Current Issues in Molecular Biology最新文献

Angiogenesis plays a pivotal role in the growth, survival, and metastasis of solid tumors, with Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) being overexpressed in many human solid tumors, making it an appealing target for anti-cancer therapies. This study aimed to identify potential lead compounds with azole moiety exhibiting VEGFR-2 inhibitory effects. A ligand-based pharmacophore model was constructed using the X-ray crystallographic structure of VEGFR-2 complexed with tivozanib (PDB ID: 4ASE) to screen the ZINC15 database. Following virtual screening, six compounds demonstrated promising docking scores and drug-likeness comparable to tivozanib. These hits underwent detailed pharmacokinetic analysis to assess their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Furthermore, Density Functional Theory (DFT) analysis was employed to investigate the molecular orbital properties of the top hits from molecular docking. Molecular dynamics (MD) simulations were conducted to evaluate the conformational stability of the complexes over a 100 ns run. Results indicated that the compounds (ZINC8914312, ZINC8739578, ZINC8927502, and ZINC17138581) exhibited the most promising lead requirements for inhibiting VEGFR-2 and suppressing angiogenesis in cancer therapy. This integrated approach, combining pharmacophore modeling, molecular docking, ADMET studies, DFT analysis, and MD simulations, provides valuable insights into the identification of potential anti-cancer agents targeting VEGFR-2.

Platycladus orientalis is a traditional oriental herbal medicinal plant that is widely used as a component of complex prescriptions for alopecia treatment in Eastern Asia. The effect of PO on hair growth and its underlying mechanism, however, have not been demonstrated or clarified. In this study, we investigated the hair-growth-promoting effect of PO in cultured human dermal papilla cells (hDPCs). Platycladus orientalis leaf extract (POLE) was found to stimulate the proliferation of hDPCs. POLE with higher quercitrin concentration, especially, showed a high level of cellular viability. In the context of cellular senescence, POLE decreased the expression of p16 (CDKN2A) and p21(CDKN1A), which resulted in enhanced proliferation. In addition, growth factor receptors, FGFR1 and VEGFR2/3, and non-receptor tyrosine kinases, ACK1 and HCK, were significantly activated. In addition, LEF1, a transcription factor of Wnt/β-catenin signaling, was enhanced, but DKK1, an inhibitor of Wnt/β-catenin signaling, was downregulated by POLE treatment in cultured hDPCs. As a consequence, the expression of growth factors such as bFGF, KGF, and VEGF were also increased by POLE. We further investigated the hair-growth-promoting effect of topically administered POLE over a 12-week period. Our data suggest that POLE could support terminal hair growth by stimulating proliferation of DPCs and that enhanced production of growth factors, especially KGF, occurred as a result of tyrosine kinase ACK1 activation.

Sarcopenia is a condition characterized by a progressive loss of muscle mass and function which are influenced by certain factors such as aging, nutritional deficiencies, and chronic diseases. Despite numerous efforts to prevent or treat sarcopenia, effective therapeutic options for this disease remain limited. This study aims to evaluate the effects of KGC01CE treatment, a mixture of Cervus elaphus (Ce) and Eucommia ulmoides (Eu), which are well-known traditional herbal medicines in Asia, on age-related muscle loss and functional decline in aged rats. KGC01CE has been found to be more effective than the individual extracts in inhibiting dexamethasone (DEX)-induced muscle atrophy and improving muscle mass and grip strength in C2C12 cells and aged rats. Moreover, animal studies were conducted to determine the minimum effective dose, and a 12-week oral administration of KGC01CE treatment at doses of 50, 100, and 200 mg/kg to 15-month-old aged rats resulted in a dose-dependent increase in lean mass, muscle mass, grip strength, and muscle cross-sectional area (CSA), which had decreased due to aging. Furthermore, it was shown that KGC01CE activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and inhibited the expression of muscle-degrading proteins MuRF, Atrogin-1, and myostatin. These results suggest that KGC01CE treatment may effectively prevent muscle loss and functional decline, providing a novel therapeutic strategy for sarcopenia.

Gamma-aminobutyric acid (GABA) is one of the inhibitory neurotransmitters with beneficial effects including sedative properties. However, despite various clinical trials, scientific evidence regarding the impact on sleep of orally ingested GABA, whether natural or synthesized through biological pathways, is not clear. GABALAGEN (GBL) is the product of fermented collagen by Lactobacillus brevis BJ20 (L. brevis BJ20) and Lactobacillus plantarum BJ21 (L. plantarum BJ21), enriched with GABA and characterized by low molecular weight. The aim of this study was to investigate the effect of GBL on sleep improvement via a receptor binding assay in a pentobarbital-induced sleep-related rat model. We utilized a pentobarbital-induced sleep-related rat model to conduct this research. The present study investigated the sedative effects of GBL through electroencephalography (EEG) analysis in the pentobarbital-induced sleep animal model. Exploration of the neural basis of these positive effects involved evaluating orexin in the brain via immunohistochemical methods and 5-HT in the serum using an enzyme-linked immunosorbent assay (ELISA). Furthermore, we conducted a binding assay for 5-HT_2C receptors, as these are considered pivotal targets in the mechanism of action for sleep aids. Diazepam (DZP) was used as a positive control to compare the efficacy of GBL. Results: In the binding assay, GBL displayed binding affinity to the 5-HT_2C receptor (IC50 value, 5.911 µg/mL). Administration of a low dose of GBL (GBL_L; 100 mg/kg) increased non-rapid eye movement sleep time and decreased wake time based on EEG data in pentobarbital-induced rats. Administration of a high dose of GBL (GBL_H; 250 mg/kg) increased non-rapid eye movement sleep time. Additionally, GBL groups significantly increased concentration of the 5-HT level in the serum. GBL_H decreased orexin expression in the lateral hypothalamus. Conclusion: Overall, the sedative effect of GBL may be linked to the activation of serotonergic systems, as indicated by the heightened affinity of the 5-HT_2C receptor binding and elevated levels of 5-HT observed in the serum. This suggests that GBL holds promise as a novel compound for inducing sleep in natural products.

This study presents a comparative analysis of molecular docking data, focusing on the binding interactions of the natural compounds apigenin and luteolin with the proteins TP-53, pRb, and APOBEC, in comparison to conventional pharmacological ligands. Advanced bioinformatics techniques were employed to evaluate and contrast binding energies, showing that apigenin and luteolin demonstrate significantly higher affinities for TP-53, pRb, and APOBEC, with binding energies of -6.9 kcal/mol and -6.6 kcal/mol, respectively. These values suggest strong potential for therapeutic intervention against HPV-16. Conventional ligands, by comparison, exhibited lower affinities, with energies ranging from -4.5 to -5.5 kcal/mol. Additionally, protein-protein docking simulations were performed to assess the interaction between HPV-16 E6 oncoprotein and tumor suppressors TP-53 and pRb, which revealed high binding energies around -976.7 kcal/mol, indicative of their complex interaction. A conversion formula was applied to translate these protein-protein interaction energies to a comparable scale for non-protein interactions, further underscoring the superior binding potential of apigenin and luteolin. These findings highlight the therapeutic promise of these natural compounds in preventing HPV-16-induced oncogenesis, warranting further experimental validation for clinical applications.

Cancer, a group of diseases characterized by uncontrollable cell proliferation and metastasis, remains a global health challenge. This study investigates quercetin, a natural compound found in many fruits and vegetables, for its potential to inhibit the phosphomonoesterase activity of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), a key immune response regulator implicated in cancer and autoimmune diseases. We started by screening seven (7) natural compounds against the activities of PTPN22 in vitro. The initial screening identified quercetin with the highest percentage inhibition (81%) among the screened compounds when compared with ursolic acid that has 84%. After the identification of quercetin, we proceeded by investigating the effect of increasing concentrations of the compound on the activity of PTPN22. In vitro studies showed that quercetin inhibited PTPN22 with an IC₅₀ of 29.59 μM, outperforming the reference standard ursolic acid, which had an IC₅₀ of 37.19 μM. Kinetic studies indicated a non-competitive inhibition by quercetin with a Ki of 550 μM. In silico analysis supported these findings, showing quercetin's better binding affinity (ΔGbind -24.56 kcal/mol) compared to ursolic acid, attributed to its higher reactivity and electron interaction capabilities at PTPN22's binding pocket. Both quercetin and ursolic acid improved the structural stability of PTPN22 during simulations. These results suggest quercetin's potential as an anticancer agent, meriting further research. However, in vivo studies and clinical trials are necessary to fully assess its efficacy and safety, and to better understand its mechanisms of action.

The objective of this systematic review (SR) was to select studies on the use of gene editing by CRISPR technology related to plant resistance to biotic stresses. We sought to evaluate articles deposited in six electronic databases, using pre-defined inclusion and exclusion criteria. This SR demonstrates that countries such as China and the United States of America stand out in studies with CRISPR/Cas. Among the most studied crops are rice, tomatoes and the model plant Arabidopsis thaliana. The most cited biotic agents include the genera, Xanthomonas, Manaporthe, Pseudomonas and Phytophthora. This SR also identifies several CRISPR/Cas-edited genes and demonstrates that plant responses to stressors are mediated by many complex signaling pathways. The Cas9 enzyme is used in most articles and Cas12 and 13 are used as additional editing tools. Furthermore, the quality of the articles included in this SR was validated by a risk of bias analysis. The information collected in this SR helps to understand the state of the art of CRISPR/Cas aimed at improving resistance to diseases and pests to understand the mechanisms involved in most host-pathogen relationships. This SR shows that the CRISPR/Cas system provides a straightforward method for rapid gene targeting, providing useful information for plant breeding programs.

Seventy years ago, Robin Mole introduced the concept of the abscopal effect to describe a rare phenomenon. This occurs when local radiation triggers an immune-mediated reduction in tumors outside the treated area but within the same organism. Observing this effect has been linked to improved overall and progression-free survival in patients who experience it. While the abscopal effect was once considered rare, it is now being observed more frequently due to the combination of radiation with immunotherapy. As a result, more researchers are exploring this study area, which shows promise for excellent results. This review focuses explicitly on the immunological implications of activating the abscopal effect through ionizing radiation in the central nervous system and explores the potentially involved immunological pathways.

COVID-19 continues to impact healthcare workers (HCWs), making it crucial to investigate vaccine response rates. This study examined HCWs' humoral and cellular immunological responses to COVID-19 booster dosages. We enrolled thirty-four vaccinated HCWs. Twelve received a booster. Post-immunization, the participants' anti-COVID-19 IgG antibodies and IFN-γ secretion were assessed. The median second immunization response time was 406.5 days. Eighteen of twenty-two (81.8%) experienced breakthrough infections after the second vaccination, whereas ten out of twelve individuals who received booster doses had breakthrough infections (83.3%). Six of thirty-four HCWs (17.6%) had no breakthrough infections. Booster-injection recipients had a median antibody titer of 19,592 AU/mL, compared to 7513.55 AU/mL. HCWs with breakthrough infections exhibited a median antibody titer of 13,271.9 AU/mL, compared to 7770.65 AU/mL for those without infections. Breakthrough-infection and booster-injection groups had a slightly higher median T-cell response to antigens 1, 2, and 3. SARS-CoV-2 antibody titer and T-cell responsiveness were positively associated. HCWs sustain cellular and humoral immunity for over 10 months. Irrespective of the type of vaccine, booster injections enhance these immune responses. The results of our research are consistent with previous studies, and a multicenter investigation could validate the findings.

L-ascorbic acid (AsA, vitamin C) plays a vital role in preventing various diseases, particularly scurvy. AsA is known for its antioxidant properties, which help protect against reactive oxygen species generated from metabolic activities; however, at high doses, it may exhibit pro-oxidative effects. The final step in AsA biosynthesis is catalyzed by L-gulono-γ-lactone oxidase (GULO). This enzyme is present in many organisms, but some animals, including humans, guinea pigs, bats, and other primates, are unable to synthesize AsA due to the absence of a functional GULO gene. The GULO enzyme belongs to the family of aldonolactone oxidoreductases (AlORs) and contains two conserved domains, an N-terminal FAD-binding region and a C-terminal HWXK motif capable of binding the flavin cofactor. In this review, we explore AsA production, the biosynthetic pathways of AsA, and the localization of GULO-like enzymes in both animal and plant cells. Additionally, we compare the amino acid sequences of AlORs across different species and summarize the findings related to their enzymatic activity. Interestingly, a recombinant C-terminal rat GULO (the cytoplasmic domain of the rat GULO expressed in Escherichia coli) demonstrated enzymatic activity. This suggests that the binding of the flavin cofactor to the HWXK motif at the C-terminus is sufficient for the formation of the enzyme's active site. Another enzyme, GULLO7 from Arabidopsis thaliana, also lacks the N-terminal FAD-binding domain and is strongly expressed in mature pollen, although its activity has not been specifically measured.