Investigating Potential Cancer Therapeutics: Insight into Histone Deacetylases (HDACs) Inhibitions.

Histone deacetylases (HDACs) are enzymes that remove acetyl groups from ɛ-amino of histone, and their involvement in the development and progression of cancer disorders makes them an interesting therapeutic target. This study seeks to discover new inhibitors that selectively inhibit HDAC enzymes which are linked to deadly disorders like T-cell lymphoma, childhood neuroblastoma, and colon cancer. MOE was used to dock libraries of ZINC database molecules within the catalytic active pocket of target HDACs. The top three hits were submitted to MD simulations ranked on binding affinities and well-occupied interaction mechanisms determined from molecular docking studies. Inside the catalytic active site of HDACs, the two stable inhibitors LIG1 and LIG2 affect the protein flexibility, as evidenced by RMSD, RMSF, Rg, and PCA. MD simulations of HDACs complexes revealed an alteration from extended to bent motional changes within loop regions. The structural deviation following superimposition shows flexibility via a visual inspection of movable loops at different timeframes. According to PCA, the activity of HDACs inhibitors induces structural dynamics that might potentially be utilized to define the nature of protein inhibition. The findings suggest that this study offers solid proof to investigate LIG1 and LIG2 as potential HDAC inhibitors.

Development of new benzil-hydrazone derivatives as anticholinesterase inhibitors: synthesis, X-ray analysis, DFT study and in vitro/in silico evaluation.

Alzheimer's disease (AD) is a complex neurodegenerative disorder affecting the central nervous system. Current drugs for AD have limited effectiveness and often come with side effects. Consequently, there is a pressing need to develop new, safe, and more effective treatments for Alzheimer's disease. In this work, two novel benzil-hydrazone compounds, abbreviated 2-ClMHB and 2-ClBHB, were synthesized for the first time by refluxing the benzil with 2-Chloro phenyl hydrazine and they have been tested for their in vitro anti-cholinesterase activities and in silico acetyl and butyryl enzymes inhibition. The resulting products were characterized using UV-Vis and IR spectroscopy, while the single-crystal X-ray diffraction investigation was successful in establishing the structures of these compounds. DFT calculations have been successfully made to correlate the experimental data. According to biological studies, the synthesized hydrazones significantly inhibited both butyrylcholinesterase (2-ClMHB: 20.95 ± 1.29 µM and 2-ClBHB: 31.21 ± 1.50 µM) and acetylcholinesterase (2-ClMHB: 21.80 ± 1.10 µM and 2-ClBHB: 10.38 ± 1.27 µM). Moreover, molecular docking was also employed to locate the molecule with the optimum interaction and stability as well as to explain the experimental findings. The compound's dynamic nature, binding interaction, and protein-ligand stability were investigated using molecular dynamics (MD) simulations. Analyzing parameters such as RMSD and RMSF indicated that the compound remained stable throughout the 100 ns MD simulation. Finally, the drugs displayed high oral bioavailability, as per projected ADME and pharmacokinetic parameters.Communicated by Ramaswamy H. Sarma.

Computational exploration of allosteric inhibitors targeting CDK4/CDK6 proteins: a promising approach for multi-target drug development.

Cyclin-dependent kinases (CDKs) play a pivotal role in orchestrating the intricate regulation of the cell cycle, a fundamental process governing cell growth and division. In particular, CDK4 and CDK6 are critical for the transition from the G1 phase to the S phase, where Deoxyribonucleic acid (DNA) replication occurs, and their dysregulation is linked to various diseases, notably cancer. While ATP-binding site inhibitors for CDKs are well-documented, this study focuses on uncovering allosteric inhibitors, providing a fresh perspective on CDK inhibition. Computational techniques were employed in this investigation, utilizing Molecular Operating Environment (MOE) for virtual screening of a drug-like compound library. Moreover, the stability of the most promising binding inhibitors was assessed through Molecular Dynamics (MD) simulations and MMPBSA/MMGBSA analyses. The outcome reveals that three inhibitors (C1, C2, and C3) exhibited the strongest binding affinity for CDK4/CDK6, as corroborated by docking and simulation analyses. The computed binding energies ranged from -6.1 to -7.6 kcal/mol, underscoring the potency of these allosteric inhibitors. Notably, this study identifies key residues (PHE31, HIS95, HIS100, VAL101, ASP102, ASP104, and THR107) that play pivotal roles in mediating inhibitor binding within the allosteric sites. Among the findings, the C1-CDK4 complex and C2-CDK6 complex emerge as particularly promising inhibitors, exhibiting high binding energies, favorable interaction patterns, and sustained presence within the active site. This study contributes significantly to the pursuit of multi-target drugs against CDK4/CDK6 proteins, with potential implications for the development of innovative therapies across various disorders, including cancer and other cell cycle-related conditions.Communicated by Ramaswamy H. Sarma.

Process optimization, antioxidant, antibacterial, and drug adjuvant properties of bioactive keratin microparticles derived from porcupine (Hystrix indica) quills.

A structural protein called keratin is often employed in the medical industry to create medication carriers. Process improvement, antioxidant, antibacterial, and adjuvant drug studies of synthetic bioactive keratin microparticles made from lipids and keratin derived from porcupine (Hystrix indica) quills are the main objectives of this study. After coating the keratin microparticles with lipids which were obtained from the same porcupine quills, the bioactive keratin microparticles were produced. The response surface technique was applied to optimize the conditions for extraction of the keratin protein and sizing of the keratin microparticles. An infrared spectroscopy was used to analyze the chemical shifts in compositions of keratin microparticles while the optical microscopy was used to measure the size of the keratin microparticles. The results of this work revealed that a yield 27.36 to 42.25% of the keratin protein could be obtained from porcupine quills. The keratin microparticles were sized between 60.65 and 118.87 µm. Through response surface optimization, mercaptoethanol and urea were shown to be the main variables which positively affected the yield and the size of the keratin protein. The lipid stacking on the keratin microparticles' surface was confirmed by infrared spectroscopy. The 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) assay confirmed the keratin microparticle's antioxidant activity of 29.83%. Compared to lipid alone, the antibacterial properties of the keratin microparticles against Escherichia coli-a gram-negative-and Staphylococcus aureus-a gram-positive-bacteria enhanced by up to 55% following the coating of the microparticles with the lipids. The pharmacological action against these bacterial species was further improved by the lipid-loaded erythromycin that was carried on the surface of keratin microparticles. This work has demonstrated the design and uses of the keratin microparticles obtained from porcupine quills for clinical applications.

Insight into crystal structures and identification of potential styrylthieno[2,3-b]pyridine-2-carboxamidederivatives against COVID-19 Mpro through structure-guided modeling and simulation approach.

Anti-SARS-CoV-2 drugs are urgently needed to prevent the pandemic and for immunization. Their protease inhibitor treatment for COVID-19 has been used in clinical trials. In Calu-3 and THP1 cells, 3CL SARS-CoV-2 Mpro protease is required for viral expression, replication, and the activation of the cytokines IL-1, IL-6, and TNF-. The Mpro structure was chosen for this investigation because of its activity as a chymotrypsin-like enzyme and the presence of a cysteine-containing catalytic domain. Thienopyridine derivatives increase the release of nitric oxide from coronary endothelial cells, which is an important cell signaling molecule with antibacterial activity against bacteria, protozoa, and some viruses. Using DFT calculations, global descriptors are computed from HOMO-LUMO orbitals; the molecular reactivity sites are analyzed from an electrostatic potential map. NLO properties are calculated, and topological analysis is also part of the QTAIM studies. Both compounds 1 and 2 were designed from the precursor molecule pyrimidine and exhibited binding energies (-14.6708 kcal/mol and -16.4521 kcal/mol). The binding mechanisms of molecule 1 towards SARS-COV-2 3CL Mpro exhibited strong hydrogen bonding as well as Vdw interaction. In contrast, derivative 2 was bound to the active site protein's active studied that several residues and positions, including (His41, Cys44, Asp48, Met49, Pro52, Tyr54, Phe140, Leu141, Ser144, His163, Ser144, Cys145, His164, Met165, Glu166, Leu167, Asp187, Gln189, Thr190, and GLn192) are critical for the maintenance of inhibitors inside the active pocket. Molecular docking and 100 ns MD simulation analysis revealed that Both compounds 1 and 2 with higher binding affinity and stability toward the SARS-COV-2 3CL Mpro protein. Binding free energy calculations and other MD parameters support the finding.Communicated by Ramaswamy H. Sarma.

Comparison of Percutaneous Coronary Intervention-Related Adverse Cardiac Outcomes in Patients With in-stent vs de novo Chronic Total Occlusion: A Systematic Review and Meta-Analysis.

Contemporary literature reveals a range of cardiac complications in patients who receive the percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). This study compared the adverse cardiac outcomes and procedural/technical success rates between the patients groups of in-stent (IS) CTO PCI and de novo CTO PCI. This systematic review and meta-analysis compared odds for primary (all-cause mortality, MACE, cardiac death post PCI, stroke) and secondary (bleeding requiring blood transfusion, ischemia-driven target-vessel revascularization, PCI procedural success, PCI technical success, and target-vessel MI) endpoints between 2734 patients who received PCI for IS CTO and 17,808 for de novo CTO. Odds ratios for outcome variables were calculated within 95% confidence intervals (CIs) via the Mantel-Haenszel method. The pooled analysis was undertaken for observational (retrospective/prospective) single- and multicentered studies published between January 2005 and December 2021. We found 57% higher, 166% higher, 129% higher, and 57% lower odds for MACE (OR: 1.57, 95% CI 1.31, 1.89, P < 0.001), ischemia-driven target-vessel revascularization (OR: 2.66, 95% CI 2.01, 3.53, P < 0.001), target-vessel myocardial infarction (MI) (OR: 2.29, 95% CI 1.70, 3.10, P < 0.001), and bleeding requiring blood transfusion (OR: 0.43, 95% CI 0.19, 1.00, P = 0.05), respectively, in patients with IS CTO PCI as compared to that of the de novo CTO PCI. No statistically significant differences between the study groups were recorded for the other primary/secondary outcome variables. The findings from this study indicated a high predisposition for MACE, ischemia-driven target-vessel revascularization, target vessel MI, and a lower incidence of bleeding episodes among IS CTO PCI patients as compared to those with de novo CTO PCI. The prognostic outcomes in CTO PCI cases require further investigation with randomized controlled trials.

Identification of natural marine compounds as potential inhibitors of CDK2 using molecular docking and molecular dynamics simulation approach.

The multifunctional enzyme cyclin-dependent kinase 2 (CDK2) protein is essential for cell proliferation, transcription and modulation of the cell cycle. There is a dysfunction that is connected to various diseases, such as cancer, making it an important treatment target in oncology and beyond. The goal of this study is to identify novel CDK2 ATP binding site inhibitors using in silico drug designing. To find competitive inhibitors for the ATP site, molecular docking, molecular dynamics (MD) simulation and free-binding energy calculations were used. Natural compounds retrieved from marine sources (fungi and algae) were docked against protein, and the best-binding compounds were further evaluated using MD simulations. LIG1, LIG2 and LIG3 (ΔGPB = -19.98, -15.82 and -12.98 kcal/mol, respectively) were placed in the top positions based on their overall binding energy calculated using MMPBSA approach. Stability of the complexes was confirmed by carefully analyzing the rmsd and rmsf patterns retrieved from the MD trajectories. Several residues and areas (Leu124, Val123, Phe80, Leu83, Glu81, Arg 126, Asn132, Leu134, Gln131, Lys88 and Glu195) appear to be critical for inhibitor retention across the active pocket, according to RMSD and RMSF. The dynamics of the ligands inside the active pocket were mapped using principle component analysis. It has been observed that LIG1-3 appear to be the best possible inhibitors due to their high binding energies, interaction pattern and retention inside the active pocket.Communicated by Ramaswamy H. Sarma.

Activity patterns of Asiatic black bear (Ursus thibetanus) in the moist temperate forests of Machiara National Park, Azad Jammu and Kashmir, Pakistan.

The Asiatic black bear (Ursus thibetanus) is an environmental indicator species whose activity patterns may be highly impacted by habitat changes. We monitored the monthly and daily activity patterns of black bears in the moist temperate forests of Machiara National Park. We used infrared camera traps and local ecological knowledge for data collection from April 2019 to April 2021. Camera traps recorded 109 [inside forest = 107, outside forest (near crop fields and human settlements) = 2] independent registrations (IR) in 5541 (692.63 ± 36.72, mean ± SD) camera days. We found (i) spring and autumn to be the lowest activity seasons for black bears inside the forest. (ii) The highest activity was recorded in summer, with a peak in August followed closely by July. (iii) The activity level sharply declined after August and halted from December to March, indicative of the bears' hibernation period. Local knowledge revealed that (i) bears remained active from May to November and hibernated the rest of the period. (ii) Bear activity was at its peak inside the forest in summer and outside the forest in autumn when bears sought to raid the widely cultivated maize crop (Zea mays) planted along forest edges. This increased activity outside of the forest is likely driven by decreased food availability inside the forest area and maize crop being a preferred anthropogenic food type for bears. Based on the daily activity pattern, bears exhibited cathemeral behavior (i.e., active throughout the day) with maximum overlap between camera trap and local ecological knowledge data. Human activity may be impacting the daily activity patterns of bears via disturbance and interference. The data collected in this study can help mitigate conflicts between humans and black bears and consequently assist in future conservation of black bears in the area.

Clinical Prevalence, Antibiogram Profiling and Gompertz Growth Kinetics of Resistant Staphylococcus epidermidis Treated with Nanoparticles of Rosin Extracted from Pinus roxburghii.

The rise of methicillin-resistant Staphylococcus epidermidis (MRSE) makes it difficult to treat infections that increase morbidity and mortality rates in various parts of the world. The study's objectives include identifying the clinical prevalence, antibiogram profile, and Gompertz growth kinetics of MRSE treated with synthetically created nanoparticles of rosin obtained from Pinus roxburghii. A total of 64 of 200 clinical isolates of S. epidermidis (32% of the total) displayed sensitivity (40.62%) and resistance (59.37%) to seven different antibiotic classes. The most sensitive patterns of antibiotic resistance were seen in 20 (78.95%) and 24 (94.74%) isolates of MRSE against piperacillin/tazobactam and cephradine, respectively. Fosfomycine was found to be the most effective antibiotic against MRSE in 34 (89.47%) isolates, followed by amoxicillin. Successfully produced, described, and used against MRSE were rosin maleic anhydride nanoparticles with a size range of 250 nm to 350 nm. Five different concentrations of 25, 50, 75, 100, and 150 mg mL-1 rosin maleic anhydride nanoparticles were investigated to treat MRSE resistance. According to Gompertz growth kinetics, the maximal growth response was 32.54% higher and the lag phase was also 10.26% longer compared to the control when the amount of rosin maleic anhydride nanoparticles was increased in the MRSE. Following the application of rosin maleic anhydride nanoparticles, the growth period is extended from 6 to 8 h. A potential mechanism for cell disintegration and distortion is put forth. This investigation came to the conclusion that rosin maleic anhydride nanoparticles better interfere with the surface of MRSE and demonstrated a preferred bacteriostatic action.

Not all lytic bone lesions are malignant: A report of syphilitic osteitis presenting with multiple lytic skull lesions.

Syphilitic osteitis is one of the rare and often under-reported complications of early syphilis. Recognizing this entity is important as it may mimic other conditions like multiple myeloma, lymphoma, or metastatic malignancies. Misdiagnosis and delayed management can lead to irreversible destructive lesions. We herein report a case of calvaria syphilitic osteitis that was initially investigated for possible lymphoma and later diagnosed as secondary syphilis.

Impact of Stent Types on In-Hospital Outcomes of Patients With Cancer Undergoing Percutaneous Coronary Intervention: A Nationwide Analysis.

BACKGROUND: Cardiovascular disease and cancer frequently coexist, and patients with cancer are at increased risk of cardiovascular events, including myocardial infarction and stroke. However, the impact of stent types on in-hospital outcomes of patients with malignancy is largely unknown. METHODS: Patients with concomitant diagnosis of cancer undergoing PCI between January 2005 and December 2014 were identified in the National Inpatient Sample. They were then categorized into those who have undergone coronary stenting with bare-metal stent (BMS) or drug-eluting stent (DES). Primary outcomes were in-hospital mortality and stent thrombosis. Adjusted and unadjusted analysis was employed on appropriate variables of interest. RESULTS: 8755 patients were included in the BMS group and 11,611 patients in the DES group. Following propensity matching, 4313 patients were randomly selected in both groups using a 1:1 ratio. There was high use of BMS stent in cancer patient (BMS 43.0%, DES 57.0%) compared to general population (BMS 23.2%, DES 76.8%). When comparing BMS to DES group, there was no statistically significant difference in mortality (4.7% vs. 3.8%, p = 0.097), acute kidney injury (11.3% vs. 10.6%, p = 0.425), bleeding complications (3.50% vs. 3.45%, p = 0.914), and length of hospital stay (5.4% vs. 5.2%, p = 0.119). However, an increased incidence of stent thrombosis was observed in the DES group (4.26% vs. 3.01%, p = 0.002). CONCLUSION: A higher incidence of BMS placement was noted in patients with cancer than in the general population. Paradoxically there was a high incidence of stent thrombosis in the DES group without increasing mortality.

Clinical Characteristics and Predictors of Mortality in Minority Patients Hospitalized with COVID-19 Infection.

OBJECTIVES: To identify the early mortality predictors in minority patients hospitalized with coronavirus disease 2019 (COVID-19). DESIGN: Demographics, presenting characteristics, admission laboratory data, ICU admission, and mortality data were collected from 200 consecutively hospitalized patients with COVID-19. RESULTS: The mean (SD) age was 58.9 (15.1) years, 121(60.5%) were men, 143 (71.5%) were African Americans, and 33 (16.5%) were Latino. Common presenting symptoms were cough 130 (65.0%), shortness of breath 129 (64.5%), and fever 121 (60.5%). One or more comorbid illness occurred in 171 (85.5%) and common comorbidities were hypertension (130 (65.2%)), diabetes (100 (50.0%)) and chronic kidney disease (60 (30.0%)). Of the 200 patients, 71 (35.5%) were treated in the ICU, 47 (24.2%) received mechanical ventilation, 45 (22.5%) died, and 155(77.5%) patients discharged home alive. The non-survivors were significantly older and had elevated markers of inflammation, coagulation, and acute organ damage on presentation. Age ≥ 65 years (odds ratio (OR), 3.78; 95% CI, 1.74-8.22; P = .001), lactate dehydrogenase level > 400 IU/L (OR, 9.1; 95% CI, 2.97-28.1; p < 0.001), C-reactive protein > 20 mg/dl (OR, 5.56; 95%CI, 1.84-16.8; p < 0.001), ferritin > 2000 ng/ml (OR, 5.42; 95%CI, 1.63-17.9; p = 0.006), creatinine kinase > 1000 iu/l (OR, 3.57; 95% CI, 1.23 10.3; p = 0.019), procalcitonin > 2.5 ng/ml (OR, 4.21; 95% CI, 1.47-12.0; p = 0.007), D-dimer level > 3.0 µg/ml (OR,10.9; 95% CI, 3.33-36.2; p = < 0.001), creatinine > 2 mg/dl (OR, 4.5; 95% CI, 1.29-15.8; P = 0.018) at admission were associated independently with increases risk of in-hospital mortality. CONCLUSION: Patients of advanced age that present with elevated biomarkers of inflammation, coagulation, and end-organ damage were at higher risk of mortality.

Impact of climate change on Asiatic black bear (Ursus thibetanus) and its autumn diet in the northern highlands of Pakistan.

Approximately 20%-30% of plant and animal species are at risk of extinction by the end of the 21st century owing to climate change. Range shifts and range contractions in plant species will dramatically affect the distribution of animals relying on them for food and shelter. The negative impacts of climate change on forested landscapes of the northern highlands of Pakistan (NHP) could change the species composition and distribution. The Asiatic black bear (Ursus thibetanus), a forest-dwelling species, primarily depends on plants for foraging, and is assumed to be affected by climate change in NHP. Scat analyses and indigenous knowledge from Machiara National Park revealed the maximum consumption of Quercus species (natural food) and Zea mays (human grown food) by the Asiatic black bear in autumn season. We collected the occurrence data of the Asiatic black bear and its commonly used food (three Quercus spp.) in the NHP. We used the MaxEnt model to simulate current and future (in 2050 and 2070) distribution of the species under RCP4.5 (medium carbon emission scenario) and RCP8.5 (extreme carbon emission scenario). The results predict range reduction and extreme fragmentation in the habitats of all the Quercus spp. Besides, a dramatic decrease in the suitable (SH) and very highly suitable (HSH) habitats was predicted in the future. Range shift and range reduction of Quercus spp. may interrupt the denning chronology of Asiatic black bears, escalate the human-black bear conflicts and local extirpation of the species. Given the extent and magnitude of climate change, it will likely not be enough to focus solely on the conservation of the Asiatic black bear. We need more dynamic planning aiming at mitigating the effect of climate change in forested landscapes including the Quercus forests.