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PI3K/Akt signaling is activated in cancers and governs tumor initiation and progression, but how Akt is activated under diverse stresses is poorly understood. Here we identify AMPK as an essential regulator for Akt activation by various stresses. Surprisingly, AMPK is also activated by growth factor EGF through Ca2+/Calmodulin-dependent kinase and is essential for EGF-mediated Akt activation and biological functions. AMPK phosphorylates Skp2 at S256 and promotes the integrity and E3 ligase activity of Skp2 SCF complex leading to K63-linked ubiquitination and activation of Akt and subsequent oncogenic processes. Importantly, AMPK-mediated Skp2 S256 phosphorylation promotes breast cancer progression in mouse tumor models, correlates with Akt and AMPK activation in breast cancer patients, and predicts poor survival outcomes. Finally, targeting AMPK-mediated Skp2 S256 phosphorylation sensitizes cells to anti-EGF receptor targeted therapy. Our study sheds light on how stress and EGF induce Akt activation and new mechanisms for AMPK-mediated oncogenesis and drug resistance. How Akt pathway is activated under stress is poorly understood. Here, the authors demonstrate the crucial role of AMPK for cellular stresses and growth factors- mediated Akt activation through a mechanism involving the E3 ubiquitin ligase Skp2 and Cullin-1.

Background/Aim: Matrix metalloproteinase-9 (MMP-9) has been associated with the development and progression of breast cancer (BCa). However, the relationship between MMP-9 genetic variants and BCa susceptibility remains contentious and inconclusive. This study aimed to evaluate the association of MMP-9 rs3918242 promoter polymorphisms with BCa, with a particular focus on the risk of triple-negative breast cancer (TNBC).Materials and Methods: A case-control study was conducted involving 1,232 BCa patients and 1,232 healthy controls. The MMP-9 rs3918242 genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.Results: The genotype distribution of MMP-9 rs3918242 among the control group adhered to Hardy-Weinberg equilibrium (p=0.3265). No statistically significant differences were observed in the genotype frequencies between BCa cases and controls (p for trend=0.2555). Although the homozygous variant genotype (TT) showed a potential risk-increasing effect, this was not statistically significant [odds ratio (OR)=1.43, 95% confidence interval (CI)=0.88-2.36, p=0.1869]. Similarly, allele frequency analysis indicated no significant association between the variant T allele and overall BCa risk (OR=1.13, 95%CI=0.97-1.33, p=0.1265). Additionally, no interaction was detected between MMP-9 rs3918242 genotypes and the age of BCa onset (both p>0.05). Notably, the TT genotype of MMP-9 rs3918242 was significantly associated with an increased risk of TNBC (OR=2.49, 95%CI=1.32-4.72, p=0.0072).Conclusion: The MMP-9 rs3918242 TT genotype may serve as a potential predictive biomarker for TNBC in the Taiwanese population.

Bladder cancer progression is closely linked to metabolic changes within the tumor microenvironment (TME), particularly elevated lactate levels. Lipocalin 2 (LCN2), a protein involved in iron regulation, has been implicated in tumor progression in several cancers, but its regulatory mechanisms and role in bladder cancer remain unclear. Bladder cancer cell lines were treated with exogenous lactate or subjected to inhibition of endogenous lactate production to evaluate changes in LCN2 expression. The role of Signal Transducer and Activator of Transcription 3 (STAT3) was assessed using genetic knockdown and pharmacological inhibitors. Functional assays including migration, epithelial-to-mesenchymal transition (EMT), sphere formation, and stemness marker analysis were performed to determine the biological effects of LCN2. Chemoresistance to gemcitabine was examined with and without LCN2 silencing. Clinically, LCN2 expression was significantly associated with the pathological relevance of bladder tumors. Lactate significantly induced LCN2 expression in bladder cancer cells through activation of STAT3. Disruption of STAT3 signaling reduced LCN2 levels. High LCN2 expression correlated with advanced tumor grade, poor prognosis, and shorter overall survival. Functionally, LCN2 promoted EMT, enhanced cell migration, and increased stem cell-like properties, as evidenced by elevated stemness markers and sphere-forming ability. Moreover, lactate-induced LCN2 expression conferred resistance to gemcitabine treatment, while LCN2 knockdown restored chemosensitivity. This study identifies tumor-derived lactate as a key inducer of LCN2 expression via STAT3 activation in bladder cancer. LCN2 contributes to tumor aggressiveness, cancer stemness, and chemoresistance. Targeting the STAT3-LCN2 signaling axis may offer a promising therapeutic strategy to suppress bladder cancer progression and overcome treatment resistance within a lactate-rich TME.

N-(2-hydroxy) propyl-3-trimethylammonium chitosan chloride (HTCC) is a type of quaternary ammonium chitosan derivative with an antibacterial activity superior to the pristine chitosan, but its electrospinnability is limited. In this study, polyvinyl alcohol (PVA) was blended with HTCC to improve the electrospinnability of nanofibers. The electrospinning of PVA–HTCC nanofiber membranes was optimized in terms of structural stability and antimicrobial performance. Based on scanning electron microscopic analysis, the morphology and diameter of the produced nanofibers were influenced by the applied voltage, flow rate of the feed solution, and weight ratio of the polymer blend. An increase in the HTCC content decreased the average nanofiber diameter. The maximum water solubility of the PVA–HTCC nanofibers reached the maximum value of 70.92% at 12 h and 25 °C. The antibacterial activity of PVA–HTCC nanofiber membranes against Escherichia coli was ~90%, which is significantly higher than that of PVA–chitosan nanofiber membrane. Moreover, the antibacterial efficiency of PVA–HTCC nanofiber membranes remained unaffected after 5 cycles of antibacterial treatment. The good antibacterial performance and biocompatibility of PVA–HTCC nanofiber membrane makes them attractive for biomedical and biochemical applications that necessitate sterile conditions.

6-hydroxydopamine (6-OHDA) is used to induce oxidative damage in neuronal cells, which can serve as an experimental model of Parkinson’s disease (PD). Jujuboside A and B confer free radical scavenging effects but have never been examined for their neuroprotective effects, especially in PD; therefore, in this study, we aimed to investigate the feasibility of jujubosides as protectors of neurons against 6-OHDA and the underlying mechanisms. 6-OHDA-induced neurotoxicity in the human neuronal cell lines SH-SY5Y and SK-N-SH, was used to evaluate the protective effects of jujubosides. These findings indicated that jujuboside A and B were both capable of rescuing the 6-OHDA-induced loss of cell viability, activation of apoptosis, elevation of reactive oxygen species, and downregulation of the expression levels of superoxide dismutase, catalase, and glutathione peroxidase. In addition, jujuboside A and B can reverse a 6-OHDA-elevated Bax/Bcl-2 ratio, downregulate phosphorylated PI3K and AKT, and activate caspase-3, -7, and -9. These findings showed that jujubosides were capable of protecting both SH-SY5Y and SK-N-SH neuronal cells from 6-OHDA-induced toxicity via the rebalancing of the redox system, together with the resetting of the PI3K/AKT apoptotic signaling cascade. In conclusion, jujuboside may be a potential drug for PD prevention.

Gastric adenocarcinoma (GACA) remains a major global health concern, particularly in Asia, due to its poor prognosis and complex etiology. The interaction between genetic factors and environmental exposures, such as smoking, alcohol consumption, and ( ) infection, plays a crucial role in GACA risk. gene promoter polymorphic rs2243248 (T-1099G), rs2243250 (C-589T), and rs2070874 (C-33T) genotypes were analyzed in 161 GACA patients and 483 non-cancer control subjects from a Taiwanese population by PCR-RFLP methodology. The gene-environment interactions were evaluated by stratified analysis. Genotypic analysis revealed no significant association between polymorphisms and GACA risk (all >0.05). However, interactions between C-589T and C-33T genotypes with infection were observed ( =0.0114 and 0.0009). In addition, T-1099G and C-33T genotypes interacted with alcohol consumption ( =0.0346 and 0.0295). T-1099G and C-589T variant genotypes were associated with an increased risk of metastasis ( =0.0313 and 0.0118). Moreover, polymorphisms did not correlate with smoking behavior in influencing GACA susceptibility. While polymorphisms alone are not predictors of GACA risk, their interactions with environmental factors may contribute to the progression of the disease. Our study emphasizes the need for further research to explore the clinical implications of genetic variants in diverse populations and their role in GACA progression.

Asthma is a complex inflammatory airway disease influenced by genetic and environmental factors. , particularly its promoter polymorphism rs1800925 and coding variant rs20541, have been implicated in asthma pathogenesis. This study investigated their associations with asthma susceptibility and severity in a Taiwanese population. A total of 198 adult patients with asthma and 453 controls without asthma were genotyped for rs1800925 and rs20541 using PCR-based assays. Associations with disease risk, age, sex, and asthma severity were analyzed using logistic regression models. Genotype frequencies of rs1800925 and rs20541 conformed to Hardy-Weinberg equilibrium in controls ( =0.1209 and 0.6860). No significant association was found between asthma risk and rs1800925 [CT CC: odds ratio (OR)=1.16, 95% confidence interval (CI)=0.80-1.65, =0.4793; TT CC: OR=1.31, 95%CI=0.70-2.45, =0.5043] or rs20541 (AG GG: OR=0.93, 95%CI=0.66-1.33, =0.7652; AA GG: OR=0.84, 95%CI=0.46-1.51, =0.6577). However, stratified analysis revealed that among individuals aged 25-40, the rs1800925 TT genotype was associated with increased asthma risk (OR=2.16, 95%CI=1.02-4.56, =0.0637). Notably, rs1800925 CT and TT genotypes were significantly associated with severe asthma symptoms (CT CC: OR=2.11, =0.0287; TT CC: OR=4.83, =0.0057), with carriers of CT+TT genotypes having higher odds of severe asthma (OR=2.46, 95%CI=1.36-4.45, =0.0041). While rs1800925 and rs20541 polymorphisms were not significantly associated with overall asthma susceptibility, the rs1800925 TT genotype may confer increased risk in younger adults and is significantly linked to more severe asthma severity. rs1800925 may serve as a potential genetic biomarker for asthma severity prediction and management in Taiwanese populations.

The UCLA Loneliness Scale (Version 3; UCLA-LSV3) is widely used for assessing loneliness. Nevertheless, the validity of this scale for assessing loneliness in individuals with schizophrenia or schizoaffective disorder has not been determined. Additionally, studies validating the eight-item and three-item versions of UCLA-LSV3 have not included individuals with severe mental illness; therefore, whether the short versions are comparable to the full 20-item version of UCLA-LSV3 for this population is unclear. The present study examined the unidimensional structure, internal consistency, concurrent validity, and test–retest reliability of the Chinese versions of UCLA-LSV3 (i.e., 20-item, 8-item, and 3-item versions) to determine which version is most appropriate for assessing loneliness in individuals with schizophrenia or schizoaffective disorder in Taiwan. A total of 300 participants (267 with schizophrenia and 33 with schizoaffective disorder) completed the scales, comprising UCLA-LSV3, the Center for Epidemiological Studies Depression Scale (CES-D), the suicidality module of the Kiddie Schedule for Affective Disorders and Schizophrenia–Epidemiological Version (K-SADS-E), and the family and peer Adaptation, Partnership, Growth, Affection, and Resolve (APGAR) index. Construct validity was evaluated through confirmatory factor analysis. The three versions of UCLA-LSV3 were compared with the CES-D, the suicidality module of the K-SADS-E, and the family and peer APGAR index to establish concurrent validity. The results indicated that all three versions of UCLA-LSV3 exhibited acceptable to satisfactory psychometric properties in terms of unidimensional constructs, concurrent validity, and test–retest reliability. The full version of UCLA-LSV3 had the best performance, followed by the eight-item version and the three-item version. Moreover, the three versions had relatively strong associations with each other. Therefore, when deliberating which version of UCLA-LSV3 is the best choice for assessing loneliness in individuals with schizophrenia or schizoaffective disorder, healthcare providers and therapists should consider time availability and practicality.

Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy influenced by Epstein-Barr virus (EBV) infection, genetic susceptibility, and environmental factors. Matrix metalloproteinase-7 (MMP-7), a key regulator of extracellular matrix remodeling, has been implicated in NPC progression. This study investigated the association between rs11568818 and rs11568819 genotypes and NPC susceptibility in a Taiwanese cohort consisted of 208 NPC cases and 416 cancer-free controls. The genotypic patterns of rs11568818 and rs11568819 were revealed by utilizing PCR-RFLP methodology. In addition, the interaction between genotypes and lifestyle factors (including smoking, alcohol consumption, and betel quid chewing) was also analyzed in a stratified manner. Genotypic distribution analysis of rs11568818 showed no significant association with NPC risk ( for trend=0.4641). Individuals carrying the AG (OR=1.22, 95%CI=0.79-1.90, =0.4384) or GG (OR=1.74, 95%CI=0.52-5.79, =0.5539) genotypes exhibited a modestly elevated, but statistically non-significant, risk compared to AA carriers. Similarly, allelic frequency analysis indicated that the G allele did not significantly contribute to NPC susceptibility (OR=1.28, 95%CI=0.87-1.87, =0.2433). Stratified analysis revealed a significant interaction between rs11568818 and smoking status ( for trend=0.0018). Among smokers, AG and GG genotypes were associated with an increased NPC risk (AG: OR=2.70, 95%CI=1.34-5.44, =0.0076; GG: OR=9.27, 95%CI=1.01-84.66, =0.0345), which remained significant after adjusting for confounders (adjusted OR=2.53, 95%CI=1.27-4.88; adjusted OR=7.89, 95%CI=1.02-47.38). No interactions were observed with alcohol consumption or betel quid chewing. Additionally, no polymorphic genotypes were detected for rs11568819 in the studied population. While rs11568818 does not directly influence NPC susceptibility in a Taiwanese population, its interaction with smoking may contribute to elevated NPC risk.

We aimed to investigate the association between genotypes for mir146a and mir196a-2 and the risk of developing colorectal cancer (CRC). We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the mir146a rs2910164 and mir196a-2 rs11614913 genotypes in 362 CRC patients and 362 controls. We also assessed the interactions between these genotypes and age, gender, smoking, alcohol consumption, and BMI status on CRC risk. Additionally, the serum expression level of mir196a-2 was quantified using quantitative reverse transcription-PCR. Our findings demonstrated that among the controls, the proportions of TT, CT, and CC genotypes of mir196a-2 rs11614913 were 32.3%, 48.1%, and 19.6%, respectively. As for the cases, the proportions were 24.6%, 45.0%, and 30.4%, respectively. Logistic regression analysis revealed that the CC genotype carriers had a 2.04-fold increased risk (95% confidence interval [CI] = 1.36–3.06, p = 0.0008). Furthermore, carriers of the CT + CC genotypes also exhibited a significant association with CRC risk (odds ratio [OR] = 1.46, 95% CI = 1.06–2.03, p = 0.0261). Moreover, carriers of the CC genotype had significantly higher serum levels of mir196a-2 compared to those with the TT genotype (p < 0.0001), indicating a genotype-phenotype correlation. No association was found regarding mir146a rs2910164. In conclusion, mir196a-2 rs2910164 genotypes, along with their associated expression, can serve as predictive markers for CRC risk.