Tzu Chi Medical Journal最新文献

Objectives: The objective of this study was to investigate the role of type I insulin-like growth factor receptor (IGF-1R) in pemetrexed-resistant lung cancer cells and its interaction with B lymphoma Mo-MLV insertion region 1 homolog (BMI1), previously identified as a key resistance gene.

Materials and methods: The study started with the analysis of the activation of IGF-1R in pemetrexed-resistant A549 (A400) lung cancer cells by Western blot analysis of its form of phosphorylation. Cancer stem cell (CSC) activity was assessed by tumor sphere culture. IGF-1R inhibition was performed by picropodophyllin (PPP), an IGF-1R inhibitor, or by shRNA-mediated RNA silencing. A Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse xenograft model was used to access in vivo pemetrexed sensitivity. To further understand the relationship between IGF-1R and BMI1, both BMI1 knockdown and overexpression experiments were performed to assess IGF-1R phosphorylation by western blot.

Results: Increased IGF-1R phosphorylation was found in A400 cells, and subsequent IGF-1R inhibition resulted in a reduction in CSC activity in these resistant cells. In the in vivo studies, PPP treatment effectively suppressed tumor growth and reduced BMI1 expression in A400 tumor tissue. Further investigation showed that BMI1 knockdown in A400 cells resulted in decreased IGF-1R phosphorylation, whereas BMI1 overexpression in A549 cells resulted in increased IGF-1R phosphorylation, indicating an interaction between these two proteins.

Conclusion: A novel reciprocal regulatory relationship between IGF-1R and BMI1 has been identified in lung cancer cells, suggesting potential therapeutic strategies to combat pemetrexed resistance in lung cancer patients.

Urinary tract infection (UTI) of the urinary bladder is a common bacterial infection that predominantly affects women, with many experiencing recurrent episodes. Recurrent UTIs (rUTIs) are associated with significant physical, psychological, and social difficulties. Further, they are closely related to lower urinary tract dysfunction (LUTD). LUTD affects bladder function and structure, thereby contributing to urinary urgency, frequency, and incontinence, which, in turn, increases the risk of recurrent infections due to impaired urothelial defense mechanisms. The current study explored the pathophysiology of LUTD in women with rUTIs. Potential treatments for rUTIs include long-term prophylactic antibiotics, probiotics, D-mannose, vaccines, small molecule inhibitors, and stem cell therapy. Moreover, it evaluated the use of platelet-rich plasma (PRP) therapy as a treatment modality for LUTD. PRP has regenerative and anti-inflammatory properties. Hence, it can be a promising option for enhancing urothelial barrier integrity and reducing infection recurrence. Repeated intravesical PRP injections are effective in improving bladder symptoms and decreasing UTI recurrences by enhancing the proliferative ability of the urothelium in patients with rUTIs. Further, this review examined the potential predictors of successful PRP treatment outcomes such as cytokine and urothelial biomarker levels, which provided insights into patient selection and individualized treatment strategies. Identifying the predictive biomarkers of treatment responsiveness is essential for optimizing PRP therapy. Hence, to improve the clinical outcomes and quality of life of patients with rUTIs, future research should focus on refining the use of PRP, exploring combination therapies, and validating biomarkers.

Objectives: We aimed to identify the early-onset Alzheimer's disease (EOAD)-causing variants in the Eastern Taiwanese population.

Materials and methods: Twenty-one patients diagnosed with EOAD in the memory clinic at Hualien Tzu Chi Hospital were enrolled during 2014-2018. We conducted whole-exome sequencing to identify the disease-causing variations and validated by Sanger sequencing. SIFT, PolyPhen-2, and AlphaFold were applied to predict the functional impact of the identified variants.

Results: Two unrelated normolipidemic EOAD patients were carrying a rare heterozygous APOE variant (rs373985746, NC_000019.10:g. 44905879G>A, NM_001302688.2:c. 11G>A, and NP_001289617.1:p.Gly4Glu) with the allele frequency as 0.000206. Sanger sequencing uncovered the ∑ haplotypes in which the c.11G>A variation resided. SIFT predicted that the variant severely impacts protein structure and, maybe thus, function. AlphaFold predicted a dysfunctional conformation of the mutant APOE precursor a protein (p.Gly4Glu).

Conclusion: Our data strongly suggest that the rare p.Gly4Glu variant is associated with EOAD but does not cause dyslipidemia.

Objectives: 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is a rate-limiting enzyme involved in cholesterol synthesis. The common HMGCR variants are associated with low-density lipoprotein cholesterol (LDL-C) levels. We aimed to identify novel HMGCR variants influencing the lipid profiles of Taiwanese and assess the causal links between LDL-C levels and diabetic risk based on HMGCR genotypes.

Materials and methods: Genome-wide genotyping of 108,880 participants from Taiwan Biobank was used for the association studies and Mendelian randomization (MR) analysis.

Results: Regional association and stepwise linear regression analyses showed HMGCR rs3064191, rs150454634, and rs13354746 variants were independently associated with total cholesterol (TC), LDL-C, and non-high-density lipoprotein cholesterol (non-HDL-C) levels with the former two variants in strong linkage disequilibrium with HMGCR rs3846662, a variant influencing exonal alternative splicing, and HMGCR rs191835914 (p.Y311S), an Asian-specific nonsynonymous mutation, respectively. Multivariate MR analyses showed significant associations between weighted genetic risk scores using LDL-C-determining HMGCR variants and using genome-wide association study identifying LDL-C-determining 47 variants and the prevalence of diabetes mellitus (DM) (P = 0.0011 and P = 1.66 × 10^-8, respectively).

Conclusion: The HMGCR variants exhibited significant associations with TC, LDL-C, and non-HDL-C levels as well as causally with DM risk in our Taiwanese population. HMGCR genotypes may play an important role and serve as a reference for the prevention and treatment of cardiovascular diseases in the clinical settings.

Concussion, one of the most common types of mild traumatic brain injury, remains a global problem that poses substantial effects on individuals, families, and society. When dealing with concussion, clinicians primarily focus on symptomatic treatment and modified activity with no established therapies specifically addressing the underlying pathophysiological changes. In recent years, there has been a growing increase in attention to the effectiveness of dietary supplements (DS) and nutritional interventions as adjunctive therapy options for concussion. Hence, this review aims to comprehensively explore the existing human studies on using DS as adjunctive therapy in the management of concussion. This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The search strategy was created based on the population, intervention, comparison, outcome framework. The findings are conveyed narratively and analyzed according to the timing of the intervention. DS administered within 7 days of onset were classified as acute interventions, while those given after this period were classified as nonacute interventions. After screening, we identified 21 reports for 19 studies involving 13 DS. Thirteen DS were included in this review. Notably, omega-3 polyunsaturated fatty acids were the most extensively studied and accounted for 23.81% of studies, followed by melatonin and pine bark extract (19.05% and 9.5%). At least 13 supplements were identified in clinical studies, with 77% demonstrating favorable outcomes. However, none of the interventions reviewed offer strong enough evidence to justify regular use in clinical practice.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have convincingly demonstrated efficacy in reducing cardiovascular (CV) and renal complications in patients with diabetes mellitus, chronic kidney disease, and heart failure. However, their use is also linked to the concern of some adverse events, the most common being genital and urinary tract infections (UTIs). This review summarizes the risks of genital and UTIs of SGLT2 inhibitors across large-scale clinical trials, meta-analyses, and real-world cohort studies. SGLT2 inhibitors are shown to significantly increase the risk of genital infections in clinical trials and real-world observational studies and marginally increase the risk of UTI in meta-analyses. We also discuss the potential pathogenesis of SGLT2 inhibitor-related infections and identify the susceptible risk factors. Since most genital and UTIs associated with SGLT2 inhibitors are mild and treatable and severe infections are rare, the use of SGLT2 inhibitors is highly recommended in patients who meet the inclusion criteria of clinical trials, where the CV and renal benefits outweigh the infection risks. For all users of SGLT2 inhibitors, preventive strategies, patient education, and careful monitoring are essential to minimize the infection risks. Furthermore, we address an unmet need regarding SGLT2 inhibitors among vulnerable populations, such as older adults, frail, and immunocompromised patients, underscoring the importance of observational studies from the real-world data. Future research should focus on identifying the high-risk groups, developing SGLT2 inhibitors with a lower infection profile and establishing effective prevention strategies to mitigate the risk of genital and UTIs associated with these medications.

Objectives: The recent global coronavirus disease 2019 (COVID-19) pandemic, resulting from infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), can cause severe and fatal pneumonia along with other life-threatening complications.

Materials and methods: The rare and limited accessibility of approved therapeutic agents or vaccines is of great distress. Swiftly working on designing and identifying inhibitors against all possible viral key protein targets, seven key SARS-CoV-2 viral enzymes were selected as targets, particularly in the action on the virus-entry, viral replication, and immune evasion of COVID-19. Papain-like protease, main protease, RNA-dependent RNA polymerase, endoribonuclease (nsp15), receptor-binding domain-angiotensin-converting enzyme 2, transmembrane serine protease 2 (TMPRSS2), and 2'- O-ribose methyltransferase (2'MTase), which were subjected to an unbiased in silico screening against 22 small molecules originating from Garcinia linii concomitantly with Remdesivir, Nirmatrelvir, and Molnupiravir were approved by Food and Drug Administration as repurposing drugs against SARS-CoV-2 invasion.

Results: The in silico results showed that natural bioactive compounds containing α-Tocopheryolquinone, 6β-Hydroxystigmast-4-en-3-one, Squalene, Rutin and Quercetin have a high binding affinity with seven selected viral protein targets concurrently with the preference of absorption, distribution, metabolism, excretion, and toxicity and drug-likeness.

Conclusion: This study provides potential phytoactive compounds from G. linii through multi-target screen with molecular dynamic simulation for combating COVID-19 pandemics that need further experimental validation to confirm the prospective efficacy.

Objectives: We retrospectively investigated whether the habit of posttoilet rinsing as a hygiene method is a predisposing factor for prolonged pyuria and extended antibiotic use in females with uncomplicated acute cystitis as well as analyzed the clinical characteristics.

Materials and methods: Adult female patients with urinary tract infections (UTIs) were retrospectively reviewed between October 2021 and September 2022 at a regional hospital in Taiwan. Patients with uncomplicated acute cystitis were included. Exclusion criteria included patients younger than 18 years of age, those with vaginal discharge or irritation, fever, functional or anatomical abnormalities of the genitourinary tract, an indwelling urinary catheter, hormone replacement therapy, pregnancy, or other complicated UTIs. The collected information included age, self-reported comorbidities, habits of posttoilet rinsing as a hygiene method, antibiotic use, urine analysis, and pathogens obtained in urine cultures.

Results: In total, 823 women with UTI were identified. Of these, 133 were diagnosed with uncomplicated acute cystitis. Further, 35 patients had the habit of posttoilet rinsing (habit group; mean age, 60.54 ± 15.97 years). The control group included 98 patients without this habit (mean age, 53.26 ± 17.18 years) (P = 0.03). The percentage of cases wherein cystitis resolved within 1 week was significantly higher in the control group (61.86%) compared to that in the habit group (25.71%, P = 0.0002). The urine culture positivity rate between the control and habit groups was not significantly different (57.14% vs. 40.0%, P = 0.0812). The posttoilet rinsing habit was the only predictor of prolonged cystitis and antibiotic use in both univariable and multivariable analyses.

Conclusion: These results suggest that the habit of posttoilet rinsing may prolong the duration of uncomplicated acute cystitis.

Endothelial cells regulate vascular tone, blood flow, coagulation, and inflammation, with heterogeneous populations serving specific roles throughout the body. In the kidney, endothelial cells maintain vascular integrity and function, contribute to filtration, and support other renal structures. Nitric oxide (NO) is a key signaling molecule that maintains vascular tone and endothelial function. It is synthesized by nitric oxide synthase (NOS) isoforms, with endothelial NOS playing a central role in vascular health. Chronic kidney disease (CKD) is characterized by reduced NO bioavailability, driven by the accumulation of endogenous NOS inhibitors such as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Uremic toxins, oxidative stress, and proinflammatory cytokines contribute to a prothrombotic and proinflammatory state, contributing to endothelial dysfunction and exacerbating cardiovascular (CV) risks in CKD. Biomarkers such as ADMA, SDMA, endothelial microparticles, and soluble adhesion molecules offer insights into vascular health, while invasive or noninvasive diagnostic techniques can assess endothelial function in CKD. Effective management strategies focus on enhancing NO bioavailability, controlling oxidative stress, reducing inflammation, and optimizing dialysis to minimize uremic toxin levels. Emerging therapeutic approaches, including antioxidant therapies and endothelial progenitor cell-based interventions, show promise in preserving vascular function. A multifaceted approach to managing endothelial dysfunction is critical for mitigating CV complications and improving patient outcomes in CKD.