Cascadia Journal of Biomedical Research - Articles

dos Santos, T., de Oliveira, V., Cardoso, M., de Assunção, M., da Silva, A., Vieira, R., Barbosa, L., Maynart, W., dos Santos, E., Ferreira, H.

This article describes the methodological aspects of the Study of Nutrition, Health, and Food Security of Indigenous Peoples in Alagoas (ENSSAIA), conducted between August 2022 and December 2023. The objective of ENSSAIA was to investigate the nutrition, health, and food security conditions of indigenous peoples in Alagoas. This was a cross‐sectional, population‐based household survey assessing all 11 indigenous ethnic groups in the state, with a random selection of 14 out of 29 existing villages. All individuals registered in the Indigenous Health Care Subsystem of the selected villages were eligible for the study. A total of 1400 families were assessed, with data collected on environmental, demographic, and socioeconomic conditions; access to policies and public service infrastructure; household food security; health of children (< 5 years), pregnant women, women (19–59 years), and the elderly (≥ 60 years); breastfeeding practices among children < 2 years; individuals with disabilities and genetic alterations; nutritional status through anthropometric indicators (all household members), biochemical markers: hemoglobin (children aged 6 months to < 5 years and pregnant women), lipid profile, and glycated hemoglobin (women); dietary indicators (women, pregnant women, and children < 5 years); non‐communicable diseases; and alcohol and tobacco use (women, men, and elderly). The results produced by ENSSAIA are expected to support the formulation or revision of public policies that ensure greater access to healthcare, healthy food, and improved quality of life for indigenous peoples, considering their traditions, cultures, and ways of life.

Wang, S., Guo, J., Wang, Z., Chen, K., Liu, X., Cui, Y., Wang, Y., Li, Z., Cai, H., Ma, G., Zhang, Z., Wang, G., Xiu, L., Li, S., Li, H., Jia, H., Yu, B., Fang, S.

Background Dysfunctional mitochondria are a prominent feature of myocardial ischemic-reperfusion (I/R) injury, but the clinical translation is scarce. Congenital dysbolism methylmalonic acidemia causes fatal mitochondrial lesions and premature death. However, the biological impact of mitochondrial metabolite methylmalonic acid (MMA) in the pathogenesis of I/R and its translational relevance were unknown. Methods MMA and relevant metabolites were measured in 3 independent human cohorts and animals. Cardiac Mmut-conditional knockout (endogenous MMA elevation) and exogenous MMA administration were conducted in mouse I/R model. The potential mechanism was explored through multiomics, chromatin immunoprecipitation, and site-directed mutagenesis assays. The translational value of targeting MMA metabolism was assessed in a porcine I/R model. Results Circulating MMA predicts myocardial injury or heart failure risk post-reperfusion, which outmatches its isomer succinate in humans. Both MMA and succinate were elevated in heart tissues of mice at the initial period post-I/R, while later, MMA maintained higher levels, but succinate rapidly decreased to baseline levels. Endogenous and exogenous MMA, not succinate, increased susceptibility to myocardial I/R injury and mitochondrial dyshomeostasis, including impaired mitochondrial bioenergetics, biogenesis, and renovation. Mechanistically, MMA elevation inhibited the deacetylase activity of SIRT1; thus, hyperacetylation of transcription factor CREBK309 blunted its binding to the BNIP3 promoter and inhibited BNIP3-mediated mitochondrial quality control. Adeno-associated virus 9-containing MMUT gene delivery ameliorated impaired MMA metabolism to improve mitochondrial quality and cardiac phenotypes in I/R pigs. Conclusions This study revealed an unrecognized harmful effect of MMA on myocardial vulnerability distinct from its isomer succinate. Targeting MMA metabolism represents a promising strategy to optimize risk stratification and mitigate myocardial injury in patients with AMI. Graphical Abstract Compared with its well-known isomer succinate, the mitochondria-derived metabolite MMA is more robustly associated with myocardial injury post-reperfusion in both humans and animals. An increase in MMA but not succinate increased myocardial susceptibility and mitochondrial dysfunction under I/R conditions via inhibiting SIRT1/CREB/BNIP3-mediated mitochondrial quality control. In large animal experiments, promoting MMA metabolism through in vivo injection of AAV9-containing MMUT significantly mitigated the infarct size, mitochondrial dysfunction, and cardiac remodeling post-I/R. HF, heart failure; MI, myocardial infarction; CVD, cardiovascular disease. Supplementary Information The online version contains supplementary material available at 10.1186/s12916-025-04596-9.

Khan, S., Molden, J., Iversrud, C., Mattonen, D., Rossetti, S., Laing, L.

The oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway, which is often associated with loss of PTEN, is an important adaptive mechanism to androgen-targeted therapy in castration-resistant prostate cancer (CRPC). The concomitant targeting of the PAM pathway and the androgen receptor (AR) pathway is a promising therapeutic strategy for CRPC. Many PAM pathway inhibitors only target one component of the PAM pathway, which can limit efficacy due to the activation of the uninhibited components. We previously showed that the multi-target pan-PI3K-mTORC1/2 inhibitor, gedatolisib, exerts greater growth-inhibitory effects than single-target PAM pathway inhibitors in prostate cancer (PC) cells, regardless of PTEN or AR status. In the present study, we investigated the molecular and cellular effects of gedatolisib in combination with darolutamide in both PTEN+ and PTEN-deficient PC cell lines, including AR+ PC cell lines adapted to long-term treatment with darolutamide. We found that the gedatolisib + darolutamide combination exerted greater anti-proliferative and cytotoxic effects than the single agents in most AR+ PC cell models, regardless of their PTEN status. The gedatolisib + darolutamide combination inhibited AR and PAM pathway activities, blocked cell cycle progression, induced apoptotic cell death, and reduced glucose and lipid metabolism. The drug combination was effective in both darolutamide-naïve and darolutamide-adapted cell lines, suggesting potential benefit in prostate tumors that progressed after androgen-targeted therapy. These results provide a strong rationale for clinical studies evaluating gedatolisib in combination with AR inhibitors in CRPC.

Li, L., Xu, K., Bai, X., Wang, Z., Tian, X., Chen, X.

Age-related hearing loss (ARHL) is the most common cause of hearing loss in the elderly. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme involved in several types of human disease. The present study aimed to investigate the effect of UCHL1 on a hydrogen peroxide (H2O2)-induced ARHL model in cochlear hair cells and uncover its underlying mechanism. Reverse transcription-quantitative (RT-q)PCR and western blot analysis were used to assess UCHL1 expression in HEI-OC1 cells exposed to H2O2. Following UCHL1 overexpression in H2O2-induced HEI-OC1 cells, cell activity was assessed by Cell Counting Kit-8 assay. The content of oxidative stress-associated markers including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and reactive oxygen species (ROS ) was measured using corresponding commercial kits. Cell apoptosis was evaluated by TUNEL assay and western blot analysis. Cell senescence was assessed by senescence-associated β-galactosidase staining and western blot analysis. RT-qPCR and western blot analysis were applied to measure mRNA and protein expression levels, respectively, of specificity protein 1 (Sp1) in H2O2-treated HEI-OC1 cells. In addition, the association between UCHL1 and Sp1 was verified by luciferase reporter and chromatin immunoprecipitation (ChIP) assay. The mRNA and protein expression levels of UCHL1 were also determined in Sp1-overexpressing cells by RT-qPCR and western blot analysis, respectively. Following Sp1 overexpression in UCHL1-overexpressing H2O2-treated HEI-OC1 cells, cell activity, oxidative stress, apoptosis and senescence were assessed. Finally, the expression levels of NF-κB signaling-related proteins p-NF-κB p65 and NF-κB p65 were detected using western blot analysis. The results showed that UCHL1 was downregulated in H2O2-treated HEI-OC1 cells. In addition, UCHL1 overexpression enhanced cell viability and promoted oxidative damage, apoptosis and senescence in H2O2-induced HEI-OC1 cells. Furthermore, Sp1 was upregulated in H2O2-treated HEI-OC1 cells. Additionally, luciferase reporter and ChIP assays demonstrated that Sp1 interacted with the UCHL1 promoter to inhibit UCHL1 transcription. Sp1 overexpression reversed the effect of UCHL1 overexpression on cell viability, oxidative stress, apoptosis, senescence and activation of the NF-κB signaling pathway in H2O2-exposed HEI-OC1 cells. Collectively, the results suggested that UCHL1 transcriptional suppression by Sp1 protected cochlear hair cells from H2O2-triggered senescence and oxidative damage.

Tousen, Y., Sasaki, N., Kaneda, Y., Shimomura, C., Nishiwaki, N., Oya, H., Fujita, M., Hayashi, M., Ogasawara, K., Fujioka, A., Kobori, T., Kobori, M., Takimoto, H.

Although many online-based dietary surveys have been developed in recent years, systems that easily survey the dietary balance based on the Japanese diet are insufficient. This study aimed to evaluate the relationship between dietary balance scores from an online survey system based on the Japanese Food Guide Spinning Top, and nutrient/food intake calculated using the weighing method from dietary records (DRs), as well as to assess the system’s utility and applicability. An online dietary balance survey and semi-weighted DR assessment with food photographs were conducted in Japanese participants (n = 34). Registered dietitians entered the balance scores into the system based on the participants’ food photographs, and the scores were calculated using the system. Significant positive correlations (p < 0.001) were found between the online dietary balance scores and nutrient/food intake from DRs; especially for ‘grain dishes’ and carbohydrates (r = 0.704); ‘vegetable dishes’ and the vegetable dish group (sum of potatoes, vegetables, mushrooms, and algae) (r = 0.774); ‘main dishes’ and protein (r = 0.661); ‘milk’ and the milk and milk products group (r = 0.744); and ‘fruits’ and the fruits group (r = 0.748). Bland–Altman analysis showed that the dietary balance scores obtained by this system tended to underestimate the intake compared with the weighing method. Although there are limitations to the accurate estimation of nutrient and food intake, the online dietary balance scores obtained from the online dietary balance survey system were useful for understanding the dietary balance in the Japanese diet.

Tousen, Y., Sasaki, N., Kaneda, Y., Shimomura, C., Nishiwaki, N., Oya, H., Fujita, M., Hayashi, M., Ogasawara, K., Fujioka, A., Kobori, T., Kobori, M., Takimoto, H.

Although many online-based dietary surveys have been developed in recent years, systems that easily survey the dietary balance based on the Japanese diet are insufficient. This study aimed to evaluate the relationship between dietary balance scores from an online survey system based on the Japanese Food Guide Spinning Top, and nutrient/food intake calculated using the weighing method from dietary records (DRs), as well as to assess the system’s utility and applicability. An online dietary balance survey and semi-weighted DR assessment with food photographs were conducted in Japanese participants (n = 34). Registered dietitians entered the balance scores into the system based on the participants’ food photographs, and the scores were calculated using the system. Significant positive correlations (p < 0.001) were found between the online dietary balance scores and nutrient/food intake from DRs; especially for ‘grain dishes’ and carbohydrates (r = 0.704); ‘vegetable dishes’ and the vegetable dish group (sum of potatoes, vegetables, mushrooms, and algae) (r = 0.774); ‘main dishes’ and protein (r = 0.661); ‘milk’ and the milk and milk products group (r = 0.744); and ‘fruits’ and the fruits group (r = 0.748). Bland–Altman analysis showed that the dietary balance scores obtained by this system tended to underestimate the intake compared with the weighing method. Although there are limitations to the accurate estimation of nutrient and food intake, the online dietary balance scores obtained from the online dietary balance survey system were useful for understanding the dietary balance in the Japanese diet.

Álvarez, P., Chatterjee, R., Wójcik, A.

Prostate cancer is among the most prevalent malignancies worldwide, and cardiovascular disease (CVD) is a major non‐cancer cause of death in affected patients. Androgen deprivation therapy (ADT), a mainstay treatment, has raised concerns about cardiotoxicity, yet the CVD risks of individual ADT agents remain unclear. To assess cardiovascular adverse events (AEs) associated with specific ADT drugs using data from the U.S. FDA Adverse Event Reporting System (FAERS).

Santos, L.

Beaumont, L., Khalil, F., Lemaire, Z.

Chronic kidney disease is a major health issue and is gaining prevalence. Using a Drosophila model for chronic kidney disease, we show that a high-fat diet (HFD) disrupts the slit diaphragm filtration structure in nephrocytes, the fly functional equivalent of mammalian podocytes. The structural disruption resulted in reduced filtration function in the affected nephrocytes. We demonstrate that HFD activates the JAK-STAT pathway in nephrocytes, which has previously been linked to diabetic kidney disease. JAK-STAT activation was initiated by increased expression and release of the adipokine, Upd2, from the fat body. This leptin-like hormone is a known ligand of JAK-STAT. Both genetic and pharmacological inhibition of JAK-STAT restored nephrocyte HFD-associated dysfunction. Altogether, our study reveals the importance of the JAK-STAT signaling pathway in the adipose tissue−nephrocyte axis and its contribution to HFD-associated nephropathy. These findings open new avenues for intervention in treating diabetic nephropathy and chronic kidney disease.

Dubois, O., Sharma, S., Dubois, M.

Renal cell carcinoma (RCC) is a highly vascularized and immunogenic malignancy with a complex tumor microenvironment (TME) that shapes disease progression and therapeutic resistance. Despite advances in immune checkpoint inhibitors (ICIs) and targeted therapies, clinical responses remain heterogeneous, underscoring the need for a deeper understanding of RCC immunobiology. This review comprehensively examines the immunosuppressive TME of RCC, emphasizing the roles of cytotoxic and immunosuppressive immune cells, carcinoma-associated fibroblasts (CAFs), abnormal vasculature, and extracellular matrix (ECM) remodeling in fostering immune evasion. This review summarized emerging biomarkers—including PD-L1 expression, tumor mutational burden (TMB), gene mutations, and immune-based subtypes—that may predict ICI response. Furthermore, we evaluate current immunotherapeutic strategies, such as ICIs, combination therapies, and novel approaches targeting immunosuppressive cells and metabolic pathways. While combination therapies have improved outcomes, challenges like toxicity and resistance persist, necessitating biomarker-driven patient stratification and optimized treatment sequencing. Future directions should focus on deciphering TME heterogeneity and developing precision immunotherapy strategies to enhance clinical efficacy in RCC.