Natural autophagy activators: A promising strategy for combating photoaging.

BACKGROUND: Photodamage to the skin stands out as one of the most widespread epidermal challenges globally. Prolonged exposure to sunlight containing ultraviolet radiation (UVR) instigates stress, thereby compromising the skin's functionality and culminating in photoaging. Recent investigations have shed light on the importance of autophagy in shielding the skin from photodamage. Despite the acknowledgment of numerous phytochemicals possessing photoprotective attributes, their potential to induce autophagy remains relatively unexplored. PURPOSE: Diminished autophagy activity in photoaged skin underscores the potential benefits of restoring autophagy through natural compounds to enhance photoprotection. Consequently, this study aims to highlight the role of natural compounds in safeguarding against photodamage and to assess their potential to induce autophagy via an in-silico approach. METHODS: A thorough search of the literature was done using several databases, including PUBMED, Science Direct, and Google Scholar, to gather relevant studies. Several keywords such as Phytochemical, Photoprotection, mTOR, Ultraviolet Radiation, Reactive oxygen species, Photoaging, and Autophagy were utilized to ensure thorough exploration. To assess the autophagy potential of phytochemicals through virtual screening, computational methodologies such as molecular docking were employed, utilizing tools like AutoDock Vina. Receptor preparation for docking was facilitated using MGLTools. RESULTS: The initiation of structural and functional deterioration in the skin due to ultraviolet radiation (UVR) or sunlight-induced reactive oxygen species/reactive nitrogen species (ROS/RNS) involves the modulation of various pathways. Natural compounds like phenolics, flavonoids, flavones, and anthocyanins, among others, possess chromophores capable of absorbing light, thereby offering photoprotection by modulating these pathways. In our molecular docking study, these phytochemicals have shown binding affinity with mTOR, a negative regulator of autophagy, indicating their potential as autophagy modulators. CONCLUSION: This integrated review underscores the photoprotective characteristics of natural compounds, while the in-silico analysis reveals their potential to modulate autophagy, which could significantly contribute to their anti-photoaging properties. The findings of this study hold promise for the advancement of cosmeceuticals and therapeutics containing natural compounds aimed at addressing photoaging and various skin-related diseases. By leveraging their dual benefits of photoprotection and autophagy modulation, these natural compounds offer a multifaceted approach to combatting skin aging and related conditions.

Screening and analysis of single nucleotide polymorphism in the 3'-UTR microRNA target regions and its implications for lung tumorigenesis.

Aim: The study aims to identify high-impact single nucleotide polymorphisms (SNPs) in miRNA target sites of genes associated with lung cancer. Materials & methods: Lung cancer genes were obtained from Uniprot KB. miRNA target site SNPs were mined from MirSNP, miRdSNP and TargetScan. SNPs were shortlisted based on binding impact, minor allele frequency and conservation. Gene expression was analyzed in genes with high-impact SNPs in healthy versus lung cancer tissue. Additionally, enrichment, pathway and network analyzes were performed. Results: 19 high-impact SNPs were identified in miRNA target sites of lung cancer-associated genes. These SNPs affect miRNA binding and gene expression. The genes are involved in key cancer related pathways. Conclusion: The identified high-impact miRNA target site SNPs and associated genes provide a starting point for case-control studies in lung cancer patients in different populations.

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In silico analysis of Diosmetin as an effective chemopreventive agent against prostate cancer: molecular docking, validation, dynamic simulation and pharmacokinetic prediction-based studies.

Prostate cancer is the second most dangerous cancer type worldwide. While various treatment options are present i.e. agonists and antagonists, their utilization leads to adverse effects and due to this resistance developing, ultimately the outcome is remission. So, to overcome this issue, we have undertaken an in-silico investigation to identify promising and unique flavonoid candidates for combating prostate cancer. Using GOLD software, the study assessed the effectiveness of 560 natural secondary polyphenols against CDKN2. Protein Data Bank was used to retrieve the 3D crystal structure of CDKN2 (PDB Id: 4EK3) and we retrieved the structure of selected secondary polyphenols from the PubChem database. The compound Diosmetin shows the highest GOLD score with the selected Protein i.e. CDKN2 which is 58.72. To better understand the 2-dimensional and 3-dimensional interactions, the interacting amino acid residues were visualised using Discovery Studio 3.5 and Maestro 13.5. Using Schrodinger-Glide, the Diosmetin and CDKN2 were re-docked, and decoy ligands were docked to CDKN2, which was used to further ascertain the study. The ligands with the highest Gold score were forecasted for pharmacokinetics characteristics, and the results were tabulated and analysed. Utilising the Gromacs software and Desmond packages, 100 ns of Diosmetin molecular dynamics simulations were run to evaluate the structural persistence and variations of protein-ligand complexes. Additionally, our investigation revealed that Diosmetin had a better binding affinity with CDKN2 measuring 58.72, and it also showed remarkable stability across a 100-ns simulation. Thus, following in-vitro and in-vivo clinical studies, diosmetin might lead to the Prostate regimen.Communicated by Ramaswamy H. Sarma.

In silico study of novel alpha tocopheroids as effective inhibitors of aldo-keto reductase 1c3 (AKR1C3) enzyme.

Aldo-keto reductase 1C3 (AKR1C3) is a monomeric enzyme expressed in steroidogenic tissues such as the testis, prostate, uterus, and breast. Overexpression of this AKR1C3 is associated with vast cancers such as breast, colon, colorectal, endometrial, prostate, and acute myeloid leukaemia. Regarding the treatment of castration-resistant prostate cancer, breast cancer, and acute myeloid leukaemia, AKR1C3 inhibitors may offer clear advantages over currently available therapies. Thus, discovering novel and specific AKR1C3 inhibitors is a promising way to obstruct drug resistance in cancer. Derivatives of alpha-tocopherol and alpha-tocopheroids were selected as possible therapeutics to act as AKR1C3 inhibitors. The precise targets of several ligands were determined using computational screening methods. The molecular structure of AKR1C3 and its ligands were used as the foundation for in silico predictions, modelling, and dynamic simulations. Compounds were selected based on their biological properties and filtered according to their ADMET and drug-likeness properties. Additionally, simulations of all-atom molecular dynamics on AKR1C3 with the cleared compounds revealed stability over the simulated trajectories of 100 ns. When seen collectively, alpha-tocospiro A may be considered prospective AKR1C3 inhibitors for creating anticancer therapies.Communicated by Ramaswamy H. Sarma.

miRNAs are now starring in "No Time to Die: Overcoming the chemoresistance in cancer".

Cancer is a leading cause of death globally, with about 19.3 million new cases reported each year. Current therapies for cancer management include-chemotherapy, radiotherapy, and surgery. However, they are loaded with side effects and tend to cause toxicity in the patient's body posttreatment, ultimately hindering the response towards the treatment building up resistance. This is where noncoding RNAs such as miRNAs help provide us with a helping hand for taming the chemoresistance and providing potential holistic cancer management. MicroRNAs are promising targets for anticancer therapy as they perform critical regulatory roles in various signaling cascades related to cell proliferation, apoptosis, migration, and invasion. Combining miRNAs and anticancer drugs and devising a combination therapy has managed cancer well in various independent studies. This review aims to provide insights into how miRNAs play a mechanistic role in cancer development and progression and regulate drug resistance in various types of cancers. Furthermore, next-generation novel therapies using miRNAs in combination with anticancer treatments in multiple cancers have been put forth and how they improve the efficacy of the treatments. Exemplary studies currently in the preclinical and clinical models have been summarized. Ultimately, we briefly talk through the challenges that come forward with it and minimize them.

Design of a multi-epitope vaccine against the pathogenic fungi Candida tropicalis using an in silico approach.

BACKGROUND: Candida tropicalis causes tropical invasive fungal infections, with a high mortality. This fungus has been found to be resistant to antifungal classes such as azoles, echinocandins, and polyenes in several studies. As a result, it is vital to identify novel approaches to prevent and treat C. tropicalis infections. In this study, an in silico technique was utilized to deduce and evaluate a powerful multivalent epitope-based vaccine against C. tropicalis, which targets the secreted aspartic protease 2 (SAP2) protein. This protein is implicated in virulence and host invasion. RESULTS: By focusing on the Sap2 protein, 11 highly antigenic, non-allergic, non-toxic, and conserved epitopes were identified. These were subsequently paired with RS09 and flagellin adjuvants, as well as a pan HLA DR-binding epitope (PADRE) sequence to create a vaccine candidate that elicited both cell-mediated and humoral immune responses. It was projected that the vaccine design would be soluble, stable, antigenic, and non-allergic. Ramachandran plot analysis was applied to validate the vaccine construct's 3-dimensional model. The vaccine construct was tested (at 100 ns) using molecular docking and molecular dynamics simulations, which demonstrated that it can stably connect with MHC-I and Toll-like receptor molecules. Based on in silico studies, we have shown that the vaccine construct can be expressed in E. coli. We surmise that the vaccine design is unrelated to any human proteins, indicating that it is safe to use. CONCLUSIONS: The vaccine design looks to be an effective option for preventing C. tropicalis infections, based on the outcomes of the studies. A fungal vaccine can be proposed as prophylactic medicine and could provide initial protection as sometimes diagnosis of infection could be challenging. However, more in vitro and in vivo research is needed to prove the efficacy and safety of the proposed vaccine design.

Development, In-Vitro Characterization and Preclinical Evaluation of Esomeprazole-Encapsulated Proniosomal Formulation for the Enhancement of Anti-Ulcer Activity.

Objective: The present study aimed to develop and optimize esomeprazole loaded proniosomes (EZL-PNs) to improve bioavailability and therapeutic efficacy. Method: EZL-PNs formulation was developed by slurry method and optimized by 33 box-Bhekhen statistical design software. Span 60 (surfactant), cholesterol, EZL concentration were taken as independent variables and their effects were evaluated on vesicle size (nm), entrapment efficiency (%, EE) and drug release (%, DR). Furthermore, optimized EZL-PNs (EZL-PNs-opt) formulation was evaluated for ex vivo permeation, pharmacokinetic and ulcer protection activity. Result: The EZL-PNs-opt formulation showed 616 ± 13.21 nm of vesicle size, and 81.21 ± 2.35% of EE. EZL-PNs-opt exhibited negative zeta potential and spherical confirmed scanning electron microscopy. EZL-PNs-opt showed sustained release of EZL (95.07 ± 2.10% in 12 h) than pure EZL dispersion. The ex-vivo gut permeation result exhibited a significantly (p < 0.05) enhanced flux than pure EZL. The in vivo results revealed 4.02-fold enhancement in bioavailability and 61.65% protection in ulcer than pure EZL dispersion (43.82%). Conclusion: Our findings revealed that EZL-PNs formulation could be an alternative delivery system of EZL to enhance oral bioavailability and antiulcer activity.

Structural insights into the amino acid usage variations in the profilin gene family.

Profilin protein is present ubiquitously in all forms of life and is allied with allergic responses among atopic individuals. In addition to this, profilins from various food sources are also associated with IgE cross-reactivity and are thus classified as pan-allergens. The present study unravels the physicochemical basis of differential amino acid usage patterns observed in the profilin gene family. Correspondence analysis based on amino acid usage of allergen and non-allergen profilins revealed discrete clusters among them, signifying differential patterns of amino acid usage. The amino acids, namely methionine, proline, histidine, glutamine, glutamic acid, tryptophan and glycine were found to be more frequently utilised by the allergen profilins compared to the non-allergens. Correlation analysis revealed that physicochemical features like protein disorder, trypsin digestion and solubility differed significantly among the allergen and non-allergen profilins, thus supporting the observations from correspondence analysis. In addition, comprehensive sequence analysis revealed that the allergen profilins possess conserved motifs which may correlate with their distinct physicochemical features. An in-depth structural analysis revealed that the over-represented amino acids in allergen profilins have a propensity of being exposed on the surface, which may be attributed to their distinct allergenic characteristics. The distinguished physicochemical features observed among allergens and non-allergens can be employed as descriptors to develop machine learning-based allergenicity prediction models.

Bioaccumulation and Toxicity of As in the Alga Chlorococcum sp.: Prospects for As Bioremediation.

Ubiquitous distribution, fast growth rate and manifold relevance has credited algae a potential bioresource in current state of affairs of environmental degradation. In the present study, green alga Chlorococcum sp. has been collected from waste water, isolated and cultured to assess their accumulation and toxicity responses at different As(III) concentration. Results revealed that Chlorococcum sp. treated with 10 µM As(III) showed a minimal reduction (21%) in chlorophyll concentration with high proline and carotenoids content indicating its adaptive tolerance potential against As(III). The EC50 of As(III) for inhibiting growth of the microalgae after 10 days of experiment was 9.4 µM. Further, Chlorococcum sp. accumulated 239.09 µg g- 1 dw As at the concentration of 10 µM of As(III) after 10 days of treatment. Concentration dependent accumulation pattern and antioxidant responses in Chlorococcum sp. could be a used as a potential bioindicator and bioremediator of As from waste water.

T-cell epitope-based vaccine designing against Orthohantavirus: a causative agent of deadly cardio-pulmonary disease.

Orthohantavirus, a zoonotic virus responsible for causing human cardio-pulmonary disease, is proven to be a fatal disease. Due to the paucity of regimens to cure the disease and efficient management to eradicate this deadly virus, there is a constant need to expand in-silico approaches belonging to immunology domain to formulate best feasible peptide-based vaccine against it. In lieu of that, we have predicted and validated an epitope of nine-residue-long sequence "MIGLLSSRI". The predicted epitope has shown best interactions with HLA alleles of MHC Class II proteins, namely HLA DRB1_0101, DRB1_0401, DRB1_0405, DRB1_0701, DRB1_0901, DRB1_1302, and DRB1_1501. The structure of the epitope was modeled by deploying PEPFOLD 3.5 and verified by Ramachandran plot analysis. Molecular docking and simulation studies reveal that this epitope has satisfactory binding scores, ACE value and global energies for docked complexes along with selectable range of RMSD and RMSF values. Also, the predicted epitope "MIGLLSSRI" exhibits population coverage of more than 62% in world population and maximum of 70% in the United States of America. In this intensive study, we have used many tools like AllergenFP, NETMHCII 3.2, VaxiJen, ToxinPred, PEPFOLD 3.5, DINC, IEDB-Population coverage, MHCPred and JCat server. Most of these tools are based on modern innovative statistical algorithms like HMM, ANN, ML, etc. that help in better predictions of putative candidates for vaccine crafting. This innovative methodology is facile, cost-effective and time-efficient, which could facilitate designing of a vaccine against this virus.

Screening of potent drug inhibitors against SARS-CoV-2 RNA polymerase: an in silico approach.

COVID-19 has emerged as a rapidly escalating serious global health issue, affecting every section of population in a detrimental way. Present situation invigorated researchers to look for potent targets, development as well as repurposing of conventional therapeutic drugs. NSP12, a RNA polymerase, is key player in viral RNA replication and, hence, viral multiplication. In our study, we have screened a battery of FDA-approved drugs against SARS-CoV-2 RNA polymerase using in silico molecular docking approach. Identification of potent inhibitors against SARS-CoV-2 NSP12 (RNA polymerase) were screeened from FDA approved drugs by virtual screening for therapeutic applications in treatment of COVID-19. In this study, virtual screening of 1749 antiviral drugs was executed using AutoDock Vina in PyRx software. Binding affinities between NSP12 and drug molecules were determined using Ligplot+ and PyMOL was used for visualization of docking between interacting residues. Screening of 1749 compounds resulted in 14 compounds that rendered high binding affinity for NSP12 target molecule. Out of 14 compounds, 5 compounds which include 3a (Paritaprevir), 3d (Glecaprevir), 3h (Velpatasvir), 3j (Remdesivir) and 3l (Ribavirin) had a binding affinity of - 10.2 kcal/mol, -9.6 kcal/mol, - 8.5 kcal/mol, - 8.0 kcal/mol and - 6.8 kcal/mol, respectively. Moreover, a number of hydrophobic interactions and hydrogen bonding between these 5 compounds and NSP12 active site were observed. Further, 3l (Ribavirin) was docked with 6M71 and molecular dynamic simulation of the complex was also performed to check the stability of the conformation. In silico analysis postulated the potential of conventional antiviral drugs in treatment of COVID-19. However, these finding may be further supported by experimental data for its possible clinical application in present scenario.

Transcriptome analysis reveals plasticity in gene regulation due to environmental cues in Primula sikkimensis, a high altitude plant species.

BACKGROUND: Studying plasticity in gene expression in natural systems is crucial, for predicting and managing the effects of climate change on plant species. To understand the contribution of gene expression level variations to abiotic stress compensation in a Himalaya plant (Primula sikkimensis), we carried out a transplant experiment within (Ambient), and beyond (Below Ambient and Above Ambient) the altitudinal range limit of species. We sequenced nine transcriptomes (three each from each altitudinal range condition) using Illumina sequencing technology. We compared the fitness variation of transplants among three transplant conditions. RESULTS: A large number of significantly differentially expressed genes (DEGs) between below ambient versus ambient (109) and above ambient versus ambient (85) were identified. Transcripts involved in plant growth and development were mostly up-regulated in below ambient conditions. Transcripts involved in signalling, defence, and membrane transport were mostly up-regulated in above ambient condition. Pathway analysis revealed that most of the genes involved in metabolic processes, secondary metabolism, and flavonoid biosynthesis were differentially expressed in below ambient conditions, whereas most of the genes involved in photosynthesis and plant hormone signalling were differentially expressed in above ambient conditions. In addition, we observed higher reproductive fitness in transplant individuals at below ambient condition compared to above ambient conditions; contrary to what we expect from the cold adaptive P. sikkimensis plants. CONCLUSIONS: We reveal P. sikkimensis's capacity for rapid adaptation to climate change through transcriptome variation, which may facilitate the phenotypic plasticity observed in morphological and life history traits. The genes and pathways identified provide a genetic resource for understanding the temperature stress (both the hot and cold stress) tolerance mechanism of P. sikkimensis in their natural environment.

Genome-Wide Analysis of Domain-Swap Predicted Products in the Genome of Anti-Stress Medicinal Plant: Ocimum tenuiflorum.

Computational approaches to high-throughput data are gaining importance because of explosion of sequences in the post-genomic era. This explosion of sequence data creates a huge gap among the domains of sequence structure and function, since the experimental techniques to determine the structure and function are very expensive, time taking, and laborious in nature. Therefore, there is an urgent need to emphasize on the development of computational approaches in the field of biological systems. Engagement of proteins in quaternary arrangements, such as domain swapping, might be relevant for higher compatibility of such genes at stress conditions. In this study, the capacity to engage in domain swapping was predicted from mere sequence information in the whole genome of holy Basil (Ocimum tenuiflorum), which is well known to be an anti-stress agent. Approximately, one-fourth of the proteins of O tenuiflorum are predicted to undergo three-dimensional (3D)-domain swapping. Furthermore, function annotation was carried out on all the predicted domain-swap sequences from the O tenuiflorum and Arabidopsis thaliana for their distribution in different Pfam protein families and gene ontology (GO) terms. These domain-swapped protein sequences are associated with many Pfam protein families with a wide range of GO annotation terms. A comparative analysis of domain-swap-predicted sequences in O tenuiflorum with gene products in A thaliana reveals that around 26% (2522 sequences) are close homologues across the 2 genomes. Functional annotation of predicted domain-swapped sequences infers that predicted domain-swap sequences are involved in diverse molecular functions, such as in gene regulation of abiotic stress conditions and adaptation to different environmental niches. Finally, the positively predicted sequences of A thaliana and O tenuiflorum were also examined for their presence in stress regulome, as recorded in our STIFDB database, to check the involvement of these proteins in different abiotic stresses.

GABA accretion reduces Lsi-1 and Lsi-2 gene expressions and modulates physiological responses in Oryza sativa to provide tolerance towards arsenic.

GABA counteracts wide range of stresses through regulation of GABA shunt pathway in plants. Although, GABA assisted tolerance against As toxicity in plants is still unexplored. We have examined GABA induced tolerance in rice seedlings with two exposure periods of GABA i.e., short term and long term. Results showed that accumulation of GABA reduced the expressions of Lsi-1 and Lsi-2 transporter genes, which ultimately decreased the accumulation of As in rice seedlings. The accumulation of GABA also modulated the gene expression of GABA shunt pathway and activity of antioxidant enzymes, which strongly induced the tolerance in plants. Antioxidant enzymes such as CAT, POD, GPX and SOD showed maximum alteration in activity with GABA accretion. In both exposure periods, long term accumulation of GABA was highly efficient to provide tolerance to plants against As(III), while higher level of GABA at short term was toxic. Tolerance responses of GABA towards As(III) was reflected by minimal changes in various physiological (WUE, A, gs, PhiPS2, qp, NPQ, ETR and Trmmol) and growth parameters with concomitant accumulation. Oxidative stress marker such as TBARS and H2O2 contents were reduced with GABA accumulation. These results suggested that GABA sturdily inhibits As accumulation and provides tolerance towards As(III).

Genome-Wide Prediction and Analysis of 3D-Domain Swapped Proteins in the Human Genome from Sequence Information.

3D-domain swapping is one of the mechanisms of protein oligomerization and the proteins exhibiting this phenomenon have many biological functions. These proteins, which undergo domain swapping, have acquired much attention owing to their involvement in human diseases, such as conformational diseases, amyloidosis, serpinopathies, proteionopathies etc. Early realisation of proteins in the whole human genome that retain tendency to domain swap will enable many aspects of disease control management. Predictive models were developed by using machine learning approaches with an average accuracy of 78% (85.6% of sensitivity, 87.5% of specificity and an MCC value of 0.72) to predict putative domain swapping in protein sequences. These models were applied to many complete genomes with special emphasis on the human genome. Nearly 44% of the protein sequences in the human genome were predicted positive for domain swapping. Enrichment analysis was performed on the positively predicted sequences from human genome for their domain distribution, disease association and functional importance based on Gene Ontology (GO). Enrichment analysis was also performed to infer a better understanding of the functional importance of these sequences. Finally, we developed hinge region prediction, in the given putative domain swapped sequence, by using important physicochemical properties of amino acids.