The tumor microenvironment is a crucial factor in tumor occurrence and progression. The hypoxic microenvironment is widely present in tumor tissue and is a key endogenous factor accelerating tumor deterioration. The "blood stasis toxin" theory, as an emerging perspective in tumor research, is regarded as the unique "soil" in tumor progression from the perspective of traditional Chinese medicine(TCM) due to its dynamic evolution mechanism, which closely resembles the formation of the hypoxic microenvironment. Scientifically integrating TCM theories with the biological characteristics of tumors and exploring precise syndrome differentiation and treatment strategies are key to achieving comprehensive tumor prevention and control. This article focused on the hypoxic microenvironment of the tumor, elucidating its formation mechanisms and evolutionary processes and carefully analyzing the internal relationship between the "blood stasis toxin" theory and the hypoxic microenvironment. Additionally, it explored the interaction among blood stasis, toxic pathogens, and hypoxic environment and proposed micro-level prevention and treatment strategies targeting the hypoxic microenvironment based on the "blood stasis toxin" theory, aiming to provide TCM-based theoretical support and therapeutic approaches for precise regulation of the hypoxic microenvironment.
Humans ; Tumor Microenvironment/drug effects* ; Neoplasms/therapy* ; Animals ; Medicine, Chinese Traditional ; Disease Progression ; Drugs, Chinese Herbal

This study assessed the role and mechanism of the recombinant Bacillus Calmette-Gue?rin vaccine(rBCG)with c-di-AMP adjuvant in regulating metabolism and immunity in epididymal white adipose(eWAT)in mice.Male C57BL/6 mice were intravenously immunized with BCG and rBCG,and their body weights were monitored.eWAT was isolated from the mice,and the stromal vascular fractions(SVFs)cell number was counted with a hemocytometer.Sections of mouse adipose tissue were prepared,and the size,number,and morphology of eWAT adipocytes and crown-like structure(CLS)formation were compared under a microscope after HE staining.The transcription levels of lipid metabolism-associated factors,cytokines and aging-associated genes in each group were determined with qRT-PCR.The body weights of mice gradually increased after immunization with BCG and rBCG.The proportions of eWAT increased,and the SVFs cell number decreased,in rBCG immunized mice.HE staining indicated that BCG immunization promoted hyperplasia,whereas rBCG immunization promoted hypertrophy of eWAT adipocytes;moreover,both BCG and rBCG immunization induced CLS formation in eWAT.The qRT-PCR results indicated that rBCG immunization inhibited the expression of genes associated with lipolysis and energy expenditure in eWAT.BCG immunization had little effect on cytokine transcription,whereas rBCG significantly induced the transcription of IFN-γ and IL-1Ra,and inhibited that of IL-15 and IL-2,but did not induce the expression of aging-associated genes.Thus,rBCG immunization induced eWAT adipocyte hypertrophy,which was associated with the inhibition of eWAT lipolysis and the regulation of cytokine expression.

Diabetes is a very complex endocrine disease whose common feature is the increase in blood glucose concentration. Persistent hyperglycemia can lead to blindness, kidney and heart disease, neurodegeneration, and many other serious complications that have a significant impact on human health and quality of life. The number of people with diabetes is increasing yearly. The global diabetes prevalence in 20-79 year olds in 2021 was estimated to be 10.5% (536.6 million), and it will rise to 12.2% (783.2 million) in 2045. The main modes of intervention for diabetes include medication, dietary management, and exercise conditioning. Medication is the mainstay of treatment. Marketed diabetes drugs such as metformin and insulin, as well as GLP-1 receptor agonists, are effective in controlling blood sugar levels to some extent, but the preventive and therapeutic effects are still unsatisfactory. Peptide drugs have many advantages such as low toxicity, high target specificity, and good biocompatibility, which opens up new avenues for the treatment of diabetes and other diseases. Currently, insulin and its analogs are by far the main life-saving drugs in clinical diabetes treatment, enabling effective control of blood glucose levels, but the risk of hypoglycemia is relatively high and treatment is limited by the route of delivery. New and oral anti-diabetic drugs have always been a market demand and research hotspot. Inhibitor cystine knot (ICK) peptides are a class of multifunctional cyclic peptides. In structure, they contain three conserved disulfide bonds (C3-C20, C7-C22, and C15-C32) form a compact “knot” structure, which can resist degradation of digestive protease. Recent studies have shown that ICK peptides derived from legume, such as PA1b, Aglycin, Vglycin, Iglycin, Dglycin, and aM₁, exhibit excellent regulatory activities on glucose and lipid metabolism at the cellular and animal levels. Mechanistically, ICK peptides promote glucose utilization by muscle and liver through activation of IR/AKT signaling pathway, which also improves insulin resistance. They can repair the damaged pancrease through activation of PI3K/AKT/Erk signaling pathway, thus lowering blood glucose. The biostability and hypoglycemic efficacy of the ICK peptides meet the requirements for commercialization of oral drugs, and in theory, they can be developed into natural oral anti-diabetes peptide drugs. In this review, the structural properties, activity and mechanism of ICK pattern peptides in regulating glucose and lipid metabolism were summaried, which provided a reference for the development of new oral peptides for diabetes.

Objective:To investigate the short-term efficacy of transverse osteotomy of the first metatarsal and fixation with Kirschner wires for mild to moderate hallux valgus (HV).Methods:This was a retrospective cohort study. A total of 44 patients (55 feet) with HV who underwent surgical treatment in the Foot and Ankle Ward Two, Tianjin Hospital, Tianjin University from March 2022 to June 2023 were enrolled, including 41 females and 3 males. Based on the different surgical methods, they were divided into a transverse osteotomy group and Scarf group. The transverse osteotomy group was treated with transverse osteotomy of the first metatarsal and fixation with two Kirschner wires, and the Scarf group was treated with "Z" osteotomy and screw fixation. The transverse osteotomy group consisted of 20 patients (25 feet), all female, with an average age of 54.56±3.13 years (range, 50-62 years), including 12 left feet and 13 right feet. Among them, 7 feet had mild HV, and 18 feet had moderate HV. The Scarf osteotomy group included 24 patients (30 feet), 3 males and 21 females, with an average age of 52.43±5.46 years (range, 39-60 years), including 15 left feet and 15 right feet. Among them, 3 feet had mild HV and 27 feet had moderate HV. Observation indicators: (1) The imaging indicators of the two groups were compared before operation and at the last follow-up. These indicators included hallux valgus angle (HVA), intermetatarsal angle (IMA). (2) The clinical efficacy of the two groups was compared, including American Orthopaedic Foot and Ankle Society (AOFAS) forefoot score and visual analogue scale (VAS), as well as postoperative complications. (3) The operation time of the two groups was recorded respectively.Results:Both groups were followed up for an average duration of 6-18 months (13.28±4.42 months). There were no significant differences in preoperative baseline characteristics between the transverse osteotomy group and the Scarf group ( P>0.05). The mean operation time was 28.96±4.10 min for the transverse osteotomy group and 45.37±4.72 min for the Scarf group, with a statistically significant difference ( t=13.612, P<0.001). In the transverse osteotomy, the preoperative HVA was 32.48°±3.9°and decreased to 8.59°±3.06° at the last follow-up, while IMA reduced from 14.53°±1.89° before surgery to 5.07°±1.74° at the last follow-up with statistical significance ( P<0.05). Similarly, in the Scarf group, preoperative HVA was 32.83°±2.33° and decreased to 9.87°±2.66° at the last follow-up, whereas IMA decreased from 13.7°±2.03° before surgery to 5.73°±1.74° at the last follow-up with statistical significance ( P<0.05). There was no significant difference in HVA and IMA between the two groups before surgery and the last follow-up ( P>0.05). In the transverse osteotomy, the preoperative VAS score was 6.0(5.5, 7.0), and at the last follow-up, it improved to 2.0(1.0, 2.0). The preoperative AOFAS score was 48.40±6.04 and increased significantly to 87.36±5.02 at the last follow-up ( P<0.05). In the Scarf group, the preoperative VAS score was 6.0(5.0, 6.0), which decreased to 2.0(2.0, 2.0) at the last follow-up assessment. The preoperative AOFAS score was 50.70±7.31 and showed a significant improvement with a mean of 84.43±3.45 at the final evaluation ( P<0.05). There were no significant differences in preoperative VAS scores between the two groups; however, at the last follow-up assessment, patients in the transverse osteotomy group had higher scores compared to those in the Scarf group, indicating better outcomes ( t=2.610, P=0.012). Postoperatively, only 1 foot in the transverse osteotomy group developed metastatic metatarsal pain, with a complication rate of 4% (1/25). In the Scarf osteotomy group, 1 foot developed superficial wound infection, 1 foot developed metastatic metatarsal pain, and 6 feet experienced joint stiffness, with a complication rate of 27%(8/30). Conclusions:Transverse osteotomy of the first metatarsal and fixation with Kirschner wires is simple, effective, and fast. It can effectively relieve pain, quickly restore function, shorten operation time, reduce soft tissue trauma, and minimize complications, demonstrating good clinical efficacy in the short term.

As a tethering complex localized on the Golgi membrane,the conserved oligomeric Golgi(COG)complex is divided into lobes A(COG1-4)and B(COG5-8)and forms a complete hetero-oc-tamer structure through the dynamic linkage of COG1 to COG8.Through coordinated interactions with Rab GTPases,SNARE proteins,and Golgi-associated coiled-coil tethers(CCTs),the COG complex par-ticipates in coatomer complex Ⅰ(COP Ⅰ)-mediated retrograde transport,coatomer complex Ⅱ(COP Ⅱ)-mediated anterograde transport,and various autophagic processes.The functional mechanism of the COG complex includes two models.First,the"disassembly and assembly model",in which lobe A anchors the Golgi membrane,while lobe B binds to the vesicle membrane,and both lobes assemble into the com-plete COG complex to narrow the distance between vesicle and target membranes.Second,the"docking station assembly model",in which COG complexes cooperate with SNARE,Rab and other molecules to form a stable docking platform,to enhance the stability of SNARE complexes and promote membrane fu-sion efficiency.Additionally,the COG complex is involved in macroautophagy,the vacuole targeting(Cvt)pathway,and pexophagy.In this review,we introduce the regulatory mechanism of the COG com-plex in several species,and summarize the factors that have synergetic effects with the COG complex in vesicle transport.

Aim To study the role and mechanism of ML210 in glioma.Methods The cell viability was detected by CCK8 assay.The percentage of dead cells was detected by SYTOXstaining.The role of ferroptosis-signaling pathway in gliomas was detected bygenomics.Cell proliferation was observed by EdU staining and clone formation assay.Cell migration ability was detec-ted by scratch healing assay.The apoptosis was detec-ted by flow cytometry.Cell mitochondrial function was assesses by JC-1 staining.The mechanism of action of ML210 was detected by molecular docking coupled with immunoblotting assay(Western blot).The levels of ROS,MDA were observed by ELISA.Results Compared with the control group,ML210 treatment dose-dependently decreased glioma cell viability,in-hibited cell proliferation,migration,and increased cell apoptosis and mitochondrial dysfunction,which were reversed by ferroptosis antagonists.Gene microarray screening showed that 688 genes of the ferroptosissig-naling pathway were aberrant and 10 signaling path-ways were altered in gliomas.Molecular docking re-sults showed that ML210 binding to GPX4 significantly inhibited the protein expression level of GPX4 and pro-moted the elevation of ROS and MDA levels.Conclu-sions ML210 produces anti-glioma cells via GPX4-mediated ferroptosis pathway.

As a tethering complex localized on the Golgi membrane,the conserved oligomeric Golgi(COG)complex is divided into lobes A(COG1-4)and B(COG5-8)and forms a complete hetero-oc-tamer structure through the dynamic linkage of COG1 to COG8.Through coordinated interactions with Rab GTPases,SNARE proteins,and Golgi-associated coiled-coil tethers(CCTs),the COG complex par-ticipates in coatomer complex Ⅰ(COP Ⅰ)-mediated retrograde transport,coatomer complex Ⅱ(COP Ⅱ)-mediated anterograde transport,and various autophagic processes.The functional mechanism of the COG complex includes two models.First,the"disassembly and assembly model",in which lobe A anchors the Golgi membrane,while lobe B binds to the vesicle membrane,and both lobes assemble into the com-plete COG complex to narrow the distance between vesicle and target membranes.Second,the"docking station assembly model",in which COG complexes cooperate with SNARE,Rab and other molecules to form a stable docking platform,to enhance the stability of SNARE complexes and promote membrane fu-sion efficiency.Additionally,the COG complex is involved in macroautophagy,the vacuole targeting(Cvt)pathway,and pexophagy.In this review,we introduce the regulatory mechanism of the COG com-plex in several species,and summarize the factors that have synergetic effects with the COG complex in vesicle transport.

Objective:To investigate the short-term efficacy of transverse osteotomy of the first metatarsal and fixation with Kirschner wires for mild to moderate hallux valgus (HV).Methods:This was a retrospective cohort study. A total of 44 patients (55 feet) with HV who underwent surgical treatment in the Foot and Ankle Ward Two, Tianjin Hospital, Tianjin University from March 2022 to June 2023 were enrolled, including 41 females and 3 males. Based on the different surgical methods, they were divided into a transverse osteotomy group and Scarf group. The transverse osteotomy group was treated with transverse osteotomy of the first metatarsal and fixation with two Kirschner wires, and the Scarf group was treated with "Z" osteotomy and screw fixation. The transverse osteotomy group consisted of 20 patients (25 feet), all female, with an average age of 54.56±3.13 years (range, 50-62 years), including 12 left feet and 13 right feet. Among them, 7 feet had mild HV, and 18 feet had moderate HV. The Scarf osteotomy group included 24 patients (30 feet), 3 males and 21 females, with an average age of 52.43±5.46 years (range, 39-60 years), including 15 left feet and 15 right feet. Among them, 3 feet had mild HV and 27 feet had moderate HV. Observation indicators: (1) The imaging indicators of the two groups were compared before operation and at the last follow-up. These indicators included hallux valgus angle (HVA), intermetatarsal angle (IMA). (2) The clinical efficacy of the two groups was compared, including American Orthopaedic Foot and Ankle Society (AOFAS) forefoot score and visual analogue scale (VAS), as well as postoperative complications. (3) The operation time of the two groups was recorded respectively.Results:Both groups were followed up for an average duration of 6-18 months (13.28±4.42 months). There were no significant differences in preoperative baseline characteristics between the transverse osteotomy group and the Scarf group ( P>0.05). The mean operation time was 28.96±4.10 min for the transverse osteotomy group and 45.37±4.72 min for the Scarf group, with a statistically significant difference ( t=13.612, P<0.001). In the transverse osteotomy, the preoperative HVA was 32.48°±3.9°and decreased to 8.59°±3.06° at the last follow-up, while IMA reduced from 14.53°±1.89° before surgery to 5.07°±1.74° at the last follow-up with statistical significance ( P<0.05). Similarly, in the Scarf group, preoperative HVA was 32.83°±2.33° and decreased to 9.87°±2.66° at the last follow-up, whereas IMA decreased from 13.7°±2.03° before surgery to 5.73°±1.74° at the last follow-up with statistical significance ( P<0.05). There was no significant difference in HVA and IMA between the two groups before surgery and the last follow-up ( P>0.05). In the transverse osteotomy, the preoperative VAS score was 6.0(5.5, 7.0), and at the last follow-up, it improved to 2.0(1.0, 2.0). The preoperative AOFAS score was 48.40±6.04 and increased significantly to 87.36±5.02 at the last follow-up ( P<0.05). In the Scarf group, the preoperative VAS score was 6.0(5.0, 6.0), which decreased to 2.0(2.0, 2.0) at the last follow-up assessment. The preoperative AOFAS score was 50.70±7.31 and showed a significant improvement with a mean of 84.43±3.45 at the final evaluation ( P<0.05). There were no significant differences in preoperative VAS scores between the two groups; however, at the last follow-up assessment, patients in the transverse osteotomy group had higher scores compared to those in the Scarf group, indicating better outcomes ( t=2.610, P=0.012). Postoperatively, only 1 foot in the transverse osteotomy group developed metastatic metatarsal pain, with a complication rate of 4% (1/25). In the Scarf osteotomy group, 1 foot developed superficial wound infection, 1 foot developed metastatic metatarsal pain, and 6 feet experienced joint stiffness, with a complication rate of 27%(8/30). Conclusions:Transverse osteotomy of the first metatarsal and fixation with Kirschner wires is simple, effective, and fast. It can effectively relieve pain, quickly restore function, shorten operation time, reduce soft tissue trauma, and minimize complications, demonstrating good clinical efficacy in the short term.

Aim To study the role and mechanism of ML210 in glioma.Methods The cell viability was detected by CCK8 assay.The percentage of dead cells was detected by SYTOXstaining.The role of ferroptosis-signaling pathway in gliomas was detected bygenomics.Cell proliferation was observed by EdU staining and clone formation assay.Cell migration ability was detec-ted by scratch healing assay.The apoptosis was detec-ted by flow cytometry.Cell mitochondrial function was assesses by JC-1 staining.The mechanism of action of ML210 was detected by molecular docking coupled with immunoblotting assay(Western blot).The levels of ROS,MDA were observed by ELISA.Results Compared with the control group,ML210 treatment dose-dependently decreased glioma cell viability,in-hibited cell proliferation,migration,and increased cell apoptosis and mitochondrial dysfunction,which were reversed by ferroptosis antagonists.Gene microarray screening showed that 688 genes of the ferroptosissig-naling pathway were aberrant and 10 signaling path-ways were altered in gliomas.Molecular docking re-sults showed that ML210 binding to GPX4 significantly inhibited the protein expression level of GPX4 and pro-moted the elevation of ROS and MDA levels.Conclu-sions ML210 produces anti-glioma cells via GPX4-mediated ferroptosis pathway.

This study assessed the role and mechanism of the recombinant Bacillus Calmette-Gue?rin vaccine(rBCG)with c-di-AMP adjuvant in regulating metabolism and immunity in epididymal white adipose(eWAT)in mice.Male C57BL/6 mice were intravenously immunized with BCG and rBCG,and their body weights were monitored.eWAT was isolated from the mice,and the stromal vascular fractions(SVFs)cell number was counted with a hemocytometer.Sections of mouse adipose tissue were prepared,and the size,number,and morphology of eWAT adipocytes and crown-like structure(CLS)formation were compared under a microscope after HE staining.The transcription levels of lipid metabolism-associated factors,cytokines and aging-associated genes in each group were determined with qRT-PCR.The body weights of mice gradually increased after immunization with BCG and rBCG.The proportions of eWAT increased,and the SVFs cell number decreased,in rBCG immunized mice.HE staining indicated that BCG immunization promoted hyperplasia,whereas rBCG immunization promoted hypertrophy of eWAT adipocytes;moreover,both BCG and rBCG immunization induced CLS formation in eWAT.The qRT-PCR results indicated that rBCG immunization inhibited the expression of genes associated with lipolysis and energy expenditure in eWAT.BCG immunization had little effect on cytokine transcription,whereas rBCG significantly induced the transcription of IFN-γ and IL-1Ra,and inhibited that of IL-15 and IL-2,but did not induce the expression of aging-associated genes.Thus,rBCG immunization induced eWAT adipocyte hypertrophy,which was associated with the inhibition of eWAT lipolysis and the regulation of cytokine expression.