International Journal of Molecular Sciences最新文献

Skeletal muscle atrophy is a major health concern, severely affecting the patient's mobility and life quality. In the pathological process of skeletal muscle atrophy, with the progressive decline in muscle quality, strength, and function, the incidence of falling, fracture, and death is greatly increased. Unfortunately, there are no effective treatments for this devastating disease. Thus, it is imperative to investigate the exact pathological molecular mechanisms underlying the development of skeletal muscle atrophy and to identify new therapeutic targets. Decreased muscle mass, strength, and muscle fiber cross-sectional area are typical pathological features and manifestations of skeletal muscle atrophy. Ferroptosis, an emerging type of programmed cell death, is characterized by iron-dependent oxidative damage, lipid peroxidation, and reactive oxygen species accumulation. Notably, the understanding of its role in skeletal muscle atrophy is emerging. Ferroptosis has been found to play an important role in the intricate interplay between the pathological mechanisms of skeletal muscle atrophy and its progression caused by multiple factors. This provides new opportunities and challenges in the treatment of skeletal muscle atrophy. Therefore, we systematically elucidated the ferroptosis mechanism and its progress in skeletal muscle atrophy, aiming to provide a comprehensive insight into the intricate relationship between ferroptosis and skeletal muscle atrophy from the perspectives of iron metabolism and lipid peroxidation and to provide new insights for targeting the pathways related to ferroptosis and the treatment of skeletal muscle atrophy.

The subject of this study is the interaction between 5,10,15,20-tetrakis (4-sulfonatophenyl)-porphyrin (TSPP), a potential photosensitizer for photodynamic therapy (PDT) and radiotherapy, and human serum albumin (HSA), a crucial protein in the body. The main objective was to investigate the binding mechanisms, structural changes, and potential implications of these interactions for drug delivery and therapeutic applications. Spectroscopic techniques and computational methods were employed to investigate the mechanism and effects of TSPP binding by HSA. The results suggest the possibility of simultaneous binding of three TSPP ions at binding sites of different affinity within albumin. The estimated values of the binding constant K_b for these sites were in the range of 0.6 to 6.6 μM^-1. Laser flash photolysis indicated the stabilization of TSPP in the HSA structure, which resulted in prolonged lifetimes of the excited states (singlet and triplet) of porphyrin. Circular dichroism analysis was used to assess the changes in the secondary and tertiary structures of HSA upon TSPP binding. An analysis of the molecular docking results allowed us to identify the preferred TSPP binding sites within HSA and provided information on the specific interactions of amino acids involved in the stabilization of TSPP-HSA complexes. The estimated free energy of the binding of porphyrin at the three most favorable docking sites found in the HSA structure that was considered native were in the range of -80 to -41 kcal/mol. Finally, thermal unfolding studies showed that TSPP increased the stability of the secondary structure of albumin. All these findings contribute to the understanding of the interactions between TSPP and HSA, offering valuable insights for the development of novel cancer therapy approaches.

Mycobacterium tuberculosis (M. tb) is a remarkably versatile pathogen that possesses a unique ability to counteract the host's defence mechanisms to control the infection. Several mycobacterial protein kinases and phosphatases were found to play a key role in impeding phagosome maturation in macrophages and accordingly blocking the phagosome-lysosome fusion, therefore allowing the bacteria to survive. During phagocytosis, both M. tb and the host's phagocytic cells develop mechanisms to fight each other, resulting in pathogen elimination or survival. In this respect, M. tb uses a phosphorylation-based signal transduction mechanism, whereby it senses extracellular signals from the host and initiates the appropriate adaptation responses. Indeed, the ability of M. tb to exist in different states in the host (persistent quiescent state or actively replicating mode) is mainly mediated through protein phosphorylation/dephosphorylation signalling. The M. tb regulatory and defensive responses coordinate different aspects of the bacilli's physiology, for instance, cell wall components, metabolic activity, virulence, and growth. Herein, we will discuss the implication of M. tb kinases and phosphatases in hijacking the host immune system, perpetuating the infection. In addition, the role of PknG, MPtpA, MPtpB, and SapM inhibitors in resetting the host immune system will be highlighted.

Autism spectrum disorder (ASD) is a neurological disease and lifelong condition. The treatment gap in ASD has led to growing interest in alternative therapies, particularly in phytocannabinoids, which are naturally present in Cannabis sativa. Studies indicate that treatment with cannabidiol (CBD)-rich cannabis may possess the potential to improve fundamental ASD symptoms as well as comorbid symptoms. This systematic review aims to assess the safety and efficacy of CBD-rich cannabis in alleviating the symptoms of ASD in both children and adults, addressing the treatment gap and growing interest in CBD as an alternative treatment. A comprehensive literature search was conducted in February 2024 using the PUBMED and Scopus databases while following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search focused on studies from 2020 onward involving human populations diagnosed with ASD and treated with CBD. Four studies met the inclusion criteria and were analyzed. The review included 353 participants with ASD from studies conducted in Israel, Turkey, and Brazil. The studies varied in design, sample size, dose, and treatment duration. Dosages of CBD were often combined with trace amounts of THC. Improvements were noted in behavioral symptoms, social responsiveness, and communication, but cognitive benefits were less consistent. Adverse effects ranged in severity. Mild effects such as somnolence and decreased appetite were common, while more concerning effects, including increased aggression, led to some cases of treatment discontinuation. CBD-rich cannabis shows promise in improving behavioral symptoms associated with ASD. However, variations in study designs, dosages, and outcome measures highlight the need for standardized assessment tools and further research to understand pharmacological interactions and optimize treatment protocols. Despite the mild adverse effects observed, larger, well-controlled trials are necessary to establish comprehensive safety and efficacy profiles.

Pathogenic variants in KCNC3, which encodes the voltage-gated potassium channel Kv3.3, are associated with spinocerebellar ataxia type 13. SCA13 is a neurodegenerative disease characterized by ataxia, dysarthria and oculomotor dysfunction, often in combination with other signs and symptoms such as cognitive impairment. Known disease-causing variants are localized in the protein coding regions and predominantly in the transmembrane and voltage sensing domains. In a patient with an ataxic movement disorder and progressive cognitive decline, the c.-6C>A variant was detected in the Kozak sequence of KCNC3. The Kozak sequence is responsible for efficient initiation of translation. Functional analysis of the new c.-6C>A variant and the upstream 5'-UTR region of KCNC3 by luciferase assays, quantitative PCR and methylation analysis shows increased protein expression but no effect on transcription rate. Therefore, increased translation initiation of KCNC3 transcripts compared to wild-type Kozak sequence seems to be the cause of the increased expression. Variants in the regulatory elements of disease-causing genes probably play an underestimated role.

Extracellular vesicles (EVs) secreted by astrocytes (ADEVs) mediate numerous biological processes, providing insights into damage, repair, and protection following ischemic stroke (IS). This pilot study aimed to broaden the current knowledge on the astrocyte response to ischemia by dynamically assessing the aquaporin-4 (AQP4) and glial cell line-derived neurotrophic factor (GDNF) as cargo proteins of these vesicles in eighteen acute IS patients and nine controls. EV proteins were detected by Western blotting and followed 24 h (D1), 7 days (D7), and one month (M1) after symptoms onset. The post-ischemic ADEV AQP4 and GDNF levels were higher at D1 compared to the control group (p = 0.006 and p = 0.023). Significant differences were observed in ADEV AQP4 during the three evaluated time points (n = 12, p = 0.013) and between D1 and D7 (z = 2.858, p = 0.012), but not in EV GDNF. There was a positive relationship between the severity of stroke at D1 according to the National Institutes of Health Stroke Scale, and ADEV AQP4 at D1 (r = 0.50, p = 0.031), as well as ADEV GDNF at D1 and D7 (r = 0.49, p = 0.035 and r = 0.53, p = 0.021, respectively). The release of EVs with distinct protein profiles can be an attractive platform for the development of biomarkers in IS.

The use of next-generation sequencing (NGS) has recently enabled the discovery of genetic causes of primary ovarian insufficiency (POI) with high genetic heterogeneity. In contrast, the causes of diminished ovarian reserve (DOR) remain poorly understood. Here, we identified by NGS and whole exome sequencing (WES) the cause of isolated DOR in a 14-year-old patient. Two frameshift mutations in BRCA1 (NM_007294.4) were found: in exon 8 (c.470_471del; p.Ser157Ter) and in exon 11 (c.791_794del, p.Ser264MetfsTer33). Unexpectedly, the patient presented no signs of Fanconi anemia (FA), i.e., no developmental abnormalities or indications of bone marrow failure. However, high chromosomal fragility was found in the patient's cells, consistent with an FA diagnosis. RT-PCR and Western-blot analysis support the fact that the c. 791_794del BRCA1 allele is transcribed and translated into a shorter protein (del11q), while no expression of the full-length BRCA1 protein was found. DNA damage response (DDR) studies after genotoxic agents demonstrate normal activation of the early stages of the DDR and FANC/BRCA pathway. This is consistent with the maintenance of residual repair activity for the del11q BRCA1 isoform. Our observation is the first implication of bi-allelic BRCA1 mutations in isolated ovarian dysfunction or infertility in humans, without clinical signs of FA, and highlights the importance of BRCA1 in ovarian development and function.

Fused in sarcoma (FUS) is involved in the formation of nuclear biomolecular condensates associated with poly(ADP-ribose) [PAR] synthesis catalyzed by a DNA damage sensor such as PARP1. Here, we studied FUS microphase separation induced by poly(ADP-ribosyl)ated PARP1^WT [PAR-PARP1^WT] or its catalytic variants PARP1^Y986S and PARP1^Y986H, respectively, synthesizing (short PAR)-PARP1^Y986S or (short hyperbranched PAR)-PARP1^Y986H using dynamic light scattering, fluorescence microscopy, turbidity assays, and atomic force microscopy. We observed that biologically relevant cations such as Mg²⁺, Ca²⁺, or Mn²⁺ or polyamines (spermine⁴⁺ or spermidine³⁺) were essential for the assembly of FUS with PAR-PARP1^WT and FUS with PAR-PARP1^Y986S in vitro. We estimated the range of the FUS-to-PAR-PARP1 molar ratio and the cation concentration that are favorable for the stability of the protein's microphase-separated state. We also found that FUS microphase separation induced by PAR-PARP1^Y986H (i.e., a PARP1 variant attaching short hyperbranched PAR to itself) can occur in the absence of cations. The dependence of PAR-PARP1-induced FUS microphase separation on cations and on the branching of the PAR structure points to a potential role of the latter in the regulation of the formation of FUS-related biological condensates and requires further investigation.

This study assessed the effectiveness of the local use of green propolis-loaded lipid nanoparticles (GPlnp) as an adjuvant therapy to scaling and root planing (SRP) to manage experimental periodontitis (EP) in ovariectomized rats treated with zoledronate. Ten weeks before the experiment, 48 female rats were ovariectomized. On day 0, a ligature was installed in the lower first molar to induce EP. From day 0 to day 42, half of the rats were treated with vehicle (VEH), while the other half were treated with 100μg/Kg of zoledronate (ZOL). On day 14, the rats were allocated into the following groups: VEH-NLT, VEH-SRP, VEH-SRP-GPlnp, ZOL-NLT, ZOL-SRP, and ZOL-SRP-GPlnp. VEH-NLT and ZOL-NLT received no local treatment. VEH-SRP and ZOL-SRP received SRP and irrigation with physiological saline solution. VEH-SRP-GPlnp and ZOL-SRP-GPlnp received SRP and irrigation with GPlnp. A single SRP session was carried out, and four irrigation sessions were conducted (on days 14, 16, 18, and 20). On day 42, all animals were euthanized. The hemimandibles were processed for histological, histometric (percentage of total bone tissue (PTBT) and non-vital bone tissue (PNVBT)) and immunohistochemical (TNFα, IL-1β, and TRAP) analysis. VEH-SRP-GPlnp showed better tissue repair, higher PTBT, and lower immunolabeling for TNFα and IL-1β compared to the groups treated with VEH. ZOL-SRP-GPlnp showed a favorable tissue repair, with lower PNVBT, less local inflammation, and lower immunolabeling for TNFα and IL-1β compared to the groups treated with ZOL. Irrigation with GPlnp proved to be effective as an adjuvant therapy to SRP in treating EP in ovariectomized rats treated with zoledronate.

The aim of this study was to investigate the effects of treating maize (Zea mays L.) seeds with fish collagen hydrolysate (FC) and keratin (KE) derived from animal waste by-products of leather and meat production, as well as poly(hexamethylene biguanide) hydrochloride (P) and bentonite (B). This research is in line with the search for new, environmentally friendly methods to increase yields of industrial crops in a way that is compatible with sustainable development. The effect of the binders used was investigated by analysing the grown maize seedlings by determining changes in parameters of chlorophyll fluorescence, photosynthetic pigments, elemental composition and FTIR analysis on maize shoots. The results indicated a slightly higher fresh weight (FW) of shoots in plants treated with fish collagen, PHMB and bentonite (FC+P+B) and FW of roots in plants treated with keratin, PHMB and bentonite (KE+P+B). Unexpectedly, the FW and dry weight (DW) of both roots and shoots of all bentonite-treated plants were significantly higher than the corresponding non-bentonite-treated groups. In addition, changes in chlorophyll-a fluorescence were observed for the keratin, PHMB and bentonite variants. This study showed that the proposed materials could be promising seed pelleting agents to improve seed growth and yield.