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Abstract Supercritical fluids (SCFs) can be used to prepare drugs nanoparticles with improved solubility. SCFs have shown superior advantages in pharmaceutical industry as an environmentally friendly alternative to toxic/harmful organic solvents. They possess gas-like transport characteristics and liquid-like solvation power for solutes. Evaluation of chemotherapeutic drugs’ solubility in supercritical carbon dioxide (SCCO2) has been recently an attractive subject for developing this method in pharmaceutical sector. To reach this purpose, the utilization of accurate models is of great necessity to estimate experimental-based solubility data. In this paper, the authors tried to employ machine learning (ML) approaches to estimate the solubility of Letrozole (LET) drug as chemotherapeutic agent and correlate its values in wide ranges of temperature and pressure. To do this, PAR (Passive Aggressive Regression), RF (Random Forest), and RBF-SVM are the models used (Support Vector Machine with RBF kernel). These models optimized in terms of their hyper-parameters using GA algorithm. The optimized PAR, RF, RBF-SVM models obtained coefficients of determination (R-squared) of 0.8277, 0.9534, and 0.9947. Also, the MSE error rate of the models are 0.1342, 0.0305, and 0.0045, in the same order. The final result of the evaluations shows the optimized RBF-SVM model as the most appropriate model in this research. The model exhibits a maximum prediction error of 0.1289.

Clostridium histolyticum is a Gram-positive anaerobic bacterium belonging to the Clostridium genus. It produces collagenase, an enzyme involved in breaking down collagen which is a key component of connective tissues. However, antimicrobial resistance (AMR) poses a great challenge in combating infections caused by this bacteria. The lengthy nature of traditional drug development techniques has resulted in a shift to computer-aided drug design and other modern drug discovery approaches. The above method offers a cost-effective means for gathering comprehensive information about how ligands interact with their target proteins. The objective of this study is to create novel, explicit drugs that specifically inhibit the C. histolyticum collagenase enzyme. Through structure-based virtual screening, a library containing 1830 compounds was screened to identify potential drug candidates against collagenase enzymes. Following that, molecular dynamic (MD) simulation was performed in an aqueous solution to evaluate the behavior of protein and ligand in a dynamic environment while density functional theory (DFT) analysis was executed to predict the molecular properties and structure of lead compounds, and the WaterSwap technique was utilized to obtain insights into the drug–protein interaction with water molecules. Furthermore, principal component analysis (PCA) was performed to reveal conformational changes, salt bridges to express electrostatic interaction and protein stability, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) to assess the pharmacokinetics profile of top compounds and control molecules. Three potent drug candidates were identified MSID000001, MSID000002, MSID000003, and the control with a binding score of −10.7 kcal/mol, −9.8 kcal/mol, −9.5 kcal/mol, and −8 kcal/mol, respectively. Furthermore, Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA) analysis of the simulation trajectories revealed energy scores of −79.54 kcal/mol, −73.99 kcal/mol, −62.26 kcal/mol, and −70.66 kcal/mol, correspondingly. The pharmacokinetics properties exhibited were under the acceptable range. The compounds hold the potential to be novel drugs; therefore, further investigation needs to be conducted to find out their anti-collagenase action against C. histolyticum infections and antibiotic resistance.

Plumbagin (PLM), a plant derivative, is well known for a wide range of therapeutic effects in humans including anti-cancer, anti-inflammatory, anti-oxidant, and anti-microbial. Cytotoxic and genotoxic potential of this phytochemical has been studied which demands further insight. DNA being a major target for several drugs was taken to study against PLM to understand its effects on the cellular system. UV-Vis spectroscopy has indicated the binding of PLM to ctDNA and dye displacement assays have confirmed the formation of PLM-ctDNA complex. The insignificant changes in circular dichroism spectra suggested that PLM is not affecting the structural makeup of the ctDNA, hence the binding could be peripheral and not intercalating. Further, the relative viscosity and minimal change in melting temperature upon the complex formation supported this finding and confirmed the groove binding of PLM. Molecular docking analysis and simulation studies also show PLM as a minor groove binder to DNA and provide details on the interaction dynamics of PLM-DNA complex. Docking followed by a 100 ns simulation reveals the negative Gibbs free energy change (∆G = −6.6 kcal mol−1), and the formation of a stable complex. The PLM- DNA complex with stable dynamics was further supported by different parameters including RMSD, RMSF, SASA, Rg, and the energy profile of interaction. This study provides an insight into the cytotoxic and genotoxic mechanism of PLM which can be a crucial step forward to exploit its therapeutic potential against several diseases including cancer.

α-Mangostin (α-MG) is a natural xanthone obtained from the pericarps of mangosteen. It exhibits excellent potential, including anti-cancer, neuroprotective, antimicrobial, antioxidant, and anti-inflammatory properties, and induces apoptosis. α-MG controls cell proliferation by modulating signaling molecules, thus implicated in cancer therapy. It possesses incredible pharmacological features and modulates crucial cellular and molecular factors. Due to its lesser water solubility and pitiable target selectivity, α-MG has limited clinical application. As a known antioxidant, α-MG has gained significant attention from the scientific community, increasing interest in extensive technical and biomedical applications. Nanoparticle-based drug delivery systems were designed to improve the pharmacological features and efficiency of α-MG. This review is focused on recent developments on the therapeutic potential of α-MG in managing cancer and neurological diseases, with a special focus on its mechanism of action. In addition, we highlighted biochemical and pharmacological features, metabolism, functions, anti-inflammatory, antioxidant effects and pre-clinical applications of α-MG.

Glycogen synthase kinase-3 (GSK3β), a serine/threonine protein kinase, has been discovered as a novel target for anticancer drugs. Although GSK3β is involved in multiple pathways linked to the etiology of various cancers, no specific GSK3β inhibitor has been authorized for cancer therapy. Most of its inhibitors have toxicity effects therefore, there is a need to develop safe and more potent inhibitors. In this study, a library of 4,222 anti-cancer compounds underwent rigorous computational screening to identify potential candidates for targeting the binding pocket of GSK3β. The screening process involved various stages, including docking-based virtual screening, physicochemical and ADMET analysis, and molecular dynamics simulations. Ultimately, two hit compounds, BMS-754807 and GSK429286A, were identified as having high binding affinities to GSK3β. BMS-754807 and GSK429286A exhibited binding affinities of −11.9, and −9.8 kcal/mol, respectively, which were greater than that of the positive control (−7.6 kcal/mol). Further, molecular dynamics simulations for 100 ns were employed to optimize the interaction between the compounds and GSK3β, and the simulations demonstrated that the interaction was stable and consistent throughout the study. These hits were also anticipated to have good drug-like properties. Finally, this study suggests that BMS-754807 and GSK429286A may undergo experimental validation to evaluate their potential as cancer treatments in clinical settings.

Cathepsin L (CTSL) expression is dysregulated in a variety of cancers. Extensive empirical evidence indicates their direct participation in cancer growth, angiogenic processes, metastatic dissemination, and the development of treatment resistance. Currently, no natural CTSL inhibitors are approved for clinical use. Consequently, the development of novel CTSL inhibition strategies is an urgent necessity. In this study, a combined machine learning (ML) and structure-based virtual screening strategy was employed to identify potential natural CTSL inhibitors. The random forest ML model was trained on IC50 values. The accuracy of the trained model was over 90%. Furthermore, we used this ML model to screen the Biopurify and Targetmol natural compound libraries, yielding 149 hits with prediction scores >0.6. These hits were subsequently selected for virtual screening using a structure-based approach, yielding 13 hits with higher binding affinity compared to the positive control (AZ12878478). Two of these hits, ZINC4097985 and ZINC4098355, have been shown to strongly bind CTSL proteins. In addition to drug-like properties, both compounds demonstrated high affinity, ligand efficiency, and specificity for the CTSL binding pocket. Furthermore, in molecular dynamics simulations spanning 200 ns, these compounds formed stable protein-ligand complexes. ZINC4097985 and ZINC4098355 can be considered promising candidates for CTSL inhibition after experimental validation, with the potential to provide therapeutic benefits in cancer management.

Replication of Human Cytomegalovirus (HCMV) requires the presence of a metal-dependent endonuclease at the C-terminus of pUL89, in order to properly pack and cleave the viral genome. Therefore, pUL89 is an attractive target to design anti-CMV intervention. Herein, we used integrated structure-based and ligand-based virtual screening approaches in combination with MD simulation for the identification of potential metal binding small molecule antagonist of pUL89. In this regard, the essential chemical features needed for the inhibition of pUL89 endonuclease domain were defined and used as a 3D query to search chemical compounds from ZINC and ChEMBL database. Thereafter, the molecular docking and ligand-based shape screening were used to narrow down the compounds based on previously identified pUL89 antagonists. The selected virtual hits were further subjected to MD simulation to determine the intrinsic and ligand-induced flexibility of pUL89. The predicted binding modes showed that the compounds reside well in the binding site of endonuclease domain by chelating with the metal ions and crucial residues. Taken in concert, the in silico investigation led to the identification of potential pUL89 antagonists. This study provided promising starting point for further in vitro and in vivo studies.

Breast cancer is the leading cause of cancer-related death among women in Saudi Arabia. Many studies have suggested a strong correlation between vitamin D and multiple types of cancer. This study included 100 female Saudi patients with early or locally advanced breast cancer. Patients were recruited from King Faisal Hospital in Taif City, Saudi Arabia, from January 2020 to September 2020. We aimed to study the association between serum vitamin D, calcium, interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and chemerin and breast cancer progression. The control group consisted of 100 healthy individuals. Serum levels of vitamin D, calcium, IL-6, TNF-α and chemerin were measured in all participants. Vitamin D was significantly decreased in patients with high-grade tumours ( p < 0.0001), obesity ( p = 0.013), negative oestrogen receptors ( p < 0.0001), negative progesterone receptors ( p < 0.0001) and positive HER2 receptors ( p < 0.0001). Vitamin D was also decreased in patients with large tumours ( p < 0.0001), axillary lymph node involvement ( p < 0.0001) and advanced-stage cancers ( p < 0.0001). Moreover, higher levels of IL-6, TNF-α and chemerin were significantly associated with the presence of breast cancer, particularly in its advanced stages. Vitamin D deficiency and elevated levels of IL-6, TNF- α and chemerin were associated with adverse clinicopathological features of breast cancer. Vitamin D deficiency and elevated inflammatory cytokines (IL-6, TNF-α and chemerin) were associated with the clinicopathological features of breast cancer in female Saudi patients.

Norovirus (HNoV) is a leading cause of gastroenteritis globally, and there are currently no treatment options or vaccines available to combat it. RNA-dependent RNA polymerase (RdRp), one of the viral proteins that direct viral replication, is a feasible target for therapeutic development. Despite the discovery of a small number of HNoV RdRp inhibitors, the majority of them have been found to possess a little effect on viral replication, owing to low cell penetrability and drug-likeness. Therefore, antiviral agents that target RdRp are in high demand. For this purpose, we used in silico screening of a library of 473 natural compounds targeting the RdRp active site. The top two compounds, ZINC66112069 and ZINC69481850, were chosen based on their binding energy (BE), physicochemical and drug-likeness properties, and molecular interactions. ZINC66112069 and ZINC69481850 interacted with key residues of RdRp with BEs of −9.7, and −9.4 kcal/mol, respectively, while the positive control had a BE of −9.0 kcal/mol with RdRp. In addition, hits interacted with key residues of RdRp and shared several residues with the PPNDS, the positive control. Furthermore, the docked complexes showed good stability during the molecular dynamic simulation of 100 ns. ZINC66112069 and ZINC69481850 could be proven as potential inhibitors of the HNoV RdRp in future antiviral medication development investigations.

Background. Obesity among children became of high concern. Obesity can affect many health aspects including muscular strength. Downhill walking is a useful intervention to enhance muscular strength, especially in older adults. Objective. The current study’s purpose was to investigate the effect of repeated bouts of downhill walking on ankle isokinetic parameters in children with obesity. Methods. 32 obese male children aged from 8 to 12 years engaged in the study. The children were divided into two groups: the level walking group (LWG) (n=16) and the downhill walking group (DWG) (n=16). Participants in both groups walked 20 minutes on the treadmill, two sessions per week for 6 weeks, with a speed of 5 km/h, and the treadmill slope used for the DWG was set at –20%. Isokinetic dynamometry (Cybex 6000) was used to analyze the normalized eccentric and concentric torque of both ankle dorsiflexors and plantar flexors of the dominant leg in all participants. Results. The normalized peak torques for eccentric plantar flexion, concentric plantar flexion, eccentric dorsiflexion, and concentric dorsiflexion significantly increased by 38.66%, 23.87%, 38.58%, and 15.51%, respectively, after repeated bouts of downhill walking. Level walking resulted in nonsignificant improvement in the muscular torques. Conclusion. Downhill walking is a beneficial intervention in improving ankle muscular torques of obese children.

Cyclin-dependent kinase 6 (CDK6) is an important protein kinase that regulates cell growth, development, cell metabolism, inflammation, and apoptosis. Its overexpression is associated with reprogramming glucose metabolism through alternative pathways and apoptosis, which ultimately plays a significant role in cancer development. In the present study, we have investigated the structural and conformational changes in CDK6 at varying pH employing a multi-spectroscopic approach. Circular dichroism (CD) spectroscopy revealed at extremely acidic conditions (pH 2.0-4.0), the secondary structure of CDK6 got significantly disrupted, leading to aggregates formation. These aggregates were further characterized by employing Thioflavin T (ThT) fluorescence. No significant secondary structural changes were observed over the alkaline pH range (pH 7.0-11.0). Further, fluorescence and UV spectroscopy revealed that the tertiary structure of CDK6 was disrupted under extremely acidic conditions, with slight alteration occurring in mild acidic conditions. The tertiary structure remains intact over the entire alkaline range. Additionally, enzyme assay provided an insight into the functional aspect of CDK at varying pH; CDK6 activity was optimal in the pH range of 7.0-8.0. This study will provide a platform that provides newer insights into the pH-dependent dynamics and functional behavior of CDK6 in different CDK6 directed diseased conditions, viz. different types of cancers where changes in pH contribute to cancer development.

Single amino-acid substitution in a protein affects its structure and function. These changes are the primary reasons for the advent of many complex diseases. Analyzing single point mutations in a protein is crucial to see their impact and to understand the disease mechanism. This has given many biophysical resources, including databases and web-based tools to explore the effects of mutations on the structure and function of human proteins. For a given mutation, each tool provides a score-based outcomes which indicate deleterious probability. In recent years, developments in existing programs and the introduction of new prediction algorithms have transformed the state-of-the-art protein mutation analysis. In this study, we have performed a systematic study of the most commonly used mutational analysis programs (10 sequence-based and 5 structure-based) to compare their prediction efficiency. We have carried out extensive mutational analyses using these tools for previously known pathogenic single point mutations of five different proteins. These analyses suggested that sequence-based tools, PolyPhen2, PROVEAN, and PMut, and structure-based web tool, mCSM have a better prediction accuracy. This study indicates that the employment of more than one program based on different approaches should significantly improve the prediction power of the available methods.

Monitoring the distribution and resistance of antibiotics to enterococcal species is critical aspect to controlling and preventing enterococcal infection. The aim of the present study is to screen the antimicrobial resistance genes within Enterococcus species isolates that collected from Taif governorate, Saudi Arabia. Out of 134 clinical samples, nineteen enterococcal isolates were identified using 16S rRNA sequence gene. Phylogenetic tree analysis using 16S rRNA gene sequence of the 19 strains divided them into 15 strains as E. faecalis and 4 strains as E. faecium. In addition, these the species of these isolates were recognized using VITEK-2 COMPACT system. The PCR technique was used to screen the multi-drug resistant genes within enterococcal isolates. The KpsII, tetL, aac(6)-Ie-aph(2)-Ia, vanA and Erm(B) genes were found in all strains. The distribute of resistance against antibiotic drugs were differs greatly between the two species, a considerably higher prevalence of resistance to penicillin, gentamicin, cefoxitin, cefotaxime, clindamycin, erthromycin and fusidic acid was identified in E. faecalis than in E. faecium, while greater spread was detected to resist to Trim/Sulf and tetracycline in E. faecalis. Finally, rep-PCR markers investigated genomic diversity of Enterococcus strains. Results of rep-PCR markers generated 142 distinct loci; 96 were polymorphic (67.6%) and 46 were monomorphic (32.4%). Number of loci for individual rep-PCR primers ranged from 9 for rep-08 to 18 for rep-02.

A continual rise in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease (COVID-19) has become a global threat. The main problem comes when SARS-CoV-2 gets mutated with the rising infection and becomes more lethal for humankind than ever. Mutations in the structural proteins of SARS-CoV-2, i.e., the spike surface glycoprotein (S), envelope (E), membrane (M) and nucleocapsid (N), and replication machinery enzymes, i.e., main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) creating more complexities towards pathogenesis and the available COVID-19 therapeutic strategies. This study analyzes how a minimal variation in these enzymes, especially in S protein at the genomic/proteomic level, affects pathogenesis. The structural variations are discussed in light of the failure of small molecule development in COVID-19 therapeutic strategies. We have performed in-depth sequence- and structure-based analyses of these proteins to get deeper insights into the mechanism of pathogenesis, structure-function relationships, and development of modern therapeutic approaches. Structural and functional consequences of the selected mutations on these proteins and their association with SARS-CoV-2 virulency and human health are discussed in detail in the light of our comparative genomics analysis.

Background The coronavirus disease 2019 (COVID-19) is a respiratory virus, the spread of which has caused a global pandemic with catastrophic consequences. The current study aimed to investigate the association between vitamin D deficiency and the clinical presentation of COVID-19. Patients and methods The current study included 166 COVID-19 patients recruited from Prince Mohammad Bin Abdulaziz Hospital in Riyadh, Saudi Arabia. The study was conducted from October 2020 to January 2021. Patients were diagnosed by positive polymerase chain reaction (PCR) results. History and clinical data were collected for all subjects. In addition, laboratory analysis was done to estimate blood levels of 25 hydroxyvitamin D (25(OH)D), C-reactive protein (CRP), ferritin, parathyroid hormone (PTH), alanine aminotransferase (ALT), D-dimer, calcium, and relative lymphocytic count. COVID-19 patients were divided into three subgroups according to their vitamin D status. Patients were considered sufficient when their vitamin D level was above 30 ng/mL. Patients with vitamin D levels below 20 ng/mL were considered deficient. Patients with vitamin D levels ranging from 20 ng/mL to 30 ng/mL were considered insufficient. Results Our results showed that 81 patients (49%) were deficient in vitamin D, and 48 patients (29%) were insufficient in vitamin D. Only 37 patients (22%) had normal vitamin D levels. Moreover, a significant difference was found regarding the inflammatory markers of COVID-19 severity. Also, vitamin D levels were inversely correlated with the markers used for monitoring the condition of COVID-19 patients: ferritin, CRP, and D-dimer. Conclusion Our results showed that vitamin D deficiency was associated with increased levels of inflammatory markers of COVID-19 infection.

Scientists have discovered many ways to treat bacteria, viruses, and parasites in aquaculture; however, there is still an impossibility in finding a permanent solution for all types of diseases. In that case, the CRISPR-Cas genome-editing technique can be the potential solution to preventing diseases for aquaculture sustainability. CRISPR-Cas is cheaper, easier, and more precise than the other existing genome-editing technologies and can be used as a new disease treatment tool to solve the far-reaching challenges in aquaculture. This technique may now be employed in novel ways, such as modifying a single nucleotide base or tagging a location in the DNA with a fluorescent protein. This review paper provides an informative discussion on adopting CRISPR technology in aquaculture disease management. Starting with the basic knowledge of CRISPR technology and phages, this study highlights the development of RNA-guided immunity to combat the Chilodonella protozoan group and nervous necrosis virus (NNV) in marine finfish. Additionally, we highlight the immunological application of CRISPR-Cas against bacterial diseases in channel catfish and the white spot syndrome virus (WSSV) in shrimp. In addition, the review summarizes a synthesis of bioinformatics tools used for CRISPR-Cas sgRNA design, and acceptable solutions are discussed, considering the limitations.

Increasing the yield of extraction of bioactive compounds from plants is of high importance. Grape stems are widely discarded during the wine-making process, despite their high content in many valuable compounds. The aim of this work was to examine whether the use of pulsed electric field (PEF) treatment of the stems could increase the yield of polyphenol and volatile compounds in the extracts. For this reason, a relatively low-energy consuming PEF process was employed (low-electric field strength, 1 kV/cm) for a short time (30 min) at the grape stems. In addition, the effect of different solvents during this pretreatment step was examined. With the use of Folin–Ciocalteu assay, the extracts were compared with the respective control samples (not pretreated with PEF). Moreover, extracts were prepared to assess whether changes occur to the volatile profile of the extracts. The results were conclusive that not only PEF can increase the yield of polyphenols (up to 35% increase recorded), but also that the solvent used during PEF pretreatment can affect the process. Furthermore, a 234% increase in the total content of volatile compounds was recorded, when PEF was used as a pretreatment step. Therefore, the combination of PEF and ultrasound-assisted extraction is highly promising to obtain grape stem extracts with a higher content of bioactive compounds.

In many regions of the world, Leishmaniasis is a cause of substantial mortality and ailment. Due to impediment in available treatment, development of novel and effective treatments is indispensable. Significance of autophagy has been accentuated in infectious disease as well as in Leishmaniasis, and it is having capability to be manifested as a therapeutic target. By evincing autophagy as a novel therapeutic regime, this study emphasized on the critical role of ATG4.1-ATG8 and ATG5-ATG12 complexes in Leishmania species. The objective here was to identify ATG8 as a potential therapeutic target in Leishmania. R71T, P56E, R18P are the significant mutations which shows detrimental effect on ATG8 while Arg276, Arg73, Cys75 of ATG4.1 and Val88, Pro89, Glu116, Asn117, and Gly120 are interacting residues of ATG8. Along with this, we also bring into spotlight an enticing role of Thiabendazole derivatives that interferes with the survival mechanisms by targeting ATG8. Further, the study claims that thiabendazole can be a potential drug candidate to target autophagy process in the infectious disease Leishmaniasis.

ObjectivesThe aim of this study was to estimate the prevalence of anemia among patients newly diagnosed with solid malignancies at King Faisal Hospital in Taif Province, Kingdom of Saudi Arabia.MethodsA descriptive, cross-sectional, hospital-based study was conducted from December 2017 to March 2020. A total of 320 patients newly diagnosed with solid malignancy were examined to assess anemia prevalence.ResultsOf 320 patients with solid cancers, 245 (76.6%) were female and 75 (23.4%) were male. The median (interquartile range) age of 57 (45 ─ 66) years, range between 16 and 108 years. The types of cancer included were breast (29.1%), female genital tract (20.0%), colorectal (25.3%), head and neck (10.3%), urinary bladder (4.7%), prostate (5.0%), lung (2.5%), liver (2.2%) and lymphoma (0.9%). The prevalence of anemia at diagnosis of cancer was 44.1% across all cancer types. A higher anemia prevalence was noted in colorectal (n = 46/81, 56.8%) (p = 0.047).ConclusionPatients with colorectal or female genital tract cancers had a higher anemia prevalence (56.8% and 43.8%, respectively) than did patients with other cancers.

PIM1, is a serine/threonine proto-oncogene kinase, involved in many biological functions, including cell survival, proliferation, and differentiation, thus play a key role in oncogenesis. It plays a crucial role in the onset and progression of various hematopoietic and non-hematopoietic malignancies, including acute myeloid leukemia and prostate cancer. Mutations in PIM1, especially in its kinase domain, can induce abnormal structural changes and thus alter functionalities that can lead to disease progression and other complexities. Herein, we have performed an extensive analysis of the PIM1 mutations at sequence and structure level while utilizing state-of-the-art computational approaches. Based on the impact on PIM1, numerous pathogenic and destabilizing mutations were identified and subsequently analyzed in detail. Finally, two amino acid substitutions (W109C and F147C) in the kinase domain of PIM1 were selected to explore their impact on the PIM1 structure in a time evolution manner using all-atom molecular dynamics (MD) simulations for 200 ns. MD results indicate significant conformational altercations in the structure of PIM1, especially upon F147C mutation. This study provides a significant insight into the PIM1 dysfunction upon single amino acid substitutions, which can be utilized to get insights into the molecular basis of PIM1-associated disease progression.

Background. Children with Down’s syndrome are more liable to vitamin D deficiency. Treating this deficiency with supplements is associated with the risk of intoxication. Aim. The study is aimed at comparing the effect of two exercise intensities on the modulation of vitamin D and parathormone levels in children with DS. Methods. Forty-four DS male children aged from 8 to 12 years participated in the study. They were assigned randomly into two equal groups. Group I received high-intensity treadmill aerobic exercises, and group II received moderate-intensity T-AE, three times per week for three months. The blood samples were collected from both groups before the intervention, after one month of intervention, then after three months of intervention to assess serum 25(OH)D and PTH levels. Results. Repeated measure MANOVA revealed that the high-intensity T-AE induced a significant increase in 25(OH)D after one month and after three months while it significantly decreased PTH only after three months. Moderate-intensity T-AE had a nonsignificant effect on both hormones. Conclusion. The current study concluded that the high-intensity T-AE improved both vitamin D and parathormone serum levels after three months of intervention.

Since the emergence of yellow fever in the Americas and the devastating 1918 influenza pandemic, biologists and clinicians have been drawn to human infecting viruses to understand their mechanisms of infection better and develop effective therapeutics against them. However, the complex molecular and cellular processes that these viruses use to infect and multiply in human cells have been a source of great concern for the scientific community since the discovery of the first human infecting virus. Viral disease outbreaks, such as the recent COVID-19 pandemic caused by a novel coronavirus, have claimed millions of lives and caused significant economic damage worldwide. In this study, we investigated the mechanisms of host-virus interaction and the molecular machinery involved in the pathogenesis of some common human viruses. We also performed a phylogenetic analysis of viral proteins involved in host-virus interaction to understand the changes in the sequence organization of these proteins during evolution for various strains of viruses to gain insights into the viral origin's evolutionary perspectives.

Background: Prolactin inducible protein (PIP) is a small secretary glycoprotein present in most biological fluids and contributes to various cellular functions, including cell growth, fertility, antitumor, and antifungal activities. Objectives: The present study evaluated the antibacterial activities of recombinant PIP against multiple broad-spectrum MDR bacterial strains. Methods: The PIP gene was cloned, expressed and purified using affinity chromatography. Disk diffusion, broth microdilution, and growth kinetic assays were used to determine the antibacterial activities of PIP. Results: Disk diffusion assay showed that PIP has a minimum and maximum zone of inhibition against E. coli and P. aeruginosa, respectively, compared to the reference drug ampicillin. Furthermore, growth kinetics studies also suggested that PIP significantly inhibited the growth of E. coli and P. aeruginosa. The minimum inhibitory concentration of PIP was 32 µg/mL for E. coli (443), a standard bacterial strain, and 64 µg/mL for Bacillus sp. (LG1), an environmental multidrug-resistant (MDR) strain. The synergistic studies of PIP with ampicillin showed better efficacies towards selected bacterial strains having MDR properties. Conclusion: Our findings suggest that PIP has a broad range of antibacterial activities with important implications in alleviating MDR problems.

Casein kinase-1 alpha (CK1α) is a multifunctional protein kinase that belongs to the serine/threonine kinases of the CK1α family. It is involved in various signaling pathways associated with chromosome segregation, cell metabolism, cell cycle progression, apoptosis, autophagy, etc. It has been known to involve in the progression of many diseases, including cancer, neurodegeneration, obesity, and behavioral disorders. The elevated expression of CK1α in diseased conditions facilitates its selective targeting for therapeutic management. Here, we have performed virtual screening of phytoconstituents from the IMPPAT database seeking potential inhibitors of CK1α. First, a cluster of compounds was retrieved based on physicochemical parameters following Lipinski’s rules and PAINS filter. Further, high-affinity hits against CK1α were obtained based on their binding affinity score. Furthermore, the ADMET, PAINS, and PASS evaluation was carried out to select more potent hits. Finally, following the interaction analysis, we elucidated three phytoconstituents, Semiglabrinol, Curcusone_A, and Liriodenine, posturing considerable affinity and specificity towards the CK1α binding pocket. The result was further evaluated by molecular dynamics (MD) simulations, dynamical cross-correlation matrix (DCCM), and principal components analysis (PCA), which revealed that binding of the selected compounds, especially Semiglabrinol, stabilizes CK1α and leads to fewer conformational fluctuations. The MM-PBSA analysis suggested an appreciable binding affinity of all three compounds toward CK1α.

Irisin is a clinically significant protein playing a valuable role in regulating various diseases. Irisin attenuates synaptic and memory dysfunction, highlighting its importance in Alzheimer’s disease. On the other hand, Microtubule Affinity Regulating Kinase 4 (MARK4) is associated with various cancer types, uncontrolled neuronal migrations, and disrupted microtubule dynamics. In addition, MARK4 has been explored as a potential drug target for cancer and Alzheimer’s disease therapy. Here, we studied the binding and subsequent inhibition of MARK4 by irisin. Irisin binds to MARK4 with an admirable affinity (K = 0.8 × 107 M−1), subsequently inhibiting its activity (IC50 = 2.71 µm). In vitro studies were further validated by docking and simulations. Molecular docking revealed several hydrogen bonds between irisin and MARK4, including critical residues, Lys38, Val40, and Ser134. Furthermore, the molecular dynamic simulation showed that the binding of irisin resulted in enhanced stability of MARK4. This study provides a rationale to use irisin as a therapeutic agent to treat MARK4-associated diseases.