Discovery medicine最新文献

In recent decades, technological advancements and scientific progress have significantly improved disease control strategies. However, the exclusive focus on these aspects often overlooks the crucial role of social and cultural factors. Local narratives, reflecting community traditions and beliefs, offer valuable insights that can influence the success of public health interventions. Case studies, such as fascioliasis control in Thailand and Schistosoma mekongi infection in Laos, demonstrate the importance of integrating local stories into health programs. These examples highlight the effectiveness of a holistic approach that considers biological, ecological, social, and cultural dynamics, aligned with the "One Health" framework. Incorporating local knowledge into disease control interventions is essential for sustainability and long-term success.

The introduction of immunomodulators as adjuvant therapies in cancer treatment has represented a significant advancement in oncology, improving therapeutic response and patient survival. Emerging targets and molecules could provide new therapeutic opportunities for cancer patients. However, these agents can induce immunological side effects, including vasculitis and connective tissue diseases, which, while uncommon, present significant clinical challenges. This review analyzes the prevalence, clinical characteristics, therapeutic strategies, and management difficulties of vasculitis and connective tissue disorders triggered by immunomodulators in the context of cancer treatment. Although rare, these conditions significantly impact patients, demanding thorough management. Common rheumatological immune-related adverse events include inflammatory arthritis, Sjogren's disease, systemic lupus erythematosus, and systemic sclerosis, all of which require prompt recognition and appropriate intervention. Treatment frequently includes corticosteroids and immunosuppressive drugs, with new alternatives currently accessible. Efficient coordination between oncologists and rheumatologists enhances patient outcomes, highlighting the necessity for organized multidisciplinary strategies. Future research initiatives emphasize the identification of biomarkers for early diagnosis and the development of preventive methods to reduce immune-related adverse events in cancer therapy.

Background: Nuclear receptor subfamily 4 group A member 3 (NR4A3) is lowly expressed in ectopic endometrium and can be degraded by ubiquitination in vascular endothelial cells. Murine double minute 2 (MDM2) is predicted to be the ubiquitin ligase of NR4A3. Hence, we investigated the effects of NR4A3 and MDM2 on endometriosis and clarified corresponding regulatory mechanisms.

Methods: The ubiquitin ligase of NR4A3 was predicted using bioinformatics and validated by immunoprecipitation. The effects of NR4A3 and MDM2 on the migration and proliferation of human endometrial stromal cells (hESCs) were examined by Transwell assay and 5-ethynyl-2'-deoxyuridine (EdU) staining. NR4A3 and MDM2 expressions were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. An endometriosis model was constructed in Sprague-Dawley rats, followed by body weight analysis, ultrasonic imaging of ectopic cysts, and Western blot.

Results: Overexpression of NR4A3 inhibited, but siNR4A3 boosted hESC migration and proliferation. MDM2 promoted NR4A3 ubiquitination and degradation. MDM2 overexpression enhanced hESC migration and proliferation and partially reversed the inhibitory effect of NR4A3 overexpression. Overexpression of NR4A3 reduced ectopic cysts in endometriotic rats, which was offset by MDM2 overexpression.

Conclusion: NR4A3, which is promoted to ubiquitination and degradation by MDM2, inhibits the proliferation and migration of hESCs in vitro, and reduces the growth of ectopic endometrial cysts in vivo, thereby inhibiting the progression of endometriosis.

Aldehyde dehydrogenases (ALDHs) constitute a group of enzymes that catalyze the oxidation of aldehydes to carboxylic acids. The human ALDH superfamily, including 19 different isoenzymes (ALDH1A1, ALDH1A2, ALDH1A3, AHDH1B1, ALDH1L1, ALDH1L2, ALDH2, ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2, ALDH4A1, ALDH5A1, ALDH6A1, ALDH7A1, ALDH8A1, ALDH9A1, ALDHA16A1, ALDH18A1), displays different key physiological and toxicological functions, with specific tissue expression and substrate specificity. Several studies have established that ALDH are interesting markers for the identification and quantification of human hematopoietic stem cells and cancer stem cells, notably leukemic stem cells. ALDH2 is the best-documented enzyme, in this family, as having an impact on hematology, particularly myeloid malignancies. ALDH2 mainly catalyzes the detoxification of toxic aldehydes (acetaldehyde, formaldehyde). For example, ALDH2 detoxifies formaldehyde, which is produced during the differentiation of hematopoietic progenitors. The trigger of alcohol dehydrogenase 5 (also known as formaldehyde dehydrogenase or S-nitrosoglutathione reductase, ADH5/FDH/GSNOR)/ALDH2 allows to eliminate formaldehyde and ensures normal hematopoiesis. Moreover, the ALDH2*2 variant allele is the most frequent ALDH2 variant, found in 35-45% of individuals of East Asian origin. It is associated with altered acetaldehyde metabolism and is involved in several hematological diseases (aplastic anemia, bone marrow failure, myelodysplastic syndrome). This review presents current knowledge of different members of the ALDH family and their involvement in normal and malignant hematopoiesis. Focus was brought to the ALDH2 isoenzyme in congenital (Fanconi anemia, Aplastic anemia, mental retardation, and dwarfism (AMeD) syndrome, and idiopathic aplastic anemia) and acquired (acute myeloid leukemia and myelodysplastic syndrome) hematological diseases. It also describes the possibilities of using ALDH as both a biomarker and therapeutic target, to identify and eradicate leukemic stem cells in malignant diseases.

Photodynamic therapy (PDT) is emerging as a promising treatment for many diseases. This non-invasive approach uses photosensitizing agents and light to selectively destroy abnormal cells, providing a valuable alternative to traditional treatments. Scientists are investigating the use of PDT in various areas of the head, and their work is focused on a growing number of new discoveries and methods for treating cancer. We have analyzed the use of photodynamic therapy in the treatment of head and neck cancer (HNC) and present the latest advances in this field, with particular emphasis on its effectiveness in improving the long-term quality of life of patients with HNC. The effectiveness of PDT in the treatment of cancer depends largely on the depth of the tumor location. PDT is particularly useful in the treatment of early diagnosed cancers and superficial tumors. Many head and neck tumors are ideal candidates for this therapy due to the possibility of precise assessment of the lesions and the provision of adequate irradiation in these locations. PDT is currently considered a revolutionary, modern form of cancer therapy. A significant advantage of PDT is that cells do not develop resistance to singlet oxygen, which makes this method extremely effective. Although this method is safe, the limited depth of light penetration limits its use in the treatment of advanced stages of cancer.

Background: The tumor suppressor wild-type p53 is known for its role in inducing apoptosis in tumor cells. This study investigated the relationship between wild-type p53 and protein phosphatase 1 (PP1) and caspase in promoting apoptosis of breast cancer cells.

Methods: Human breast cancer cell lines MCF-7 and MDA-MB-231 obtained from the American Type Culture Collection were used in this study. Small interference RNAs (Si-RNA) and plasmids were used to regulate wild-type p53 expression in these two tumor cell lines through liposome-mediated transfection. GSK-2830371 (PP1 inhibitor) and zVAD (Caspase inhibitor) were employed to further verify the PP1 activating function of wild-type p53 in Caspase-dependent MCF-7 and MDA-MB-231 apoptosis. PP1 activity was quantitatively detected by phosphorus colorimetric assay. Co-immunoprecipitation (Co-IP), flow cytometry assay, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, Western blot, the real-time reverse transcriptase-polymerase chain reaction (RT-qPCR), and immunofluorescence staining were used to analyze cell apoptosis degree and marker protein expression.

Results: The expression level of PP1 in the breast cancer cells was successfully regulated by cell transfection. The phosphatase activity was increased, and obvious apoptotic cytological characteristics were observed in p53-overexpressed breast cancer cells. p53 knockdown/overexpression increased/decreased the level of B cell lymphoma 2 (Bcl-2), and decreased/increased levels of Caspase-3, cleaved Caspase-3, cleaved Caspase-8, Cytochrome C (Cyt-C), Truncated BID (tBid), Bcl-2-associated X (Bax), and cell apoptosis (p < 0.01). The promotion of proteins and apoptosis induced by p53 overexpression was reversed by GSK-2830371 or zVAD.

Conclusion: Wild-type p53 might promote Caspase-dependent apoptosis of human breast cancer cells through PP1 activation.

Background: Detecting and treating stomach cancer requires a comprehensive understanding of how gastric cancer develops and progresses. In this context, efforts have been made to elucidate the regulation of glutamine-fructose-6-phosphate transaminase 1 (GFPT1) and Lysine demethylase 4C (KDM4C) in gastric cancer.

Methods: Bioinformatics was utilized to predict the levels and correlation of GFPT1 and KDM4C in gastric cancer, followed by determining their expressions via quantitative real-time polymerase chain reaction (qRT-PCR). The viability (assessed through Cell Counting Kit-8 (CCK-8) assay), proliferation (via colony-forming assay), migration, and invasion (utilizing transwell assay), as well as vasculogenic mimicry (examined through Tube formation assay), in gastric cancer cells, were quantified. Additionally, quantification of GFPT1 and proliferation/epithelial-mesenchymal transition (EMT)-related proteins was conducted through Western blot analysis.

Results: In gastric cancer cells, GFPT1 was found to be abundantly expressed. Overexpression of GFPT1 resulted in increased viability, proliferation, migration, invasion, vasculogenic mimicry, and EMT of gastric cancer cells, while knockdown of GFPT1 had the opposite effects. Moreover, there was a positive correlation between KDM4C and GFPT1 in gastric cancer. Overexpression of KDM4C led to increased expression of GFPT1 and enhanced the aforementioned effects of GFPT1 overexpression, whereas knockdown of KDM4C produced inverse effects. Interestingly, the effects of KDM4C overexpression combined with GFPT1 knockdown, or GFPT1 overexpression combined with KDM4C knockdown, could mutually reverse their effects on the aforementioned cell phenotypes.

Conclusion: KDM4C positively regulates GFPT1, thereby promoting gastric cancer progression. This discovery provides a new avenue for slowing down the progression of gastric cancer.

Background: The erythrocyte sedimentation rate (ESR) is a widely used haematological test that indirectly measures inflammation in the body. It is influenced by various factors, including age, sex, and physiological condition. Altitude is another critical factor due to its impact on red blood cell physiology and plasma protein composition. This study aims to evaluate how altitude influences ESR values in the Saudi Arabian population, considering demographic and clinical variables.

Methods: This cross-sectional study analyzed data from 158,539 participants collected from 42 commercial laboratory branches across 13 administrative regions in Saudi Arabia from 1 January 2015 to 31 December 2022. Participants were categorized based on city altitude and demographic characteristics including body mass index (BMI), alanine transaminase (ALT), chronic kidney disease (CKD), glycated haemoglobin (HbA1c), and thyroid-stimulating hormone (TSH) level. Univariate and multivariate logistic regression models were used to assess the factors influencing elevated ESR.

Results: The study analyzed 158,539 participants, with an equal sex distribution (49.9%) and a mean age of 40 years. The adjusted model results showed a CKD prevalence of 3%, with a higher prevalence at lower altitudes (3.8% at 0-500 meters). ESR levels were significantly influenced by sex, age, altitude, and clinical measurements. Males were less likely to have elevated ESR than females (odds ratio (OR) = 0.470, 95% confidence interval (CI): 0.440-0.510, p < 0.001). Older age was a strong predictor of elevated ESR, with those aged 90+ at a fourfold higher risk (OR = 4.540, 95% CI: 1.410-14.548, p = 0.011). Higher altitude was associated with reduced ESR, with an odds ratio of 0.660 (95% CI: 0.560-0.769, p < 0.001) above 2000 meters.

Conclusion: Altitude significantly impacts ESR values, highlighting the need for altitude-specific reference ranges to improve diagnostic accuracy in high-altitude regions. The results also emphasize the importance of considering demographic and clinical factors when interpreting ESR. These findings can guide clinicians in refining diagnostic algorithms and optimizing patient management strategies in diverse geographical settings.

Background: Atherosclerosis, a chronic inflammatory condition characterized by the accumulation of lipid and fibrous elements in the arterial wall, is a major contributor to cardiovascular disease. This study aimed to investigate the regulation of apoptosis and cellular aging in human umbilical vein endothelial cells by Thousand and One Amino Acid Kinase 1 (TAOK1) via Cell division cycle 20 (CDC20) in the context of atherosclerosis.

Methods: The study evaluated the impact of TAOK1 on Oxidized low-density lipoprotein (ox-LDL)-induced changes in cell viability, angiogenesis, cell senescence, apoptosis, cell cycle arrest, and related signaling pathways in human umbilical vein endothelial cells (HUVECs) using Cell Counting Kit-8, β-galactosidase staining, flow cytometry, and western blot. The role of CDC20 as a potential downstream target of TAOK1 was further investigated using specific small interfering (si) RNAs.

Results: Overexpression of TAOK1 partially reversed the ox-LDL-mediated reduction in cell viability and counteracted the increase in pro-inflammatory cytokines and chemokines in HUVECs, with significant differences observed (p < 0.05). Ox-LDL-induced decrease in angiogenesis and increase in cell senescence, apoptosis were observed, and cell cycle arrest was alleviated by TAOK1, with all changes being statistically significant (p < 0.05). In addition, TAOK1 transfection partially neutralized ox-LDL-induced changes in key downstream pathway proteins, including CDC20, phosphorylated p65 (p-p65), β-catenin, and glycogen synthase kinase 3 beta (GSK-3β). Co-immunoprecipitation (Co-IP) confirmed the regulatory interaction between TAOK1 and CDC20. The inhibitory effects of TAOK1 on ox-LDL-induced cellular changes were significantly reversed by CDC20 siRNA (p < 0.05), highlighting the role of CDC20 in the protective mechanisms mediated by TAOK1.

Conclusions: TAOK1 plays a pivotal role in protecting endothelial cells from ox-LDL-induced cellular stress in the atherosclerotic environment, primarily by modulating pro-inflammatory responses, angiogenesis, cell senescence, and apoptosis. This study provides important insights into the protective mechanisms of TAOK1 and its interplay with downstream signaling molecules, particularly CDC20, in the vascular endothelium under atherosclerotic conditions.