The SIRT-1/Nrf2/HO-1 axis: Guardians of neuronal health in neurological disorders.

SIRT1 (Sirtuin 1) is a NAD+-dependent deacetylase that functions through nucleoplasmic transfer and is present in nearly all mammalian tissues. SIRT1 is believed to deacetylate its protein substrates, resulting in neuroprotective actions, including reduced oxidative stress and inflammation, increased autophagy, increased nerve growth factors, and preserved neuronal integrity in aging or neurological disease. Nrf2 is a transcription factor that regulates the genes responsible for oxidative stress response and substance detoxification. The activation of Nrf2 guards cells against oxidative damage, inflammation, and carcinogenic stimuli. Several neurological abnormalities and inflammatory disorders have been associated with variations in Nrf2 activation caused by either pharmacological or genetic factors. Recent evidence indicates that Nrf2 is at the center of a complex cellular regulatory network, establishing it as a transcription factor with genuine pleiotropy. HO-1 is most likely a component of a defense mechanism in cells under stress, as it provides negative feedback for cell activation and mediator synthesis. This mediator is upregulated by Nrf2, nitric oxide (NO), and other factors in various inflammatory states. HO-1 or its metabolites, such as CO, may mitigate inflammation by modulating signal transduction pathways. Neurological diseases may be effectively treated by modulating the activity of HO-1. Multiple studies have demonstrated that SIRT1 and Nrf2 share an important connection. SIRT1 enhances Nrf2, activates HO-1, protects against oxidative injury, and decreases neuronal death. This has been associated with numerous neurodegenerative and neuropsychiatric disorders. Therefore, activating the SIRT1/Nrf2/HO-1 pathway may help treat various neurological disorders. This review focuses on the current understanding of the SIRT1 and Nrf2/HO-1 neuroprotective processes and the potential therapeutic applications of their target activators in neurodegenerative and neuropsychiatric disorders.

Valencene as a novel potential downregulator of THRB in NSCLC: network pharmacology, molecular docking, molecular dynamics simulation, ADMET analysis, and in vitro analysis.

This study investigates the molecular targets and pathways affected by valencene in non-small cell lung cancer (NSCLC) through network pharmacology and in vitro assays. Valencene's chemical structure was sourced from PubChem, and target identification utilized the PharmMapper database, cross-referenced with UniProtKB for official gene symbols. NSCLC-associated targets were identified via GeneCards, followed by protein-protein interaction analysis using STRING. Molecular docking studies employed AutoDock Vina to assess binding interactions with key nuclear receptors (RXRA, RXRB, RARA, RARB, THRB). Molecular dynamics simulations were conducted in GROMACS over 200 ns, while ADME/T properties were evaluated using Protox. In vitro assays measured cell viability in A549 and HEL 299 cells via MTT assays, assessed apoptosis through Hoechst staining, and evaluated mitochondrial potential with JC-1. Molecular docking revealed strong binding affinities of valencene (below - 5 kcal/mol) to nuclear receptors, outperforming 5-fluorouracil (5-FU). Molecular dynamics simulations indicated robust structural stability of the THRB-valencene complex, with favorable interaction energies. Notably, valencene exhibited a selectivity index of 2.293, higher than 5-FU's 2.231, suggesting enhanced safety for normal cells (HEL 299). Fluorescence microscopy confirmed dose-dependent DNA fragmentation and decreased mitochondrial membrane potential. These findings underscore valencene's potential as an effective therapeutic agent for lung cancer, demonstrating an IC50 of 16.71 µg/ml in A549 cells compared to 5-FU's 12.7 µg/ml, warranting further investigation in preclinical models and eventual clinical trials.

Tunable photo-response in the visible to NIR spectrum range of Germanium-based junctionless nanowire transistor.

In this paper, the phototransistor behavior is investigated in the germanium-on-insulator (GeOI)-based junctionless nanowire (JL-NW) transistor under various light conditions. High responsivity and photosensitivity are attributed in the fully depleted regime within the visible and near-infrared bands. The impact of light is also investigated in detail on the electronic and transfer characteristics such as energy bandgap, carrier distribution, electrostatic potential, electric field, and generation and recombination rates. Further, the channel doping and thickness are tuned to optimize the optical responsivity. The significant tunability of responsivity is observed with increasing channel thickness. The device exhibits fast optical switching performance, which is further enhanced at higher input light power. Overall, at the nanoscale dimension, our proposed phototransistor demonstrates better detectivity with a significantly smaller illumination area. Thus, the GeOI-based JL-NW phototransistors can be used for imaging (visible wavelength range) and bioimaging (near-infrared wavelength range) applications in advanced technology nodes.

Successful Treatment of Recalcitrant Chloracne With Adalimumab in an Older Man.

This case report describes a man in his 60s with recalcitrant chloracne caused by chlorantraniliprole, a chlorinated pesticide, exposure successfully treated with adalimumab.

Giant Cell Tumor of First Metatarsal: A Rare Case Report with Literature Review.

Introduction: Giant cell tumor (GCT) is a benign locally aggressive tumor with features of frequent recurrence and metastatic potential. GCT of small bones of hand and feet is rare with high recurrence and potential to metastasis. This study aims to provide a case report of GCT of the first metatarsal treated with wide excision, autologous fibular grafting, and fixation with locking plate. Case Report: An 18-year-old male patient presented with progressive swelling over the dorsomedial aspect of foot for 1 year. Upon clinical examination, the swelling was firm with local signs suggestive of a benign bony tumor arising from the base of first metatarsal of the left foot. Radiology reveals an expansile osteolytic lesion arising from the base of 1st metatarsal with coarse septations and features suggestive of a benign bone lesion. A core biopsy was obtained under local anesthesia and histopathology report suggested a GCT. Surgical intervention by en bloc excision and reconstruction by fibular autograft and stabilized with a locking plate was done. The patient was given a below-knee cast for 6 weeks postoperatively. Full weight bearing was started after 6 weeks. At 12 months of follow-up, the graft was well taken up and there were no signs of recurrence both clinically and radiologically. Conclusion: GCT of 1st metatarsal is a rare entity with higher recurrence rate compared to conventional GCT. En bloc excision and autologous fibular graft with plate fixation are preferred treatment options.

The Deepest Blue: Major Advances and Challenges in Deep Blue Emitting Quasi-2D and Nanocrystalline Perovskite LEDs.

In this review, the recent development of blue perovskite light-emitting diodes (PeLED) are summarized. On deep-blue (≤465 nm) perovskite nanomaterials of different structural forms are mainly focused, including nanocrystals (NCs), quantum dots (QDs), nanoplatelets (NPLs), quasi-2D thin film, 3D bulk thin film, as well as lead-free perovskite nanomaterials. The current challenges are also examined in producing efficient deep-blue PeLED, such as material and spectral instability, imbalance charge transport, Joule heat impact, and poor optoelectronic performance. Several strategies are further discussed to overcome these challenges and achieve efficient deep-blue PeLED for next-generation display technology.

Innovations in the management of epistaxis secondary to hereditary hemorrhagic telangiectasia: our evolution to injection sclerotherapy as the treatment of choice.

Introduction: We compared the efficacy of intralesional sclerotherapy using 3% sodium tetradecyl sulfate with non-sclerotherapy-based treatments for Hereditary Hemorrhagic Telangiectasia-associated epistaxis management. Methodology: This is a retrospective study of patients who underwent surgical intervention for HHT-associated epistaxis management from 01/2010-02/2024. Patients undergoing sclerotherapy with intralesional 3% sodium tetradecyl sulfate were included in the sclerotherapy group and others undergoing conventional non-sclerotherapy-based procedures in the non-sclerotherapy group. Outcomes like breakthrough epistaxis, emergency visits, intra-op blood loss, blood transfusions, and procedure complications in the 3-month perioperative period were compared. Results: Twenty-three patients who underwent 74 intranasal procedures were identified. In the sclerotherapy group, 17 patients underwent 47 procedures. In the non-sclerotherapy group, 10 patients underwent 27 procedures. Till the 3rd post-treatment month, fewer breakthrough epistaxis episodes were observed after sclerotherapy procedures (13/47) vs. non-sclerotherapy procedures (14/27); (p = 0.037). Intraoperative blood loss was significantly lower during sclerotherapy (median: 10 ml) vs. non-sclerotherapy procedures (median: 50 ml); p < 0.001. The time interval between successive procedures was not significantly different in the sclerotherapy (median 6.5 months) vs. the non-sclerotherapy group (median 3.5 months); p = 0.13. Nasal crusting was the most common complication in the sclerotherapy group (36.9%). Two patients in each group had new onset septal perforation, none of the patients had vision loss or cerebrovascular accident. One emergency department visit was reported in the sclerotherapy group vs. 7 (in 3 patients) in the non-sclerotherapy group. Conclusions: Compared to non-sclerotherapy treatments, intralesional sclerotherapy for epistaxis in HHT is more effective in decreasing breakthrough epistaxis, and has lower intraoperative blood loss.

Impact of salt strength on in vitro propagation and rebaudioside A content in Stevia rebaudiana under semi-solid and liquid MS media.

Stevia rebaudiana (Bertoni), commonly known as stevia, is a sought-after natural sweetener, but its conventional propagation methods are slow and inefficient. This study aims to enhance the in vitro culture for stevia by investigating the impact of different Murashige and Skoog (MS) medium salt strengths and plant growth hormones on growth and rebaudioside A content. Apical bud-containing shoot segments were used as explants and cultured on various semi-solid and liquid MS media formulations, incorporating cytokinins (BAP and Kin), auxins (NAA and IAA), and different MS major salt concentrations (MS full, ½ MS, and » MS). Assessments of shoot growth parameters, root formation, and HPLC analysis for rebaudioside A content were conducted. The optimal conditions for in vitro growth was found to be in the » MS + Kin 3 mg/L + NAA 0.1 mg/L (semi-solid) medium, resulting in significantly improved shoot growth and enhanced 30.04% rebaudioside A content. Genetic fidelity of regenerated plants was confirmed using RAPD and ISSR markers. These findings offer valuable insights for optimizing in vitro propagation of stevia and potentially enhancing rebaudioside A content.

Fluoroquinolones tackling antimicrobial resistance: Rational design, mechanistic insights and comparative analysis of norfloxacin vs ciprofloxacin derivatives.

Antimicrobial resistance poses a global health concern and develops a need to discover novel antimicrobial agents or targets to tackle this problem. Fluoroquinolone (FN), a DNA gyrase and topoisomerase IV inhibitor, has helped to conquer antimicrobial resistance as it provides flexibility to researchers to rationally modify its structure to increase potency and efficacy. This review provides insights into the rational modification of FNs, the causes of resistance to FNs, and the mechanism of action of FNs. Herein, we have explored the latest advancements in antimicrobial activities of FN analogues and the effect of various substitutions with a focus on utilizing the FN nucleus to search for novel potential antimicrobial candidates. Moreover, this review also provides a comparative analysis of two widely prescribed FNs that are ciprofloxacin and norfloxacin, explaining their rationale for their design, structure-activity relationships (SAR), causes of resistance, and mechanistic studies. These insights will prove advantageous for new researchers by aiding them in designing novel and effective FN-based compounds to combat antimicrobial resistance.

Crosstalk between ROS-inflammatory gene expression axis in the progression of lung disorders.

A significant number of deaths and disabilities worldwide are brought on by inflammatory lung diseases. Many inflammatory lung disorders, including chronic respiratory emphysema, resistant asthma, resistance to steroids, and coronavirus-infected lung infections, have severe variants for which there are no viable treatments; as a result, new treatment alternatives are needed. Here, we emphasize how oxidative imbalance contributes to the emergence of provocative lung problems that are challenging to treat. Endogenic antioxidant systems are not enough to avert free radical-mediated damage due to the induced overproduction of ROS. Pro-inflammatory mediators are then produced due to intracellular signaling events, which can harm the tissue and worsen the inflammatory response. Overproduction of ROS causes oxidative stress, which causes lung damage and various disease conditions. Invasive microorganisms or hazardous substances that are inhaled repeatedly can cause an excessive amount of ROS to be produced. By starting signal transduction pathways, increased ROS generation during inflammation may cause recurrent DNA damage and apoptosis and activate proto-oncogenes. This review provides information about new targets for conducting research in related domains or target factors to prevent, control, or treat such inflammatory oxidative stress-induced inflammatory lung disorders.

Voltage-gated calcium channels act upstream of adenylyl cyclase Ac78C to promote timely initiation of dendrite regeneration.

Most neurons are not replaced after injury and thus possess robust intrinsic mechanisms for repair after damage. Axon injury triggers a calcium wave, and calcium and cAMP can augment axon regeneration. In comparison to axon regeneration, dendrite regeneration is poorly understood. To test whether calcium and cAMP might also be involved in dendrite injury signaling, we tracked the responses of Drosophila dendritic arborization neurons to laser severing of axons and dendrites. We found that calcium and subsequently cAMP accumulate in the cell body after both dendrite and axon injury. Two voltage-gated calcium channels (VGCCs), L-Type and T-Type, are required for the calcium influx in response to dendrite injury and play a role in rapid initiation of dendrite regeneration. The AC8 family adenylyl cyclase, Ac78C, is required for cAMP production after dendrite injury and timely initiation of regeneration. Injury-induced cAMP production is sensitive to VGCC reduction, placing calcium upstream of cAMP generation. We propose that two VGCCs initiate global calcium influx in response to dendrite injury followed by production of cAMP by Ac78C. This signaling pathway promotes timely initiation of dendrite regrowth several hours after dendrite damage.

Unlocking the possibilities of therapeutic potential of silymarin and silibinin against neurodegenerative Diseases-A mechanistic overview.

Silymarin, a bioflavonoid derived from the Silybum marianum plant, was discovered in 1960. It contains C25 and has been extensively used as a therapeutic agent against liver-related diseases caused by alcohol addiction, acute viral hepatitis, and toxins-inducing liver failure. Its efficacy stems from its role as a potent anti-oxidant and scavenger of free radicals, employed through various mechanisms. Additionally, silymarin or silybin possesses immunomodulatory characteristics, impacting immune-enhancing and immune-suppressive functions. Recently, silymarin has been recognized as a potential neuroprotective therapy for various neurological conditions, including Parkinson's and Alzheimer's diseases, along with conditions related to cerebral ischemia. Its hepatoprotective qualities, primarily due to its anti-oxidant and tissue-regenerating properties, are well-established. Silymarin also enhances health by modifying processes such as inflammation, ß-amyloid accumulation, cellular estrogenic receptor mediation, and apoptotic machinery. While believed to reduce oxidative stress and support neuroprotective mechanisms, these effects represent just one aspect of the compound's multifaceted protective action. This review article further delves into the possibilities of potential therapeutic advancement of silymarin and silibinin for the management of neurodegenerative disorders via mechanics modules.

A comprehensive review of synthetic and semisynthetic xanthine oxidase inhibitors: identification of potential leads based on in-silico computed ADME characteristics.

Xanthine oxidase (XO) inhibitors, both synthetic and semisynthetic, have been developed extensively over the past few decades. The increased level of XO is not only the major cause of gout but is also responsible for various conditions associated with hyperuricemia, such as cardiovascular disorders, chronic kidney disorders, diabetes, Alzheimer's disease and chronic wounds. Marketed available XO inhibitors (allopurinol, febuxostat, and topiroxostat) are used to treat hyperuricemia but they are associated with fatal side effects, which pose serious problems for the healthcare system, rising the need for new, more potent, safer compounds. This review summarizes recent findings on XO and describes their design, synthesis, biological significance in the development of anti-hyperuricemic drugs with ADME profile, structure activity relationship (SAR) and molecular docking studies. The results might help medicinal chemists to develop more efficacious XO inhibitors.

Transcriptional and secretome analysis of Rasamsonia emersonii lytic polysaccharide mono-oxygenases.

The current study is the first to describe the temporal and differential transcriptional expression of two lytic polysaccharide monooxygenase (LPMO) genes of Rasamsonia emersonii in response to various carbon sources. The mass spectrometry based secretome analysis of carbohydrate active enzymes (CAZymes) expression in response to different carbon sources showed varying levels of LPMOs (AA9), AA3, AA7, catalase, and superoxide dismutase enzymes pointing toward the redox-interplay between the LPMOs and auxiliary enzymes. Moreover, it was observed that cello-oligosaccharides have a negative impact on the expression of LPMOs, which has not been highlighted in previous reports. The LPMO1 (30 kDa) and LPMO2 (47 kDa), cloned and expressed in Pichia pastoris, were catalytically active with (kcat/Km) of 6.6×10-2 mg-1 ml min-1 and 1.8×10-2 mg-1 ml min-1 against Avicel, respectively. The mass spectrometry of hydrolysis products of Avicel/carboxy methyl cellulose (CMC) showed presence of C1/C4 oxidized oligosaccharides indicating them to be Type 3 LPMOs. The 3D structural analysis of LPMO1 and LPMO2 revealed distinct arrangements of conserved catalytic residues at their active site. The developed enzyme cocktails consisting of cellulase from R. emersonii mutant M36 supplemented with recombinant LPMO1/LPMO2 resulted in significantly enhanced saccharification of steam/acid pretreated unwashed rice straw slurry from PRAJ industries (Pune, India). The current work indicates that LPMO1 and LPMO2 are catalytically efficient and have a high degree of thermostability, emphasizing their usefulness in improving benchmark enzyme cocktail performance. KEY POINTS: • Mass spectrometry depicts subtle interactions between LPMOs and auxiliary enzymes. • Cello-oligosaccharides strongly downregulated the LPMO1 expression. • Developed LPMO cocktails showed superior hydrolysis in comparison to CellicCTec3.

KLP-7/Kinesin-13 orchestrates axon-dendrite checkpoints for polarized trafficking in neurons.

The polarized nature of neurons depends on their microtubule dynamics and orientation determined by both microtubule-stabilizing and destabilizing factors. The role of destabilizing factors in developing and maintaining neuronal polarity is unclear. We investigated the function of KLP-7, a microtubule depolymerizing motor of the Kinesin-13 family, in axon-dendrite compartmentalization using PVD neurons in Caenorhabditis elegans. Loss of KLP-7 caused a mislocalization of axonal proteins, including RAB-3, SAD-1, and their motor UNC-104, to dendrites. This is rescued by cell-autonomous expression of the KLP-7 or colchicine treatment, indicating the involvement of KLP-7-dependent microtubule depolymerization. The high mobility of KLP-7 is correlated to increased microtubule dynamics in the dendrites, which restricts the enrichment of UNC-44, an integral component of Axon Initial Segment (AIS) in these processes. Due to the loss of KLP-7, ectopic enrichment of UNC-44 in the dendrite potentially redirects axonal traffic into dendrites that include plus-end out microtubules, axonal motors, and cargoes. These observations indicate that KLP-7-mediated depolymerization defines the microtubule dynamics conducive to the specific enrichment of AIS components in dendrites. This further compartmentalizes dendritic and axonal microtubules, motors, and cargoes, thereby influencing neuronal polarity.

Recent Advancement in NMR Based Plant Metabolomics: Techniques, Tools, and Analytical Approaches.

Plant metabolomics, a rapidly advancing field within plant biology, is dedicated to comprehensively exploring the intricate array of small molecules in plant systems. This entails precisely gathering comprehensive chemical data, detecting numerous metabolites, and ensuring accurate molecular identification. Nuclear magnetic resonance (NMR) spectroscopy, with its detailed chemical insights, is crucial in obtaining metabolite profiles. Its widespread application spans various research disciplines, aiding in comprehending chemical reactions, kinetics, and molecule characterization. Biotechnological advancements have further expanded NMR's utility in metabolomics, particularly in identifying disease biomarkers across diverse fields such as agriculture, medicine, and pharmacology. This review covers the stages of NMR-based metabolomics, including historical aspects and limitations, with sample preparation, data acquisition, spectral processing, analysis, and their application parts.

Effect of cold arid high-altitude environment on bioactive phytochemical compounds of organically grown Brassicaceae vegetables for nutri-health security in mountainous regions.

High-altitude (HA) environment presents immense physiological adversities for humans that have been overcome by supplementing bio-active phytochemicals from functional foods that support and accelerate acclimatization under these extreme environmental conditions. Several agricultural interventions have been investigated to enhance the phytochemical content in vegetables however; these studies have been limited to low-altitude (LA) regions only. In view of an existing knowledge gap, current work is designed to compare the phytochemical compositions of HA and LA-grown Brassicaceae vegetables (cabbage, cauliflower, knol-khol, and radish) using organic treatments via farm yard manure (FYM) and Azotobacter. The open field study was conducted as a two-factorial randomized block design. The first factor was treatment (T1-FYM, T2-Azotobacter, T3-FYM + Azotobacter, and T4-control) while the second was locations (HA and LA). Among all these treatments, the application of treatment T3 in HA-grown cabbage showed the highest total phenolic content (TPC; 9.56 µg/mg), total flavonoids content (TFC; 14.48 µg/mg), and antioxidant potential using 2,2-diphenyl-1-picrylhydrazyl (DPPH; 85.97%) and ferric reducing antioxidant power (FRAP; 30.77 µg/mg) compared to LA grown samples. Reverse Phase high performance liquid chromatography (RP-HPLC) analysis showed that treatment T3 at HA led to significantly high kaempferol (0.92 µg/mg) and sulforaphane (8.94 µg/mg) contents in cabbage whereas, indole-3-carbinol (1.31 µg/mg) was higher in HA grown cauliflower. The present study provides scientific evidence for the enrichment of health-promoting phytochemical compounds in Brassicaceae vegetables grown with T3 treatment specifically at HA.

Unveiling the role of exosomes as cellular messengers in neurodegenerative diseases and their potential therapeutic implications.

Exosomes are a subgroup of extracellular vesicles that function as transmitters, allowing cells to communicate more effectively with each other. However, exosomes may have both beneficial and harmful impacts on central nervous system disorders. Hence, the fundamental molecular mechanisms of the origin of illness and its progression are currently being investigated. The involvement of exosomes in the origin and propagation of neurodegenerative illness has been demonstrated recently. Exosomes provide a representation of the intracellular environment since they include various essential bioactive chemicals. The latest studies have demonstrated that exosomes transport several proteins. Additionally, these physiological vesicles are important in the regeneration of nervous tissue and the healing of neuronal lesions. They also offer a microenvironment to stimulate the conformational variation of concerning proteins for aggregation, resulting in neurodegenerative diseases. The biosynthesis, composition, and significance of exosomes as extracellular biomarkers in neurodegenerative disorders are discussed in this article, with a particular emphasis on their neuroprotective effects.