Sensorineural hearing loss (SNHL), a multifactorial progressive disorder, results from a complex interplay of genetic and environmental factors, with its underlying mechanisms remaining unclear. Several pathological factors are believed to contribute to SNHL, including genetic factors, ion homeostasis, cell apoptosis, immune inflammatory responses, oxidative stress, hormones, metabolic syndrome, human cytomegalovirus infection, mitochondrial damage, and impaired autophagy. These factors collectively interact and play significant roles in the onset and progression of SNHL. The present review offers a comprehensive overview of the various factors that contribute to SNHL, emphasizes recent developments in understanding its etiology, and explores relevant preventive and intervention measures.

Degenerative intervertebral disc disease (IVDD) is one of the main spinal surgery, conditions, which markedly increases the incidence of low back pain and deteriorates the patient\'s quality of life, and it imposes significant social and economic burdens. The molecular pathology of IVDD is highly complex and multilateral however still not ompletely understood. New findings indicate that IVDD is closely associated with inflammation, oxidative stress, cell injury and extracellular matrix metabolismdysregulation. Symptomatic management is the main therapeutic approach adopted for IVDD, but it fails to address the basic pathological changes and the causes of the disease. However, research is still focusing on molecular aspects in terms of gene expression, growth factors and cell signaling pathways in an attempt to identify specific molecular targets for IVDD treatment. The paper summarizes the most recent achievements in molecularunderstanding of the pathogenesis of IVDD and gives evidence-based recommendations for clinical practice.

Low-level light therapy (LLLT), also known as photo biomodulation (PBM), is a type of optical therapy that uses red or near-infrared lasers or light-emitting diodes (LEDs) for medical treatment. The laser wavelengths involved in PBM typically range between 600-700 nm and 780-1100 nm, with power densities ranging between 5 mW/cm2 and 5 W/cm2. PBM is a series of biochemical cascades exhibited by biological tissues after absorbing a certain amount of energy from light. PBM has been widely used in clinical practice in the past 20 years, and numerous clinical trials have demonstrated its biological efficacy. However, the underlying mechanisms have not yet been fully explored. In this paper, we have summarized the research into PBM over the past two decades, to identify the important mechanisms of the biological effects of PBM from the perspective of molecular mechanisms, cellular levels, and tissue changes. We hope our study provide a theoretical basis for future investigations into the underlying mechanisms.

The clinical application of random flaps in wound repair has been a topic of discussion. Random flaps are prone to necrosis due to the lack of well-defined vascular blood supply during transfer surgery. Their clinical utility is restricted, financial and psychological burdens is imposed on patients due to this limitation. The survival of random skin flaps depends on factors such as ischemia-reperfusion injury, oxidative stress, local inflammatory response, and neovascularization. This review aims to provide an overview of the evidence supporting the use of random flaps in clinical practice. In addition, this review explores the impact of different medications on signaling pathways within the flap\'s local microcirculation and investigates the interconnections between these pathways.

Colocasia esculenta (L.) Schott is a tuberous plant, also known as taro, employed as food worldwide for its renowned nutritional properties but also traditionally used in several countries for medical purposes. In this study, methanolic extracts were prepared from the corms and leaves of Colocasia, subsequently fractionated via molecular exclusion chromatography (RP-HPLC) and their anti-tumor activity assessed in an in vitro model of gastric adenocarcinoma (AGS cells). Vorm extract and isolated fractions II and III affected AGS cell vitality in a dose-dependent manner through the modulation of key proteins involved in cell proliferation, apoptosis, and cell cycle processes, such as caspase 3, cyclin A, cdk2, IkBα, and ERK. To identify bioactive molecules responsible for anti-tumoral activity fractions II and III were further purified via RP-HPLC and characterized via nuclear magnetic resonance (NMR) and electrospray mass spectrometry (ESI-MS) techniques. The procedure enabled the identification of ten compounds including lignans and neolignans, some isolated for the first time in taro, uncommon megastigmane derivatives, and a gallic acid derivative. However, none of the isolated constituents showed efficacy equivalent to that of the fractions and total extract. This suggests that the whole Colocasia phytocomplex has intriguing anti-tumor activity against gastric cancer.

Dementia is a significant cause of elderly disability and Alzheimer\'s disease (AD) is the most prevalent form of dementia. As an early stage of AD, the mechanism related to mild cognitive impairment (MCI) and heavy metals is still unclear. This study utilized a cross-sectional design and enrolled 514 older adults in Bejing, China. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) and fourteen blood metals were measured by inductively coupled plasma mass spectrometry (ICP-MS). In the adjusted single-metal models, we observed that copper [Cu, β (95% CI): 3.73 (-6.42, -1.03)] and lead [Pb, β (95% CI): 0.79 (-1.26, -0.32)] demonstrated negative associations with cognitive function, while selenium [Se, β (95% CI): 2.97 (1.23, 4.70)] was beneficial to cognition. Our findings were robust in secondary analysis using multi-metal models, which included generalized linear models (GLM), Bayesian kernel machine regression (BKMR), and quantile g-computation (qgcomp). Moreover, the toxic metal mixture (Cu and Pb) exhibited a significant negative association with MMSE scores and the inclusion of Se in the metal mixture attenuated the neurotoxicity of Cu-Pb mixture. The in silico analysis was used to examine the potential molecular mechanisms (genes, biological processes, pathways, and illnesses) of interaction among metal mixtures. We identified 20 cognition-related genes that are associated with both Cu-Pb and Se. Among these genes, eight (APOE, APP, BAX, BDNF, CASP3, HMOX1, TF, and TPP1) exhibited opposite effects on protein activity, mRNA expression, or protein expression in response to Se and Cu/Pb exposure, which could be the key genes accounting for the anti-neurotoxic effects of Se. Our findings support that Se can attenuate the neurotoxicity of exposure to single Cu or Pb, and Cu-Pb mixture. More research is needed to confirm our findings and gain knowledge about the molecular mechanisms of combined metal exposure on cognitive function.

Acute pancreatitis (AP) is an acute inflammatory gastrointestinal disease, the mortality and morbility of which has been on the increase in the past years. Spermidine, a natural polyamine, has a wide range of pharmacological effects including anti-inflammation, antioxidation, anti-aging, and anti-tumorigenic. This study aimed to investigate the reliable targets and molecular mechanisms of spermidine in treating AP. By employing computational biology methods including network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we explored the potential targets of spermidine in improving AP with dietary supplementation. The computational biology results revealed that spermidine had high degrees (degree: 18, betweenness: 38.91; degree: 18, betweenness: 206.41) and stable binding free energy (ΔGbind: - 12.81 ± 0.55 kcal/mol, - 15.00 ± 1.00 kcal/mol) with acetylcholinesterase (AchE) and serotonin transporter (5-HTT). Experimental validation demonstrates that spermidine treatment could reduce the necrosis and AchE activity in pancreatic acinar cells. Cellular thermal shift assay (CETSA) results revealed that spermidine could bind to and stabilize the 5-HTT protein in acinar cells. Moreover, spermidine treatment impeded the rise of the expression of 5-HTT in pancreatic tissues of caerulein induced acute pancreatitis mice. In conclusion, serotonin transporter might be a reliable target of spermidine in treating AP. This study provides new idea for the exploration of potential targets of natural compounds.

Computational modeling has emerged as a critical tool in investigating the complex molecular processes involved in biological systems and diseases. In this study, we apply Boolean modeling to uncover the molecular mechanisms underlying Parkinson\'s disease (PD), one of the most prevalent neurodegenerative disorders. Our approach is based on the PD-map, a comprehensive molecular interaction diagram that captures the key mechanisms involved in the initiation and progression of PD. Using Boolean modeling, we aim to gain a deeper understanding of the disease dynamics, identify potential drug targets, and simulate the response to treatments. Our analysis demonstrates the effectiveness of this approach in uncovering the intricacies of PD. Our results confirm existing knowledge about the disease and provide valuable insights into the underlying mechanisms, ultimately suggesting potential targets for therapeutic intervention. Moreover, our approach allows us to parametrize the models based on omics data for further disease stratification. Our study highlights the value of computational modeling in advancing our understanding of complex biological systems and diseases, emphasizing the importance of continued research in this field. Furthermore, our findings have potential implications for the development of novel therapies for PD, which is a pressing public health concern. Overall, this study represents a significant step forward in the application of computational modeling to the investigation of neurodegenerative diseases, and underscores the power of interdisciplinary approaches in tackling challenging biomedical problems.

Amyloid-beta (Aβ) protofibrils are closely related to Alzheimer\'s disease. Their behaviors with or without the presence of Aβ fibrillization inhibitors have been intensively studied by molecular dynamics simulations. In this work, the molecular mechanisms of licochalcone A and licochalcone B on destabilizing Aβ(1-42) protofibrils are explored. It is found that both two licochalcones can disorder the configuration of the Aβ(1-42) protofibril. The stable interactions between the Aβ(1-42) protofibril and licochalcone A or licochalcone B are able to be formed. A reduction of the β-sheet structure contents and an increment of the random coil structures of Aβ(1-42) protofibril are observed in the presence of either licochalcone A or licochalcone B. The hydrogen bonds inside the Aβ(1-42) protofibril could be partially collapsed to varying degrees by two licochalcones. Furthermore, the van der Waals interactions between Aβ(1-42) protofibril and licochalcone A make an important contribution to the binding free energy, while the contribution of the electrostatic interactions between Aβ(1-42) protofibril and licochalcone B is more prominent in the binding affinity. Our work may help in the development of new drug candidates for disrupting the Aβ protofibril.

Pathogenic mutations of transactivation response element DNA-binding protein 43 (TDP-43) are closely linked with amyotrophic lateral sclerosis (ALS). It was recently reported that two ALS-linked familial mutants A315T and A315E of TDP-43307-319 peptides can self-assemble into oligomers including tetramers, hexamers, and octamers, among which hexamers were suggested to form the β-barrel structure. However, due to the transient nature of oligomers, their conformational properties and the atomic mechanisms underlying the β-barrel formation remain largely elusive. Herein, we investigated the hexameric conformational distributions of the wild-type (WT) TDP-43307-319 fragment and its A315T and A315E mutants by performing all-atom explicit-solvent replica exchange with solute tempering 2 simulations. Our simulations reveal that each peptide can self-assemble into diverse conformations including ordered β-barrels, bilayer β-sheets and/or monolayer β-sheets, and disordered complexes. A315T and A315E mutants display higher propensity to form β-barrel structures than the WT, which provides atomic explanation for their enhanced neurotoxicity reported previously. Detailed interaction analysis shows that A315T and A315E mutations increase inter-molecular interactions. Also, the β-barrel structures formed by the three different peptides are stabilized by distinct inter-peptide side-chain hydrogen bonding, hydrophobic, and aromatic stacking interactions. This study demonstrates the enhanced β-barrel formation of the TDP-43307-319 hexamer by the pathogenic A315T and A315E mutations and reveals the underlying molecular determinants, which may be helpful for in-depth understanding of the ALS-mutation-induced neurotoxicity of TDP-43 protein.