Biomolecules最新文献

Vascular smooth muscle cells (VSMCs) can dynamically change their phenotype between contractile and synthetic forms in response to environmental stress, which is pivotal in maintaining vascular homeostasis and mediating pathological remodeling of blood vessels. We previously reported that suppression of canonical transient receptor potential 6 (TRPC6) channel-mediated cation entry sustains VSMCs contractile phenotype and promotes the blood flow recovery after hindlimb ischemia in mice. We also reported that Zn²⁺, a metal biomolecule mobilized by TRPC6 channel activation, exerts potential beneficial effects on cardiac contractility and remodeling. Therefore, we hypothesized that TRPC6-mediated Zn²⁺ influx participates in phenotype switching of VSMCs and vascular remodeling. We established rat aortic smooth muscle cells (RAoSMCs) stably expressing wild type (WT) and Zn²⁺ only impermeable TRPC6 (KYD) mutant. Although the resting phenotypes were similar in both RAoSMCs, pharmacological TRPC6 activation by PPZ2 prevented the transforming growth factor (TGF) β-induced reduction in the intracellular Zn²⁺ amount and contractile differentiation in RAoSMCs (WT), but failed to prevent them in RAoSMCs (KYD). There were no significant differences in TRPC6-dependent cation currents among all RAoSMCs pretreated with or without TGFβ and/or PPZ2, suggesting that TRPC6 channels are functionally expressed in RAoSMCs regardless of their phenotype. Treatment of mice with PPZ2 attenuated the progression of vascular remodeling caused by chronic angiotensin II infusion. These results suggest that Zn²⁺ influx through TRPC6 channels negatively regulates the TGFβ-induced contractile differentiation of VSMCs and the progression of vascular remodeling in rodents.

Yeast TIM8 was initially identified as a homolog of human TIMM8A/DDP1, which is associated with human deafness-dystonia syndrome. Tim8p is located in the mitochondrial intermembrane space and forms a hetero-oligomeric complex with Tim13p to facilitate protein transport through the TIM22 translocation system. Previous research has indicated that TIM8 is not essential for yeast survival but does affect the import of Tim23p in the absence of the Tim8-Tim13 complex. Previous research on TIM8 has focused mainly on its involvement in the mitochondrial protein transport pathway, and the precise biological function of TIM8 remains incompletely understood. In this study, we provide the first report that yeast TIM8 is associated with the endoplasmic reticulum (ER) stress response and chronological senescence. We found that deletion of TIM8 leads to both oxidative stress and ER stress in yeast cells while increasing resistance to the ER stress inducer tunicamycin (TM), which is accompanied by an enhanced basic unfolded protein response (UPR). More importantly, TIM8 deficiency can lead to a shortened chronological lifespan (CLS) but does not affect the replicative lifespan (RLS). Moreover, we found that improving the antioxidant capacity further increased TM resistance in the tim8Δ strain. Importantly, we provide evidence that the knockdown of TIMM8A in ARPE-19 human retinal pigment epithelium cells can also induce ER stress, suggesting the potential function of the TIM8 gene in ER stress is conserved from budding yeast to higher eukaryotes. In summary, these results suggest novel roles for TIM8 in maintaining ER homeostasis and CLS maintenance.

Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms. The first key factor is innate anti-PD-1 resistance signature (IPRES), an expression of a group of genes associated with tumor plasticity and immune evasion. IPRES promotes epithelial-to-mesenchymal transition (EMT), increasing melanoma cells' invasiveness and survival. Overexpressed AXL, TWIST2, and WNT5a induce phenotypic changes. The upregulation of pro-inflammatory cytokines frequently coincides with EMT-related changes, further promoting a resistant and aggressive tumor phenotype. Inflamed tumor microenvironment may also drive the expression of resistance. The complexity of immune resistance development suggests that combination therapies are necessary to overcome it. Furthermore, targeting epigenetic regulation and exploring novel approaches such as miR-146a modulation may provide new strategies to counter resistance in melanoma.

Cancer metastasis remains the most challenging issue in cancer therapy. Recent reports show that cancer metastasis accounts for over 90% of cancer-associated deaths in the world. Metastasis is a multi-step process by which cancer cells spread to distant tissues and organs beyond the primary site. The metastatic propagation of different cancers is under the surveillance of several regulating processes and factors related to cellular signaling pathways. Plant-derived phytochemicals are bioactive components of plants with a variety of biological and medicinal activities. Several phytochemicals have been shown to target various molecular factors in cancer cells to tackle metastasis. Sesquiterpene lactones, as a diverse group of plant-derived phytochemicals with a variety of biological activities, have been shown to suppress the promotion and progression of different cancer types by acting on multiple cell-signaling pathways. This review article briefly describes the process of metastasis and its components. Then, sesquiterpene lactones with the ability to target and inhibit invasion, migration, and metastasis along with the molecular mechanisms of their effects on different cancers are described in detail.

Neurotoxic damage resulting from lead pollution exposure constitutes a significant public health concern. The regulatory impact of lead (Pb) exposure on neuronal dendritic spine plasticity, a crucial mechanism for neuronal adaptation, warrants further investigation. To elucidate the role and mechanism of the Mitofilin-mtDNA axis in hippocampal synaptic plasticity and learning and memory impairment induced by lead exposure, in this study, both in vivo and in vitro models were subjected to chronic lead exposure. The results showed that the spatial learning and memory abilities of lead-exposed mice were significantly reduced. Furthermore, Western blotting and RT-PCR analyses demonstrated a significant down-regulation in the expression of the mitochondrial inner membrane protein Mitofilin. Extended exposure to lead has the potential to compromise the plasticity of dendritic spines within the CA1 region of hippocampal neurons and disrupt the structural integrity of neuronal mitochondria. Furthermore, lead exposure was associated with elevated levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in neurons. The study additionally demonstrated that the overexpression of Mitofilin ameliorated deficits in spatial learning and memory in mice subjected to chronic lead exposure. This overexpression also facilitated the normal formation of neuronal dendritic spines, preserved the structural integrity of the mitochondrial inner membrane, and mitigated mitochondrial damage. The study further revealed that the overexpression of Mitofilin markedly suppressed the release of mitochondrial DNA (mtDNA) in neurons subjected to chronic lead exposure, while concurrently reducing the expression levels of the inflammasome Nlrp3 and the inflammatory cytokine IL-1β. Additionally, there was a significant reduction in the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in lead-exposed neurons with Mitofilin overexpression. These findings suggest that the mitochondrial inner membrane protein Mitofilin may play a role in mediating synaptic plasticity impairment following chronic lead exposure through the regulation of mitochondrial function.

Uterine mesenchymal tumors (UMTs) are the second most common type of tumors within the uterus corpus after endometrial carcinomas. Among the UMTs, smooth muscle neoplasms are the most common subtype, followed by endometrial stromal sarcoma (ESS). ESSs are uncommon malignancies characterized by molecular heterogeneity and an aggressive behavior. Their management poses significant challenges, particularly for high-grade subtypes. Surgery is the primary intervention for localized disease, while the role of adjuvant therapies, including radiation and chemotherapy, must be better investigated. Hormonal therapy has shown efficacy in low-grade cases but limited success in high-grade tumors. Recent advancements in molecular profiling have revealed potential targets, offering promise for personalized treatments. However, novel therapeutic strategies are urgently needed to improve patient outcomes, particularly for advanced and recurrent disease. This review offers a perspective on the possible novel therapeutic approaches based on the most recent molecular analyses performed on endometrial stromal sarcomas.

Background: Urinary tract infections are a global health concern, with uropathogenic Escherichia coli (UPEC) accounting for 80-90% of cases. Given the rise in antimicrobial resistance, our aim was to elucidate the genetic mechanisms behind low-level resistance to ciprofloxacin and fosfomycin (LLCR and LLFR) in UPEC strains, using whole-genome sequencing (WGS) to identify point mutations in chromosomal and plasmid genes.

Methods: A cohort UPEC was collected from kidney transplant recipients at the Virgen del Rocío University Hospital, Spain. Minimum inhibitory concentrations were determined for ciprofloxacin and fosfomycin to categorize strains into LLCR and LLFR. Twenty strains were selected for WGS, with genome annotations. Point mutations were identified and analyzed using alignment tools, and protein stability changes were predicted.

Results: LLCR strains exhibited mutations in key quinolone resistance-determining regions of the gyrA gene, in 83% of cases. The qnrS1 plasmid gene was found in 17% of LLCR strains. LLFR strains showed mutations in the glpT and cyaA genes. Mutations in the uhp gene family were linked to the fosfomycin-resistant phenotype, suggesting a multi-step resistance evolution mechanism.

Conclusions: This study highlights the complex interplay between chromosomal and plasmid genes in UPEC's resistance to ciprofloxacin and fosfomycin. The findings contribute to understanding low-level resistance mechanisms and may guide the development of novel therapeutic strategies to combat multidrug-resistant strains.

Background: Adipose-derived mesenchymal stem cell conditioned medium (ASC-CM) improved the viability and wound closure of human tenocytes (HTCN) exposed to high glucose (HG) by activating the transforming growth factor beta 1 (TGF-β1) pathway.

Objectives: Since ASC-CM can also modulate microRNAs (miRNAs) in recipient cells, this study investigated the effects of ASC-CM on the miRNAs regulating tendon repair (miR-29a-3p, miR-210-3p and miR-21-5p) in HG-HTNC.

Methods: ASC-CM was obtained by ASCs isolated from the abdominal fat tissue of seven non-diabetic patients. HTNC were cultured in HG for 20 days, then scratched and exposed for 24 h to ASC-CM. qRT-PCR and ELISAs assessed miRNA and target levels.

Results: HG-HTNC exhibited a significant downregulation of miRNAs. ASC-CM restored the levels of miRNAs and their related targets involved in tendon repair.

Conclusions: The epigenetic modulation observed in HG-HTNC exposed to ASC-CM could be an innovative option in the management of diabetic tendinopathy.

Methicillin-resistant Staphylococcus aureus (MRSA) continues to represent a significant clinical challenge, characterized by consistently elevated rates of morbidity and mortality. Care regimen success is still difficult and necessitates assessing new antibiotics as well as supplemental services, including source control and searching for alternative approaches to combating it. Hence, we propose to synthesize silver nanoparticles (Ag-NPs) by employing a cell-free filter (CFF) of Streptomyces sp. to augment antibiotic activity and combat biofilm-forming MRSA. Seven bacterial isolates from clinical samples were identified, antibiotics were profiled with Vitek-2, and the phenotypic detecting of biofilm with Congo red medium and microplate assay was carried out. The PCR technique was used for detecting genes (icaA and icaD) coded in biofilm forming. The characterization of Ag-NPs was performed using several analytical methods, such as UV spectroscopy, dynamic light scattering (DLS), zeta potential measurement, transmission electron microscopy (TEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). The antibacterial properties of Ag-NPs and oxacillin-Ag-NPs were assessed against standard strains and clinical isolates by employing the agar well diffusion technique and the microdilution assay. The biogenic synthesis Ag-NPs resulted in uniformly spherical particles, with an average size of 20 nm. These Ag-NPs demonstrated significant activity against biofilm-forming MRSA, with minimum inhibitory concentrations (MICs) ranging from 12 to 15 μg/mL. Additionally, Ag-NPs completely impede biofilm formation by MRSA at sublethal doses of 0.75 MICs. The expression levels of the icaA and icaD genes were reduced by 1.9- to 2.2- and 2.4- to 2.8-fold, respectively. A significant synergistic effect was noted when Ag-NPs were used in combination with oxacillin, leading to reduced MICs of 1.87 μg/mL for oxacillin and 4.0 μg/mL for Ag-NPs against MRSA. The FICi of 0.375 further validated the synergistic relationship between oxacillin and Ag-NPs at the concentrations of 1.87 and 4 μg/mL. Findings from the time-kill test demonstrated the highest reduction in log₁₀ (CFU)/mL of the initial MRSA inoculum after 12-hour exposure. The cytotoxicity analysis of Ag-NPs revealed no significant cytotoxic effects on the human skin cell line HFB-4 at low concentrations, with IC₅₀ values of 61.40 µg/mL for HFB-4 and 34.2 µg/mL for HepG-2. Comparable with oxacillin-Ag-NPs, Ag-NPs showed no cytotoxic effects on HFB-4 at different concentrations and exhibited an IC₅₀ value of 31.2 against HepG-2-cells. In conclusion, the biosynthesis of Ag-NPs has demonstrated effective antibacterial activity against MRSA and has completely hindered biofilm formation, suggesting a valuable alternative for clinical applications.

This review examines representatives of organocyclophosphazenes that can act against tumor cells of the ovaries, prostate gland, mammary gland, and colon, etc., and have antimicrobial action against mycobacteria M. tuberculosis, Gram-positive bacteria B. cereus, Gram-negative bacteria K. pneumaniae, fungi of the genus Candida, and other microorganisms. Cyclomatric phosphazenes can be used as carriers of physiologically active substances and in the field of detection, as well as gels for wound surgery and drug delivery platforms. In gels, cyclophosphazenes are used as cross-linking agents. Cyclophosphazenes containing multiple bonds in organic radicals are proposed to be used in dentistry as additives to basic dental compositions. Particular attention in the review is paid to the cytotoxic and antimicrobial action of materials containing cyclophosphazenes and their advantages over commercial physiologically active substances. The review presents the prospects for the practical application of cyclophosphazenes containing various functional groups (chalcone, anthraquinone, pyrrolidine, morpholine, and ferrocene, etc.) in pharmaceuticals. The review may be of interest to researchers working in the field of organoelement chemistry, medicine, and pharmacy.