Current Issues in Molecular Biology最新文献

Cancer remains one of the most formidable diseases globally and continues to be a leading cause of mortality. While chemotherapeutic agents are crucial in cancer treatment, they often come with severe side effects. Furthermore, the development of acquired drug resistance poses a significant challenge in the ongoing battle against cancer. Combining these chemotherapeutic agents with plant-derived phenolic compounds offers a promising approach, potentially reducing side effects and counteracting drug resistance. Phytochemicals, the bioactive compounds found in plants, exhibit a range of health-promoting properties, including anticarcinogenic, antimutagenic, antiproliferative, antioxidant, antimicrobial, neuroprotective, and cardioprotective effects. Their ability to enhance treatment, coupled with their non-toxic, multi-targeted nature and synergistic potential when used alongside conventional drugs, underscores the growing importance of natural therapeutics. In this study, we investigated the anticancer effects of olaparib (OL), a small-molecule PARP inhibitor that has shown promising results in both preclinical and clinical trials, and gallic acid (GA), a phenolic compound, in olaparib-resistant human osteosarcoma U2OS cells (U2OS-PIR). Both parental U2OS and U2OS-PIR cell lines were treated with increasing concentrations of olaparib and gallic acid, and their cytotoxic effects were assessed using the WST-1 cell viability assay. The synergistic potential of OL and GA, based on their determined IC₅₀ values, was further explored in combination treatment. A colony survival assay revealed the combination's ability to significantly reduce the colony-forming capacity of cancer cells. Additionally, the apoptotic effects of OL and GA, both individually and in combination, were examined in U2OS-PIR cells using acridine orange/ethidium bromide dual staining. The anti-angiogenic properties were assessed through a VEGF ELISA, while the expression of proteins involved in DNA damage and apoptotic signaling pathways was analyzed via Western blot. The results of this study demonstrate that gallic acid effectively suppresses cell viability and colony formation, particularly when used in combination therapy to combat OL resistance. Additionally, GA inhibits angiogenesis and induces DNA damage and apoptosis by modulating key apoptosis-related proteins, including cPARP, Bcl-2, and Bax. These findings highlight gallic acid as a potential compound for enhancing therapeutic efficacy in overcoming acquired drug resistance.

(1) Background: In recent years, there has been a growing interest in understanding the innate immunity of the mouth, particularly the mechanisms through which vitamin D influences oral health. Researchers have increasingly focused on the association between vitamin D and the antimicrobial peptide LL-37 since the CAMP gene, responsible for encoding the LL-37 peptide, is a direct target of both vitamin D and its receptor (vitamin D receptor, VDR). This study aimed to explore the correlation between the 25-hydroxyvitamin D (25(OH)D) levels and the concentration of the LL-37 peptide in both serum and saliva. The objective was to compare the serum concentrations of 25(OH)D and ll-37 with those in saliva and to access the correlations between the two compounds. (2) Methods: Serum and whole saliva samples were collected from 72 healthy adults (mean age 28.68 ± 8.35). The levels of 25(OH)D and LL-37 were assessed in both the saliva and serum samples using commercially available enzyme-linked immunosorbent assay (ELISA) kits. (3) Results: The 25(OH)D levels in the serum (median 5.92 ng/mL, min-max 2.7-10.4 ng/mL) correlated with the LL-37 serum levels (62 ng/mL, min-max 18-378 ng/mL; Pearson's r 0.328, p = 0.005). Additionally, the 25(OH)D levels in saliva (median 1.16 ng/mL, min-max 0.54-2.12 ng/mL) strongly correlated with the LL-37 salivary levels (median 44 ng/mL, min-max 6.5-205 ng/mL; Pearson's r 0.667, p < 0.001). The 25(OH)D salivary levels demonstrated a robust correlation with the LL-37 salivary levels. (4) Conclusions: This discovery emphasizes the complex interplay between vitamin D and LL-37 and lay the groundwork for the further exploration of vitamin D's role in oral immune function.

Zinc plays a crucial role in spermatogenesis, sperm function, and fertilisation. Zinc homeostasis is regulated by ZIP and ZnT transporter proteins, which mediate Zn²⁺ influx and efflux across sperm cell membranes. This study analysed total Zn concentration in seminal plasma and serum of 10 normozoospermic and 32 teratozoospermic men involved in the process of infertility treatment, using inductively coupled plasma mass spectrometry. In addition, the expression of Zn transporters ZIP6 and ZIP14 in the sperm of two normozoospermic and two teratozoospermic men was analysed using immunofluorescence. Applying Student's t test and the Mann-Whitney U test, we found no significant differences in Zn concentrations in seminal plasma and serum between groups. ZIP6 was mainly localised in the sperm head, with slightly higher immunopositivity in normozoospermic than teratozoospermic samples, but there was no statistically significant difference between the groups. ZIP14 was mainly found in the sperm head, and some teratozoospermic samples showed immunopositivity in the tail, although there were no significant differences in ZIP14 immunopositivity between normozoospermic and teratozoospermic samples. The results suggest that Zn concentrations in seminal plasma and serum, and the expression of ZIP6 and ZIP14, do not differ in normo- and teratozospermic samples, and emphasise the complex interplay of factors underlying male fertility.

Artemisia argyi H. Lév. & Vaniot (A. argyi) is a perennial herb belonging to the Asteraceae family and is a medicinal plant widely used in traditional medicine. In the field of plant physiology, JAZ proteins play a central role in the jasmonic acid (JA) signaling pathway, significantly affecting plant growth and development as well as responses to biotic and abiotic stresses. This study aims to identify and analyze the JAZ gene family of A. argyi. Through a genome-wide analysis of A. argyi. 18 JAZ genes were identified and classified into three subfamilies, based on phylogenetic relationships. Additionally, for this study, we comprehensively analyzed the physical and chemical properties, gene structure, chromosomal locations, conserved domains, cis-acting elements, and evolutionary relationships of these genes. The tissue-specific expression patterns of JAZ genes were obtained from transcriptome data, revealing distinct expression profiles across different tissues in A. argyi. Finally, this research identified a candidate JAZ gene, AarJAZ18, which is involved in the development of glandular trichomes in the leaves of A. argyi. Subsequently, the relative expression levels of AarJAZ18 in different tissues were validated using quantitative real-time PCR (qRT-PCR). In summary, this study provides a foundation for further investigation into the functions of A. argyi JAZ genes and offers valuable gene resources for breeding superior varieties and enhancing germplasm innovation.

Pseudomonas syringae pv. actinidiae (Psa) is responsible for causing kiwifruit canker disease. The detection of Psa is commonly carried out using normal PCR and culture-based isolation. However, normal PCR does not differentiate between live and dead cells, potentially resulting in the incorrect estimation of the amount of infectious substance in a sample. Such an incorrect estimation could result in unnecessary phytosanitary strategies and control measures. This study attempts to establish a specific assay for detecting only live Psa bacterial cells. To achieve this, a pair of strain-specific primers designed from HopZ3 effector were used, and the traditional PCR method was assessed using a nucleic acid-binding dye (propidium monoazide-PMA), establishing a PMA-PCR system and conditions for detecting live Psa in this study. Sensitivity tests showed a detection limit of 10 cfu/mL and 1 pg/μL. This method was also tested in diseased kiwifruit tissues and can be seen as a rapid and dependable replacement to PCR methods for detecting only those infective kiwifruit materials with viable Psa.

Per- and polyfluoroalkyl substances (PFASs) are persistent and highly bioaccumulative emerging environmental contaminants of concern that display significant toxic and carcinogenic effects. An emerging PFAS is PFESA-BP2, a polyfluoroalkyl ether sulfonic acid found in drinking water and the serum of humans and animals. While PFESA-BP2-induced liver and intestinal toxicity has been demonstrated, the toxicological mechanisms and carcinogenic potential of PFESA-BP2 have remained relatively understudied. Here, we studied how different doses of PFESA-BP2 affect gene activity related to liver toxicity and the risk of liver cancer such as hepatocellular carcinoma (HCC) in mice exposed to PFESA-BP2 once daily through oral gavage for seven days. An analysis of key hepatic pathways suggested increased risk of hepatotoxicity as a result of PFESA-BP2 exposure. Increased oxidative stress response was associated with all concentrations of exposure. Liver toxicity pathways, including PXR/RXR activation and hepatic fibrosis, showed dose-dependent alteration with activation primarily at low doses, suggesting an increased risk of hepatic inflammation and injury. Additionally, an analysis of carcinogenic and HCC-specific pathways suggested PFESA-BP2-induced risk of liver cancer, particularly at low doses. Low-dose PFESA-BP2 exposure (0.03 and 0.3 mg/kg-day) was associated with an increased risk of HCC carcinogenesis, as indicated by the activation of tumor-related and HCC-associated pathways. In contrast, these pathways were inhibited at high doses (3.0 and 6.0 mg/kg-day), accompanied by the activation of HCC-suppressive pathways. The increased risk of HCC development at low doses was mechanistically linked to the activation of signaling pathways such as HIF, EGF, NOTCH4, HGF, and VEGF. Biomarkers linked to liver cancer risk, prognoses, and diagnoses were also identified as a result of exposure. Overall, our findings on liver carcinogenic and hepatotoxic pathway activation patterns suggest that PFESA-BP2 increases the risk of liver toxicity and HCC development, particularly at low doses.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) remains a global health crisis, with over 10 million people affected annually. Despite advancements in treatment, M.tb has developed mechanisms to evade host immune responses, complicating efforts to eradicate the disease. Two emerging cell death pathways, ferroptosis and cuproptosis, have been linked to TB pathogenesis. Ferroptosis, an iron-dependent form of cell death, is driven by lipid peroxidation and reactive oxygen species (ROS) accumulation. This process can limit M.tb replication by depleting intracellular iron and inducing macrophage necrosis. However, excessive ferroptosis may lead to tissue damage and aid bacterial dissemination. Cuproptosis, triggered by copper accumulation, disrupts mitochondrial metabolism, leading to protein aggregation and cell death. M.tb exploits both iron and copper metabolism to survive within macrophages, manipulating these processes to resist oxidative stress and immune responses. This review examines the roles of ferroptosis and cuproptosis in TB, discussing how M.tb manipulates these pathways for survival. While therapeutic strategies targeting these processes, such as ferroptosis inducers (Erastin, RSL3) and inhibitors (Ferrostatin-1) and copper ionophores (Disulfiram, Elesclomol) and chelators, show promise, the limited understanding of these pathways and potential off-target effects remains a significant challenge. Further exploration of these pathways may provide insights into the development of targeted therapies aimed at controlling M.tb infection while minimizing host tissue damage. By elucidating the complex interactions between ferroptosis, cuproptosis, and TB, future therapies could better address bacterial resistance and improve clinical outcomes.

Background: Meroterpenoids represent a remarkably diverse class of natural secondary metabolites, some of which are synthesized via terpenoid biosynthetic pathways. Over the past ten years, these compounds have gained interest because of their wide range of biological activities, such as anti-cholinesterase, COX-2 inhibitory, antibacterial, antiviral, antidiabetic, antioxidant, anti-inflammatory, antineoplastic, and cardioprotective properties. This review aims to consolidate the recognized neuroprotective effects of meroterpenoids from marine and terrestrial fungi.

Methods: Data compiled from several databases, including PubMed, Science Direct, Scopus, and Google Scholar, include articles published since 2000 using keywords such as "neuroprotective", "fungi", "mushroom", "marine sponge", "neurodegeneration", and "dementia" in connection with "meroterpenoids".

Results: Meroterpenoids modulate different cell signaling pathways and exhibit different and often combined mechanisms of action to ameliorate neuronal damage and dysfunction. Reported activities include anti-cholinesterase, antioxidant, BACE1 inhibition, and anti-inflammatory activities, all of which have potential in the treatment of dementia associated with neurodegenerative diseases such as Alzheimer's and Parkinson's.

Conclusions: Meroterpenoids have the potential to be developed as effective tools for neuropathological diseases. Ongoing research to elucidate the various neuroprotective pathways remains essential and requires further investigation.

Immune enhancement is an important factor that not only helps prevent infections but also affects overall health. This study aims to evaluate the immunostimulatory effects of a novel Lactobacillus strain, Lactobacillus paracasei L-30, and to elucidate its underlying mechanisms. The extract obtained from Lactobacillus paracasei L-30 significantly increased phagocytosis and the production of NO and ROS in RAW264.7 macrophages. The protein and mRNA expression levels of COX-2 and iNOS which are immune regulators were upregulated by the L-30 extract. The levels of cytokines and chemokines, such as G-CSF, IL-6, MIP-1α, MIP-1γ, RANTES, sTNF RI, and sTNF RII, were increased by the treatment with the L-30 extract. In addition, the L-30 extract degraded IκB-α and induced the phosphorylation of NF-κB. Furthermore, the MAPK signaling pathways ERK, JNK, and p38 were activated by the L-30 extract. The production of iNOS, COX-2, and NO was inhibited by MAPK pathway inhibitors. Therefore, our data suggest that the Lactobacillus paracasei L-30 extract has the potential to be developed as a healthy functional food that can enhance immune responses by activating macrophages.

(1) Malignant melanoma is the most aggressive type of malignant tumor caused by a dysfunction of melanocytes. Despite progress in the treatment of melanoma, further research and search for new potential drugs are necessary to optimize the therapy. (2) The aim of this study was to evaluate the antiproliferative activity of eight selected monoterpenes by MTT and LDH assays on four malignant melanoma cell lines. (3) Myrcene, rhodinol and nerol did not show any significant anticancer effect on melanoma cell lines, but citral, carvacrol, citronellol, thymol and geraniol showed a significant anti-viability effect. Our studies have shown that the most effective terpene among those tested in inhibiting melanoma cell viability was carvacrol, with the lowest IC50 in the range of 0.05 ± 0.00 to 0.06 ± 0.01 mM. Moreover, it did not negatively affect normal human keratinocyte cells. (4) Metastatic melanoma is very difficult to treat, and some terpenes have the ability to sensitize cells to other chemicals; so, it is worth investigating their antimelanoma potential, as terpenes could become an adjuvant to traditional treatment.