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.

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.

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.

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.

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases (CVDs), the world's primary cause of death. Ginkgo biloba, a well-known traditional Chinese medicine with notable cardiovascular actions, has been used as a cardio- and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries. Preclinical studies have shown that ginkgolide B, a bioactive component in Ginkgo biloba, can ameliorate atherosclerosis in cultured vascular cells and disease models. Of clinical relevance, several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases, such as ischemia stroke. Here, we present a comprehensive review of the pharmacological activities, pharmacokinetic characteristics, and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy. We highlight new molecular targets of ginkgolide B, including nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidase), lectin-like oxidized LDL receptor-1 (LOX-1), sirtuin 1 (SIRT1), platelet-activating factor (PAF), proprotein convertase subtilisin/kexin type 9 (PCSK9) and others. Finally, we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.

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.

Aim To construct a diabetic atherosclerosis mouse model and study the pathological characteristics of diabetic atherosclerosis.Methods Fifty 8-week-old male LDLR-/-mice were fed with standard diet for 2 weeks and then changed to high-fat diet,they were randomly divided into two groups.The diabetic atherosclerosis group was given intraperitoneal injection of low dose streptozotocin(STZ)for 5 days continuouly to establish the model,and the atheroscle-rosis group was given citrate buffer injection at the same time.The body mass,blood glucose and blood lipids of the mice in the two groups were detected for many times.At the age of 23 weeks,the mice were euthanized after glucose tolerance test.HE staining and oil red O staining were used to detect the gross and aortic root atherosclerosis,immunohistochemical staining was used to detect CD4,α-smooth muscle actin(α-SMA),EGF-like module-containing mucin-like hormone re-ceptor-like 1(EMR1),monocyte chemotactic protein-1(MCP-1),NOD-like receptor protein 3(NLRP3),vascular cell adhesion molecule-1(VCAM-1),matrix metalloproteinase-2(MMP-2)and tissue inhibitor of metalloproteinase-1(TIMP-1),Western blot was used to detect α-SMA,CD4,tumor necrosis factor-α(TNF-α),NLPR3,intercellular adhesion molecule-1(ICAM-1),and type Ⅰ and Ⅲ collagen.Results Compared with the atherosclerosis group,the body mass decreased,the levels of total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDLC)increased,and the levels of high density lipoprotein cholesterol(HDLC)decreased(P＜0.05)in the diabetic atherosclerosis group.Compared with the atherosclerosis group,the distribution of atherosclerotic plaques was diffuse and the area was increased in the diabetic atherosclerosis group,and the contents of lipids,T cells,macrophages,smooth muscle cells,type Ⅰ and Ⅲ colla-gen were increased(P＜0.05);the protein levels of TNF-α,MCP-1,MMP-2,NLRP3,ICAM-1 and VCAM-1 in vascular tissues were increased,while the content of TIMP-1 were decreased and MMP2/TIMP-1 were increased(P＜0.05).Conclusions LDLR-mouse model of diabetic atherosclerosis can be successfully established by STZ induction combined with high-fat diet,which can reflect the plaque composition and inflammatory characteristics of diabetes promoting atheroscle-rosis.It can be used as a relatively ideal pathological model for the study of diabetic macroangiopathy.