibited regional variations. Specifically, multivariate ecological factors comprehensively influenced genetic characteristics. Temperature and moisture played pivotal roles in regulating the accumulations of proteins and phenolic glycosides, respectively. These findings underscore the significant impact of ecological factors on the shaping of G. elata, highlighting their crucial role in enhancing the quality of Chinese medicinal materials.

Vein graft (VG) failure (VGF) is associated with VG intimal hyperplasia, which is characterized by abnormal accumulation of vascular smooth muscle cells (VSMCs). Most neointimal VSMCs are derived from pre-existing VSMCs via a process of VSMC phenotypic transition, also known as dedifferentiation. There is increasing evidence to suggest that ginger or its bioactive ingredients may block VSMC dedifferentiation, exerting vasoprotective functions; however, the precise mechanisms have not been fully characterized. Therefore, we investigated the effect of ginger on VSMC phenotypic transition in VG remodeling after transplantation. Ginger significantly inhibited neointimal hyperplasia and promoted lumen (L) opening in a 3-month VG, which was primarily achieved by reducing ferroptotic stress. Ferroptotic stress is a pro-ferroptotic state. Contractile VSMCs did not die but instead gained a proliferative capacity and switched to the secretory type, forming neointima (NI) after vein transplantation. Ginger and its two main vasoprotective ingredients (6-gingerol and 6-shogaol) inhibit VSMC dedifferentiation by reducing ferroptotic stress. Network pharmacology analysis revealed that 6-gingerol inhibits ferroptotic stress by targeting P53, while 6-shogaol inhibits ferroptotic stress by targeting 5-lipoxygenase (Alox5), both promoting ferroptosis. Furthermore, both ingredients co-target peroxisome proliferator-activated receptor gamma (PPARγ), decreasing PPARγ-mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (Nox1) expression. Nox1 promotes intracellular reactive oxygen species (ROS) production and directly induces VSMC dedifferentiation. In addition, Nox1 is a ferroptosis-promoting gene that encourages ferroptotic stress production, indirectly leading to VSMC dedifferentiation. Ginger, a natural multi-targeted ferroptotic stress inhibitor, finely and effectively prevents VSMC phenotypic transition and protects against venous injury remodeling.