Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both in vitro and in vivo. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.

Aim To explore the effect of ultrasound-treated polystyrene nanoplastics(PS-NP)on lipid accumu-lation in macrophage-derived foam cells.Methods The CCK-8 method was used to detect the effects of PS-NP and high-frequency ultrasound-treated PS-NP(UPS-NP)on the activity of macrophages,oil red O staining and cholesterol de-tection kit were used to detect the intracellular lipid accumulation,RT-qPCR and Western blot were used to detect the ex-pression of mRNA and protein related to cholesterol uptake and efflux,as well as mRNA levels of cell burial related recep-tors.Results UPS-NP had no significant effect on the activity of macrophages,but UPS-NP could significantly in-crease the formation of macrophage-derived foam cells and increase the lipid accumulation in foam cells.UPS-NP could significantly upregulate the mRNA and protein expression of CD36 and scavenger receptor-A1(SR-A1),but did not affect the mRNA and protein expression of cholesterol efflux related receptors ATP-binding cassette transporter A1(ABCA1)and scavenger receptor-B1(SR-B1).UPS-NP did not affect the mRNA levels of receptors related to cell burial processes.Conclusion Ultrasound-treated PS-NP can significantly increase lipid accumulation in macrophage-derived foam cells,and its mechanism is related to the upregulation of CD36 and SR-A1 expression.

Aim To explore the effect of ultrasound-treated polystyrene nanoplastics(PS-NP)on lipid accumu-lation in macrophage-derived foam cells.Methods The CCK-8 method was used to detect the effects of PS-NP and high-frequency ultrasound-treated PS-NP(UPS-NP)on the activity of macrophages,oil red O staining and cholesterol de-tection kit were used to detect the intracellular lipid accumulation,RT-qPCR and Western blot were used to detect the ex-pression of mRNA and protein related to cholesterol uptake and efflux,as well as mRNA levels of cell burial related recep-tors.Results UPS-NP had no significant effect on the activity of macrophages,but UPS-NP could significantly in-crease the formation of macrophage-derived foam cells and increase the lipid accumulation in foam cells.UPS-NP could significantly upregulate the mRNA and protein expression of CD36 and scavenger receptor-A1(SR-A1),but did not affect the mRNA and protein expression of cholesterol efflux related receptors ATP-binding cassette transporter A1(ABCA1)and scavenger receptor-B1(SR-B1).UPS-NP did not affect the mRNA levels of receptors related to cell burial processes.Conclusion Ultrasound-treated PS-NP can significantly increase lipid accumulation in macrophage-derived foam cells,and its mechanism is related to the upregulation of CD36 and SR-A1 expression.

Objective:To investigate factors influencing 18F-FDG PET/CT SUVmax,T/MB ratio and Ki-67 expression in non-Hodgkin's lymphoma(NHL),to analyze their correlations with lymphoma aggressiveness and their potential advantages in predicting therapeutic efficacy.Methods:A retrospective analysis was conducted to investigate correlations between tumor SUVmax,T/MB ratio,and Ki-67 expression with NHL aggressiveness and clinical characteristics in 99 patients;whether SUVmax,T/MB ratio and Ki-67 served as independent prognostic factors influencing therapeutic efficacy was examined,and potential utility of ΔSUVmax and ΔT/MB as biomarkers for treatment response assessment were evaluated.Results:Aggressive NHL demonstrated significantly higher SUVmax,T/MB ratio and Ki-67 level compared to indolent NHL and aggressive/indolent NHL(P<0.05).A pretreatment SUVmax≥9.05,T/MB≥5.115 or Ki-67≥55%could predict clinical remission in NHL patients post-treatment,while post-treatment reductions of ΔSUVmax≥22.65%or ΔT/MB≥34.85%were associated with achieved clinical remission.Conclusion:SUVmax,T/MB ratio and Ki-67 are closely associated with aggressiveness of NHL,which can be predicted whether NHL will be relieved after treatment.ΔSUVmax and ΔT/MB can assess whether NHL has been relieved after treatment.

Background and purpose:Tumor necrosis factor alpha-induced protein 8(TNFAIP8),also called TIPE,plays critical regulatory roles in various malignancies,yet its molecular mechanisms in metabolic reprogramming of triple-negative breast cancer(TNBC)remain elusive.This study aimed to elucidate how TIPE regulates the expression of the glycolytic key enzyme lactate dehydrogenase A to influence TNBC cell proliferation and glycolytic reprogramming,thereby providing potential molecular targets for TNBC therapy.Methods:Stable TIPE-knockdown MDA-MB-231 cell lines were established using a lentiviral shRNA system and selected with puromycin.Transcriptome sequencing was used to analyze TIPE's impact on TNBC glycolytic pathways.Extracellular acidification rate(ECAR)was measured using the Seahorse XF Analyzer,complemented by lactate production assays to evaluate glycolytic capacity.Co-IP/MS was carried out to identify TIPE-interacting proteins,with subsequent validation of TIPE-LDHA interaction through co-transfection of TIPE-Myc and LDHA-Flag plasmids in HEK-293T cells.Protein stability was assessed via cycloheximide(CHX)chase and ubiquitination assays.The cell counting kit-8(CCK-8)assay and animal experiments(Approval Number for Animal Ethics:202212007)were conducted to investigate how TIPE affects the proliferation and glucometabolic reprogramming of TNBC by mediating LDHA.Results:TIPE promoted glycolytic metabolic reprogramming in TNBC.Knockdown of TIPE significantly inhibited TNBC glycolytic activity and glycolytic capacity(P＜0.001).TIPE interacted with the key glycolytic enzyme LDHA and suppressed its degradation rate through a ubiquitination-dependent mechanism.Cellular experiments demonstrated that TIPE mediated LDHA to enhance TNBC cell proliferation(P＜0.001)and glycolytic activity(P＜0.001).Animal studies confirmed that TIPE knockdown significantly suppressed tumor volume(P＜0.05)and weight(P＜0.01),with a positive correlation between TIPE and LDHA expression levels in tumor tissues.Conclusion:TIPE enhances TNBC cell proliferation and glycolytic capacity by inhibiting LDHA ubiquitination-mediated degradation.

Background and purpose:Tumor necrosis factor alpha-induced protein 8(TNFAIP8),also called TIPE,plays critical regulatory roles in various malignancies,yet its molecular mechanisms in metabolic reprogramming of triple-negative breast cancer(TNBC)remain elusive.This study aimed to elucidate how TIPE regulates the expression of the glycolytic key enzyme lactate dehydrogenase A to influence TNBC cell proliferation and glycolytic reprogramming,thereby providing potential molecular targets for TNBC therapy.Methods:Stable TIPE-knockdown MDA-MB-231 cell lines were established using a lentiviral shRNA system and selected with puromycin.Transcriptome sequencing was used to analyze TIPE's impact on TNBC glycolytic pathways.Extracellular acidification rate(ECAR)was measured using the Seahorse XF Analyzer,complemented by lactate production assays to evaluate glycolytic capacity.Co-IP/MS was carried out to identify TIPE-interacting proteins,with subsequent validation of TIPE-LDHA interaction through co-transfection of TIPE-Myc and LDHA-Flag plasmids in HEK-293T cells.Protein stability was assessed via cycloheximide(CHX)chase and ubiquitination assays.The cell counting kit-8(CCK-8)assay and animal experiments(Approval Number for Animal Ethics:202212007)were conducted to investigate how TIPE affects the proliferation and glucometabolic reprogramming of TNBC by mediating LDHA.Results:TIPE promoted glycolytic metabolic reprogramming in TNBC.Knockdown of TIPE significantly inhibited TNBC glycolytic activity and glycolytic capacity(P＜0.001).TIPE interacted with the key glycolytic enzyme LDHA and suppressed its degradation rate through a ubiquitination-dependent mechanism.Cellular experiments demonstrated that TIPE mediated LDHA to enhance TNBC cell proliferation(P＜0.001)and glycolytic activity(P＜0.001).Animal studies confirmed that TIPE knockdown significantly suppressed tumor volume(P＜0.05)and weight(P＜0.01),with a positive correlation between TIPE and LDHA expression levels in tumor tissues.Conclusion:TIPE enhances TNBC cell proliferation and glycolytic capacity by inhibiting LDHA ubiquitination-mediated degradation.

Objective:To investigate factors influencing 18F-FDG PET/CT SUVmax,T/MB ratio and Ki-67 expression in non-Hodgkin's lymphoma(NHL),to analyze their correlations with lymphoma aggressiveness and their potential advantages in predicting therapeutic efficacy.Methods:A retrospective analysis was conducted to investigate correlations between tumor SUVmax,T/MB ratio,and Ki-67 expression with NHL aggressiveness and clinical characteristics in 99 patients;whether SUVmax,T/MB ratio and Ki-67 served as independent prognostic factors influencing therapeutic efficacy was examined,and potential utility of ΔSUVmax and ΔT/MB as biomarkers for treatment response assessment were evaluated.Results:Aggressive NHL demonstrated significantly higher SUVmax,T/MB ratio and Ki-67 level compared to indolent NHL and aggressive/indolent NHL(P<0.05).A pretreatment SUVmax≥9.05,T/MB≥5.115 or Ki-67≥55%could predict clinical remission in NHL patients post-treatment,while post-treatment reductions of ΔSUVmax≥22.65%or ΔT/MB≥34.85%were associated with achieved clinical remission.Conclusion:SUVmax,T/MB ratio and Ki-67 are closely associated with aggressiveness of NHL,which can be predicted whether NHL will be relieved after treatment.ΔSUVmax and ΔT/MB can assess whether NHL has been relieved after treatment.

Atherosclerosis is a chronic vascular wall disease and the most common pathological change in cardiovas-cular disease.Its pathogenesis is closely related to inflammation,oxidative stress,and lipid deposition.Bilirubin itself has biological activities such as antioxidant and anti-inflammatory effects,and has a protective effect on the cardiovascular system.This article summarizes the mechanism of bilirubin in the development of atherosclerosis and its research pro-gress.

Gastric cancer （GC） is one of the common malignant tumors， and the incidence and mortality of GC in China rank first in the world. At present， the pathogenesis of GC has not been fully clarified. Although surgery， radiotherapy， chemotherapy， targeted therapy， and immunotherapy have achieved good results in the treatment of GC， there are still many complications， decreased sensitivity， and severe side effects. Banxia Xiexintang， derived from Treatise on Cold Damage and Miscellaneous Diseases（《伤寒杂病论》）， has been clinically used for more than 2000 years with the effects of combining cold and warm drugs， dissipating mass， and relieving stuffiness， and is a classic prescription for treating digestive tract diseases in later generations. Through clinical observation and experimental research， it is found that Banxia Xiexintang and its single drugs have good effect in preventing and treating GC. Chinese medicine has multi-component and multi-target characteristics and can treat GC through various mechanisms. Therefore， it is necessary to carry out systematic and in-depth research from the aspects of molecular biology and network pharmacology， and comprehensively reveal the mechanism of Banxia Xiexintang in preventing and treating GC. At present， the mechanism of Banxia Xiexintang in treating GC mainly focuses on inducing apoptosis of GC cells， inhibiting proliferation， migration， and invasion of GC cells， protecting peritoneal mesothelial cells， inhibiting peritoneal metastasis of GC cells， regulating GC microenvironment， and inhibiting the malignant transformation of bone marrow mesenchymal stem cells （BMSCs）. This research group is committed to the prevention and treatment of GC with Banxia Xiexintang， aiming to comprehensively reveal the mechanism of action and the pharmacodynamic material basis of Banxia Xiexintang in the prevention and treatment of GC， and provide an important scientific basis for further clinical application of Banxia Xiexintang. After searching CNKI， PubMed， Wanfang Data， VIP， and other databases， this paper summarized Banxia Xiexintang in the treatment of GC from the aspects of prescription basis， material basis， network pharmacology， clinical and experimental studies， etc.， so as to provide references for further research on pharmacological effect of Banxia Xiexintang and its application in the clinical treatment of GC.

The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes. Progestin and adipoQ receptor 3 (PAQR3), a key regulator of inflammation and metabolism, can negatively regulate the PI3K/AKT signaling pathway. Here, we report that gentiopicroside (GPS), the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa, decreased lipid synthesis and increased glucose utilization in palmitic acid (PA) treated HepG2 cells. Additionally, GPS improved glycolipid metabolism in streptozotocin (STZ) treated high-fat diet (HFD)-induced diabetic mice. Our findings revealed that GPS promoted the activation of the PI3K/AKT axis by facilitating DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Moreover, results of surface plasmon resonance (SPR), microscale thermophoresis (MST) and thermal shift assay (TSA) indicated that GPS directly binds to PAQR3. Results of molecular docking and cellular thermal shift assay (CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH₂-terminus including Leu40, Asp42, Glu69, Tyr125 and Ser129, and spatially inhibited the interaction between PAQR3 and the PI3K catalytic subunit (P110α) to restore the PI3K/AKT signaling pathway. In summary, our study identified GPS, which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway, as a potential drug candidate for the treatment of diabetes.