Multitarget Mechanisms of Monocarbonyl Curcuminoid Analogues against HL-60 Cancer Cells: In Vitro and Network Pharmacology-Based Approach.

This study addressed the cytotoxic potential of four compounds: monocarbonyl curcuminoid, ethyl (2E)-2-benzylidene-3-oxobutanoate 1, 1,2-dimethoxy-12-methyl-13H- [1,3] benzodioxolo[5,6-c] phenanthridine 2, 3,5-dibenzyloxybenzyl bromide 3, and (E)-4-(4-chlorobenzylidene)-1-(4-nitrophenyl)hexan-3-one 4. In vitro cytotoxic assays were carried out in HL-60 and BJ cells using the MTT assay along with analysis of apoptosis with the annexin V detection kit. Additional network pharmacology and docking analyses were carried out. In the in vitro assays, compounds 2 and 4 displayed significant antiproliferative effects in HL-60 cells, exhibiting IC50 values of 5.02 and 9.50 µM, respectively. Compound 1 showed no activity, and compound 3 displayed toxicity in BJ cells. In addition, both compounds 2 and 4 induced apoptosis in HL-60 cells. Network pharmacology and docking analyses indicated that compounds 2 and 4 had synergistic effects targeting the CASP3 and PARP1 proteins. Notably, these proteins play pivotal roles in cancer-related pathways. Thus, by modulating these proteins, monocarbonyl curcuminoid has the potential to influence various cancer-related pathways. In summary, our novel findings provide valuable insights into the potential of these compounds to serve as novel anticancer therapeutic agents, warranting further mechanistic studies and clinical exploration.

Artificial intelligence in cancer diagnosis and therapy: Current status and future perspective.

Artificial intelligence (AI) in healthcare plays a pivotal role in combating many fatal diseases, such as skin, breast, and lung cancer. AI is an advanced form of technology that uses mathematical-based algorithmic principles similar to those of the human mind for cognizing complex challenges of the healthcare unit. Cancer is a lethal disease with many etiologies, including numerous genetic and epigenetic mutations. Cancer being a multifactorial disease is difficult to be diagnosed at an early stage. Therefore, genetic variations and other leading factors could be identified in due time through AI and machine learning (ML). AI is the synergetic approach for mining the drug targets, their mechanism of action, and drug-organism interaction from massive raw data. This synergetic approach is also facing several challenges in data mining but computational algorithms from different scientific communities for multi-target drug discovery are highly helpful to overcome the bottlenecks in AI for drug-target discovery. AI and ML could be the epicenter in the medical world for the diagnosis, treatment, and evaluation of almost any disease in the near future. In this comprehensive review, we explore the immense potential of AI and ML when integrated with the biological sciences, specifically in the context of cancer research. Our goal is to illuminate the many ways in which AI and ML are being applied to the study of cancer, from diagnosis to individualized treatment. We highlight the prospective role of AI in supporting oncologists and other medical professionals in making informed decisions and improving patient outcomes by examining the intersection of AI and cancer control. Although AI-based medical therapies show great potential, many challenges must be overcome before they can be implemented in clinical practice. We critically assess the current hurdles and provide insights into the future directions of AI-driven approaches, aiming to pave the way for enhanced cancer interventions and improved patient care.

Impact of Nanotechnology on Differentiation and Augmentation of Stem Cells for Liver Therapy.

The liver is one of the crucial organs of the body that performs hundreds of chemical reactions needed by the body to survive. It is also the largest gland of the body. The liver has multiple functions, including the synthesis of chemicals, metabolism of nutrients, and removal of toxins. It also acts as a storage unit. The liver has a unique ability to regenerate itself, but it can lead to permanent damage if the injury is beyond recovery. The only possible treatment of severe liver damage is liver transplant which is a costly procedure and has several other drawbacks. Therefore, attention has been shifted towards the use of stem cells that have shown the ability to differentiate into hepatocytes. Among the numerous kinds of stem cells (SCs), the mesenchymal stem cells (MSCs) are the most famous. Various studies suggest that an MSC transplant can repair liver function, improve the signs and symptoms, and increase the chances of survival. This review discusses the impact of combining stem cell therapy with nanotechnology. By integrating stem cell science and nanotechnology, the information about stem cell differentiation and regulation will increase, resulting in a better comprehension of stem cell-based treatment strategies. The augmentation of SCs with nanoparticles has been shown to boost the effect of stem cell-based therapy. Also, the function of green nanoparticles in liver therapies is discussed.

A genetic basis for cancer sex differences revealed in Xp11 translocation renal cell carcinoma.

Xp11 translocation renal cell carcinoma (tRCC) is a female-predominant kidney cancer driven by translocations between the TFE3 gene on chromosome Xp11.2 and partner genes located on either chrX or on autosomes. The rearrangement processes that underlie TFE3 fusions, and whether they are linked to the female sex bias of this cancer, are largely unexplored. Moreover, whether oncogenic TFE3 fusions arise from both the active and inactive X chromosomes in females remains unknown. Here we address these questions by haplotype-specific analyses of whole-genome sequences of 29 tRCC samples from 15 patients and by re-analysis of 145 published tRCC whole-exome sequences. We show that TFE3 fusions universally arise as reciprocal translocations with minimal DNA loss or insertion at paired break ends. Strikingly, we observe a near exact 2:1 female:male ratio in TFE3 fusions arising via X:autosomal translocation (but not via X inversion), which accounts for the female predominance of tRCC. This 2:1 ratio is at least partially attributable to oncogenic fusions involving the inactive X chromosome and is accompanied by partial re-activation of silenced chrX genes on the rearranged chromosome. Our results highlight how somatic alterations involving the X chromosome place unique constraints on tumor initiation and exemplify how genetic rearrangements of the sex chromosomes can underlie cancer sex differences.

The Golden Patient Initiative: A Systematic Review.

Operating theatres and surgical resource consumption comprise a significant proportion of healthcare costs. Inefficiencies in theatre lists remain an important focus for cost management, along with reducing patient morbidity and mortality. With the emergence of the coronavirus disease 2019 (COVID-19) pandemic, the number of patients on theatre waiting lists has surged. Hence, there is a pressing need to utilise the already limited theatre time and fraught resources with innovative methods. In this systematic review, we discuss the Golden Patient Initiative (GPI), in which the first patient on the operating list is pre-assessed the day prior to surgery, and we aim to assess its impact and overall efficacy. A literature search using the following four databases was conducted to identify and select all clinical research concerning the GPI: Medical Literature Analysis and Retrieval System Online (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Excerpta Medica Database (EMBASE), and the Cochrane library. Two independent authors screened articles against the eligibility criteria, using a process adapted from the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Data extracted included outcomes measured, follow-up period, and study design. The results showed significant heterogeneity, and hence a narrative review was conducted; 13 of the 73 eligible articles were included for analysis. Outcomes included delay in theatre start time, number of surgical case cancellations, and changes to total case numbers. Across the studies, a 19-30-minute improvement in theatre start time was reported (p<0.05), as well as a statistically significant decrease in case cancellations. Our analysis provides encouraging conclusions with regard to greater theatre efficiency following the application of GPI, a low-cost solution that can easily be implemented to help improve patient safety and lead to cost savings. However, at present, it is largely implemented among local trusts, and hence larger multi-centre studies are required to gather conclusive evidence about the efficacy of the initiative.

Utilizing Endoscopy for the Diagnosis of Acute Upper Gastrointestinal Bleeding.

Background Acute upper gastrointestinal bleeding (UGIB) is a medical emergency requiring immediate diagnosis. While endoscopy is a commonly employed procedure in the evaluation of UGIB, its timing, outcomes, and the range of identified causes vary widely across different medical settings and regions. Therefore, the purpose of this study was to use endoscopy to investigate the cause of UGIB. Methodology A cross-sectional study was conducted at the Department of Gastroenterology, Mayo Hospital, Lahore, over a period of one year, from July 1st, 2021 to June 28th, 2022. The study enrolled all patients who were 18 years of age or older and exhibited symptoms of UGIB, including hematemesis and/or melena, within 48 hours of onset. An upper gastrointestinal endoscopy procedure was conducted in order to identify the underlying cause of UGIB and to apply appropriate therapeutic interventions. In patients where the endoscopic examination revealed bleeding ulcers, a specimen for biopsy was excised to test for Helicobacter pylori. Similarly, in cases where a malignancy was suspected during the endoscopy, a biopsy was performed for confirmatory diagnosis. A pre-designed proforma was utilized to collect data including the demographic variables such as age, gender, ethnicity, family history; clinical variables such as clinical presentation, comorbidities, medical history, medication use, vital signs, biochemical evaluation, and imaging results; endoscopic findings such as endoscopic location and severity of bleeding, endoscopic diagnosis, and the use of endoscopic interventions. Information relevant to the treatment and outcomes was also observed. Under outcomes, the rates of re-bleeding, need for repeat endoscopy, length of hospital stay, and mortality were recorded. Results The study reports that the mean age of the participants was 54.72 years with a standard deviation of 12.5 years. The mean hemoglobin level at the presentation was 7.98 ± 2.88 mg/dl. Out of the 309 patients, 215 (69.58%) were male, 202 (65.37%) presented with hematemesis, 97 (31.39%) presented with melena, and 10 patients had a mixed presentation. A total of 154 (49.84%) patients had portal hypertension. Out of these, 128 (83.12%) had esophageal varices and 21 (13.64%) had gastric varices. Five patients suffered from portal hypertensive gastropathy. In 114 (36.89%) patients, the cause of bleeding was ulcerative disease and out of these, duodenal ulcers were found in 49 (42.98%) while gastric ulcers were found in 22 (19.30%) patients. In total malignant lesions were detected in 20 (6.47%) cases. Conclusion The research indicates that hematemesis was the predominant initial symptom observed in individuals experiencing UGIB. The predominant etiology of the hemorrhage was identified as esophageal and gastric varices through endoscopic assessment. The study highlights the importance of early endoscopic evaluation in patients with UGIB as it can help identify the cause and guide appropriate management. This emphasizes the need for healthcare providers to be vigilant in identifying and managing patients with UGIB promptly to improve outcomes. Further research is needed to explore effective strategies for early detection and management of UGIB.

Recent Updates on Peptide Molecules in Drug and Vaccine Development.

Peptides are of great importance in the areas of science because they can act as drug carriers and their therapeutic effect and their ability to generate an immune response. As culturing of viral agents for drugs and vaccine development is harmful, therefore, peptide-based drugs and vaccines have achieved great importance. Large immunoglobulins cannot pass the plasma membrane, so peptides are used to study this interaction because of their small size. Peptides with substituted amino acid sequences are also stable in blood serum, which makes them significant for drug development. Peptides with substituted amino acid sequences are stable in blood serum hence, their stability, small size, easy screening, cost-effectiveness, ease of administration and particularity (target specificity) make them effective to be used in pharmaceutical companies. Mostly branched peptides are used for the development of drugs because they are not prone to be degraded by proteolytic enzymes. In peptide-based vaccines, protein acts as the main constituent from which the main component that causes the infection is deleted by recombinant DNA technology, and these peptides act as antigens to stimulate the immune response. Self-assembled peptides have the main role in the delivery of drugs and vaccine molecules inside the living cells because they may also assemble into nano technological structures to improve their efficiency. This review focuses on the characteristics of peptides that make them effective to develop drugs and vaccines. Different peptides like synthetic peptides, antimicrobial peptides, signal peptides, carrier peptides, and their role against various viral, pathogenic, and microbial diseases and in cosmetics are described briefly.

A Comprehensive Update of Various Attempts by Medicinal Chemists to Combat COVID-19 through Natural Products.

The ongoing COVID-19 pandemic has resulted in a global panic because of its continual evolution and recurring spikes. This serious malignancy is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the outbreak, millions of people have been affected from December 2019 till now, which has led to a great surge in finding treatments. Despite trying to handle the pandemic with the repurposing of some drugs, such as chloroquine, hydroxychloroquine, remdesivir, lopinavir, ivermectin, etc., against COVID-19, the SARS-CoV-2 virus continues its out-of-control spread. There is a dire need to identify a new regimen of natural products to combat the deadly viral disease. This article deals with the literature reports to date of natural products showing inhibitory activity towards SARS-CoV-2 through different approaches, such as in vivo, in vitro, and in silico studies. Natural compounds targeting the proteins of SARS-CoV-2-the main protease (Mpro), papain-like protease (PLpro), spike proteins, RNA-dependent RNA polymerase (RdRp), endoribonuclease, exoribonuclease, helicase, nucleocapsid, methyltransferase, adeno diphosphate (ADP) phosphatase, other nonstructural proteins, and envelope proteins-were extracted mainly from plants, and some were isolated from bacteria, algae, fungi, and a few marine organisms.

Advanced network pharmacology study reveals multi-pathway and multi-gene regulatory molecular mechanism of Bacopa monnieri in liver cancer based on data mining, molecular modeling, and microarray data analysis.

Liver cancer is a malignant tumor that grows on the surface or inside the liver. The leading cause is a viral infection with hepatitis B or C virus. Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer. A list of studies evidences the therapeutic efficacy of Bacopa monnieri against liver cancer, but the precise molecular mechanism is yet to be discovered. This study combines data mining, network pharmacology, and molecular docking analysis to potentially revolutionize liver cancer treatment by identifying effective phytochemicals. Initially, the information on active constituents of B. monnieri and target genes of both liver cancer and B. monnieri were retrieved from literature as well as from publicly available databases. Based on the matching results between B. monnieri potential targets and liver cancer targets, the protein-protein interaction (PPI) network was constructed using the STRING database and imported into Cytoscape for screening of hub genes based on their degree of connectivity. Later, the interactions network between compounds and overlapping genes was constructed using Cytoscape software to analyze the network pharmacological prospective effects of B. monnieri on liver cancer. Gene Ontology (GO) and KEGG pathway analysis of hub genes revealed that these genes are involved in the cancer-related pathway. Lastly, the expression level of core targets was analyzed using microarray data (GSE39791, GSE76427, GSE22058, GSE87630, and GSE112790). Further, the GEPIA server and PyRx software were used for survival and molecular docking analysis, respectively. In summary, we proposed that quercetin, luteolin, apigenin, catechin, epicatechin, stigmasterol, beta-sitosterol, celastrol, and betulic acid inhibit tumor growth by affecting tumor protein 53 (TP53), interleukin 6 (IL6), RAC-alpha serine/threonine protein kinases 1 (AKT1), caspase-3 (CASP3), tumor necrosis factor (TNF), jun proto-oncogene (JUN), heat shot protein 90 AA1 (HSP90AA1), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), and SRC proto-oncogene (SRC). Through, microarray data analysis, the expression level of JUN and IL6 were found to be upregulated while the expression level of HSP90AA1 was found to be downregulated. Kaplan-Meier survival analysis indicated that HSP90AA1 and JUN are promising candidate genes that can serve as diagnostic and prognostic biomarkers for liver cancer. Moreover, the molecular docking and molecular dynamic simulation of 60ns well complemented the binding affinity of the compound and revealed strong stability of predicted compounds at the docked site. Calculation of binding free energies using MMPBSA and MMGBSA validated the strong binding affinity between the compound and binding pockets of HSP90AA1 and JUN. Despite that, in vivo and in vitro studies are mandatory to unveil pharmacokinetics and biosafety profiles to completely track the candidature status of B. monnieri in liver cancer.

Antidiabetic activity of Berberis brandisiana is possibly mediated through modulation of insulin signaling pathway, inflammatory cytokines and adipocytokines in high fat diet and streptozotocin-administered rats.

Medicinal plants play a key role in protection of chronic non-communicable ailments like diabetes, hypertension and dyslipidemia. Berberis brandisiana Ahrendt (Berberidaceae) is traditionally used to treat diabetes, liver problems, wounds, arthritis, infections, swelling and tumors. It is also known to be enriched with multiple phytoconstituents including berbamine, berberine, quercetin, gallic acid, caffeic acid, vanillic acid, benzoic acid, chlorogenic acid, syringic acid, p-coumaric acid, m-coumaric acid and ferulic acid. The efficacy of B. brandisiana has not been established yet in diabetes. This study has been planned to assess the antidiabetic activity of B. brandisiana in high fat diet and streptozotocin (HFD/STZ)-induced diabetes using animals. Administration of aqueous methanolic extract of B. brandisiana (AMEBB) and berbamine (Berb) for 8 weeks caused a dose dependent marked (p < 0.01) rise in serum insulin and HDL levels with a significant decline (p < 0.01) in glucose, triglycerides, glycosylated hemoglobin (HbA1c), cholesterol, LDL, LFTs and RFTs levels when compared with only HFD/STZ-administered rats. AMEBB and Berb also modulated inflammatory biomarkers (TNF-α, IL-6) and adipocytokines (leptin, adiponectin and chemerin). AMEBB (150 mg/kg and 300 mg/kg) and Berb (80 mg/kg and 160 mg/kg) treated rats showed a marked increase (p < 0.001) in catalase levels (Units/mg) in pancreas (42.4 ± 0.24, 47.4 ± 0.51), (38.2 ± 0.583, 48.6 ± 1.03) and liver (52 ± 1.41, 63.2 ± 0.51), (57.2 ± 0.58, 61.6 ± 1.24) and superoxide dismutase levels (Units/mg) in pancreas (34.8 ± 1.46, 38.2 ± 0.58), (33.2 ± 0.80, 40.4 ± 1.96) and liver (31.8 ± 1.52, 36.8 ± 0.96), (30 ± 0.70, 38.4 ± 0.81),respectively while a significant (p < 0.01) decrease in serum melondialdehyde levels (nmol/g) in pancreas (7.34 ± 0.17, 6.22 ± 0.22), (7.34 ± 0.20, 6.34 ± 0.11) and liver (9.08 ± 0.31,8.18 ± 0.29), (9.34 ± 0.10, 8.86 ± 0.24) compared to the data of only HFD/STZ-fed rats. Histopathological studies of pancreas, liver, kidney, heart and aorta revealed restoration of normal tissue architect in AMEBB and Berb treated rats. When mRNA expressions of candidate genes were assessed, AMEBB and Berb showed upregulation of IRS-1, SIRT1, GLUT-4 and downregulation of ADAM17. These findings suggest that AMEBB and Berb possess antidiabetic activity, possibly due to its effect on oxidative stress, glucose metabolism, inflammatory biomarkers and adipocytokines levels. Further upregulation of IRS-1, SIRT1, GLUT-4 and downregulation of ADAM17, demonstrated its potential impact on glucose homeostasis, insulin resistance and chronic inflammatory markers. Thus, this study provides support to the medicinal use of B. brandisiana and berbamine in diabetes.

Effect of cold plasma treatment on polylactic acid and polylactic acid/poly (ethylene glycol) films developed as a drug delivery system for streptomycin sulfate.

Polylactic acid (PLA) being a renewable polyester have extensively researched in the biomedical field due to its non-toxicity, high biocompatibility, and easy processing properties. However, low functionalization ability and hydrophobicity limit its applications and hence demands physical and chemical modifications to overcome these limitations. Cold plasma treatment (CPT) is frequently used to improve the hydrophilic properties of PLA-based biomaterials. This provides an advantage to obtain a controlled drug release profile in drug delivery systems. The rapid drug release profile may be advantageous in some applications such as wound application. The main objective of this study is to determine the effects of CPT on PLA or PLA@polyethylene glycol (PLA@PEG) porous films fabricated by solution casting method for use as a drug delivery system with a rapid release profile. The physical, chemical, morphological and drug release properties of PLA and PLA@PEG films, such as surface topography, thickness, porosity, water contact angle (WCA), chemical structure, and streptomycin sulfate release properties, after CPT were systematically investigated. XRD, XPS and FTIR results showed that oxygen-containing functional groups were formed on the film surface with CPT without changing the bulk properties. Along with the changes in the surface morphology such as surface roughness and porosity, the new functional groups provide the films hydrophilic properties by reducing the water contact angle. The improved surface properties enabled the selected model drug, streptomycin sulfate, to exhibit a faster release profile with drug-released mechanism fitted by first order kinetic model. Considering all the results, the prepared films showed an enormous potential for future drug delivery applications, especially in wound application where rapid drug release profile is an advantage.

Appendiceal Bulge on Routine Colonoscopy: Not All Disease Is Luminal.

Appendiceal mucocele is an extremely rare pathology accounting for 0.3-0.7% of all appendiceal pathology. It is characterized by appendiceal lumen dilatation by mucinous secretion collection. Though abdominal imaging and tissue Biopsy aids in diagnosis, suspicion should arise when a slight bulge or protrusion is seen on colonoscopy. We present a case of incidental appendiceal bulge found on a routine colonoscopy to evaluate abdominal pain that led to prompt diagnosis and management of appendiceal mucocele.

Assessment of Repeat Revascularization in Percutaneous Coronary Intervention Randomized Controlled Trials as a Surrogate for Mortality: A Meta-Regression Analysis.

The association of repeat revascularization after percutaneous coronary intervention (PCI) with mortality is uncertain. To assess the association of repeat revascularization after PCI with mortality in patients with coronary artery disease (CAD). We identified randomized controlled trials comparing PCI with coronary artery bypass graft (CABG) or optimal medical therapy (OMT) using electronic databases through January 1, 2022. We performed a random-effects meta-regression between repeat revascularization rates after PCI (absolute risk difference [%] between PCI and CABG or OMT) with the relative risks (RR) of mortality. We assessed surrogacy of repeat revascularization for mortality using the coefficient of determination (R2), with threshold of 0.80. In 33 trials (21,735 patients), at median follow-up of 4 (2-7) years, repeat revascularization was higher after PCI than CABG [RR: 2.45 (95% confidence interval, 1.99-3.03)], but lower vs OMT [RR: 0.64 (0.46-0.88)]. Overall, meta-regression showed that repeat revascularization rates after PCI had no significant association with all-cause mortality [RR: 1.01 (0.99-1.02); R2=0.10) or cardiovascular mortality [RR: 1.01 (CI: 0.99-1.03); R2=0.09]. In PCI vs CABG (R2=0.0) or PCI vs OMT trials (R2=0.28), repeat revascularization did not meet the threshold for surrogacy for all-cause or cardiovascular mortality (R2=0.0). We observed concordant results for subgroup analyses (enrollment time, follow-up, sample size, risk of bias, stent types, and coronary artery disease), and multivariable analysis adjusted for demographics, comorbidities, risk of bias, MI, and follow-up duration. In summary, this meta-regression did not establish repeat revascularization after PCI as a surrogate for all-cause or cardiovascular mortality.

Integrated System Pharmacology Approaches to Elucidate Multi-Target Mechanism of Solanum surattense against Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant liver tumors with high mortality. Chronic hepatitis B and C viruses, aflatoxins, and alcohol are among the most common causes of hepatocellular carcinoma. The limited reported data and multiple spectra of pathophysiological mechanisms of HCC make it a challenging task and a serious economic burden in health care management. Solanum surattense (S. surattense) is the herbal plant used in many regions of Asia to treat many disorders including various types of cancer. Previous in vitro studies revealed the medicinal importance of S. surattense against hepatocellular carcinoma. However, the exact molecular mechanism of S. surattense against HCC still remains unclear. In vitro and in silico experiments were performed to find the molecular mechanism of S. surattense against HCC. In this study, the network pharmacology approach was used, through which multi-targeted mechanisms of S. surattense were explored against HCC. Active ingredients and potential targets of S. surattense found in HCC were figured out. Furthermore, the molecular docking technique was employed for the validation of the successful activity of bioactive constituents against potential genes of HCC. The present study investigated the active "constituent-target-pathway" networks and determined the tumor necrosis factor (TNF), epidermal growth factor receptor (EGFR), mammalian target of rapamycin (mTOR), Bcl-2-like protein 1(BCL2L1), estrogen receptor (ER), GTPase HRas, hypoxia-inducible factor 1-alpha (HIF1-α), Harvey Rat sarcoma virus, also known as transforming protein p21 (HRAS), and AKT Serine/Threonine Kinase 1 (AKT1), and found that the genes were influenced by active ingredients of S. surattense. In vitro analysis was also performed to check the anti-cancerous activity of S. surattense on human liver cells. The result showed that S. surattense appeared to act on HCC via modulating different molecular functions, many biological processes, and potential targets implicated in 11 different pathways. Furthermore, molecular docking was employed to validate the successful activity of the active compounds against potential targets. The results showed that quercetin was successfully docked to inhibit the potential targets of HCC. This study indicates that active constituents of S. surattense and their therapeutic targets are responsible for their pharmacological activities and possible molecular mechanisms for treating HCC. Lastly, it is concluded that active compounds of S. surattense act on potential genes along with their influencing pathways to give a network analysis in system pharmacology, which has a vital role in the development and utilization of drugs. The current study lays a framework for further experimental research and widens the clinical usage of S. surattense.

Molecular Mechanisms of Cassia fistula against Epithelial Ovarian Cancer Using Network Pharmacology and Molecular Docking Approaches.

Epithelial ovarian cancer (EOC) is one of the deadliest reproductive tract malignancies that form on the external tissue covering of an ovary. Cassia fistula is popular for its anti-inflammatory and anticarcinogenic properties in conventional medications. Nevertheless, its molecular mechanisms are still unclear. The current study evaluated the potential of C. fistula for the treatment of EOC using network pharmacology approach integrated with molecular docking. Eight active constituents of C. fistula were obtained from two independent databases and the literature, and their targets were retrieved from the SwissTargetPrediction. In total, 1077 EOC associated genes were retrieved from DisGeNET and GeneCardsSuite databases, and 800 potential targets of eight active constituents of C. fistula were mapped to the 1077 EOC targets and intersected targets from two databases. Ultimately, 98 potential targets were found from C. fistula for EOC. Finally, the protein-protein interaction network (PPI) topological interpretation revealed AKT1, CTNNB1, ESR1, and CASP3 as key targets. This is the first time four genes have been found against EOC from C. fistula. The major enriched pathways of these candidate genes were established by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) investigations. To confirm the network pharmacology findings, the molecular docking approach demonstrated that active molecules have higher affinity for binding to putative targets for EOC suppression. More pharmacological and clinical research is required for the development of a drug to treat EOC.

Trapeziectomy with Ligament Reconstruction and Tendon Interposition versus Trapeziometacarpal Joint Replacement for Thumb Carpometacarpal Osteoarthritis: A Systematic Review and Meta-Analysis.

Background The trapeziometacarpal articulation in the thumb is a joint that is second-most commonly affected by osteoarthritis, and this can lead to considerable hand pain and disability. Currently, there is a multiplicity of surgical options available to address this problem, yet none has proven to be significantly superior to the others. Objective This study aims to compare the outcome of trapeziectomy with ligament reconstruction and tendon interposition versus trapeziometacarpal joint replacement for thumb carpometacarpal osteoarthritis. Materials and Methods A systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards. The NICE Healthcare Databases Advanced Search (HDAS) tool was used to search articles. One randomized controlled trial (RCT), one prospective cohort study and two retrospective cohort studies were identified. Results Our results demonstrate a significant difference in the Quick Disabilities of the Arm Shoulder and Hand (QDASH) score between the trapeziectomy with ligament reconstruction and tendon interposition (LRTI) and Joint Replacement groups with the joint replacement group exhibiting better QDASH scores than the LRTI group. We also found that those who had a joint replacement had a significantly better thumb opposition than those in the LRTI group, as demonstrated by a superior Kapandji score. However, the complication rate of joint replacement appears to be higher. Conclusion Our study reveals that while both treatment options are valid, the limited body of evidence currently available shows that joint replacement carries more risks and thus should not replace the current standard treatment of trapeziectomy with LRTI. This study highlights the need for more trials to be performed to more accurately compare the two treatment modalities. For the time being, we advocate that joint replacement is only performed by surgeons who perform this procedure regularly to reduce the risk of complications.

Associations between lung function and physical and cognitive health in the Canadian Longitudinal Study on Aging (CLSA): A cross-sectional study from a multicenter national cohort.

BACKGROUND: Low lung function is associated with high mortality and adverse cardiopulmonary outcomes. Less is known of its association with broader health indices such as self-reported respiratory symptoms, perceived general health, and cognitive and physical performance. The present study seeks to address the association between forced expiratory volume in 1 second (FEV1), an indicator of lung function, with broad markers of general health, relevant to aging trajectory in the general population. METHODS AND FINDINGS: From the Canadian general population, 22,822 adults (58% females, mean age 58.8 years [standard deviation (SD) 9.6]) were enrolled from the community between June 2012 and April 2015 from 11 Canadian cities and 7 provinces. Mixed effects regression was used to assess the cross-sectional relationship between FEV1 with self-reported respiratory symptoms, perceived poor general health, and cognitive and physical performance. All associations were adjusted for age, sex, body mass index (BMI), education, smoking status, and self-reported comorbidities and expressed as adjusted odds ratios (aORs). Based on the Global Lung Function Initiative (GLI) reference values, 38% (n = 8,626) had normal FEV1 (z-scores >0), 37% (n = 8,514) mild (z-score 0 to > -1 SD), 19% (n = 4,353) moderate (z-score -1 to > -2 SD), and 6% (n = 1,329) severely low FEV1 (z-score = < -2 SD). There was a graded association between lower FEV1 with higher aOR [95% CI] of self-reported moderate to severe respiratory symptoms (mild FEV1 1.09 [0.99 to 1.20] p = 0.08, moderate 1.45 [1.28 to 1.63] p < 0.001, and severe 2.67 [2.21 to 3.23] p < 0.001]), perceived poor health (mild 1.07 [0.9 to 1.27] p = 0.45, moderate 1.48 [1.24 to 1.78] p = <0.001, and severe 1.82 [1.42 to 2.33] p < 0.001]), and impaired cognitive performance (mild 1.03 [0.95 to 1.12] p = 0.41, moderate 1.16 [1.04 to 1.28] p < 0.001, and severe 1.40 [1.19 to 1.64] p < 0.001]). Similar graded association was observed between lower FEV1 with lower physical performance on gait speed, Timed Up and Go (TUG) test, standing balance, and handgrip strength. These associations were consistent across different strata by age, sex, tobacco smoking, obstructive, and nonobstructive impairment on spirometry. A limitation of the current study is the observational nature of these findings and that causality cannot be inferred. CONCLUSIONS: We observed graded associations between lower FEV1 with higher odds of disabling respiratory symptoms, perceived poor general health, and lower cognitive and physical performance. These findings support the broader implications of measured lung function on general health and aging trajectory.

Berberis lyceum and Fumaria indica: in vitro cytotoxicity, antioxidant activity, and in silico screening of their selected phytochemicals as novel hepatitis C virus nonstructural protein 5A inhibitors.

Berberis lyceum and Fumaria indica are two Pakistani indigenous herbal medicines used to treat liver infections, including hepatitis C virus (HCV). This study aimed to evaluate the cytotoxicity, and antioxidant activity of these plant extracts and computationally screen their selected phytoconstituents as HCV NS5A inhibitors. The viability of HepG2 cells was assessed 24 h and 48 h post-treatment using colorimetric and dye exclusion methods. Antioxidant properties were examined by the 2,2-diphenyl-1-picrylhydrazyl (DPPH), reducing power, and total antioxidant capacity assays. Seventeen known phytochemicals identified from each plant were docked into the active binding site of HCV NS5A protein. The top hit ligands were analyzed for their druglikeness properties and the indices of absorption, distribution, metabolism, elimination, and toxicity (ADMET). The results showed that both plant extracts were non-toxic (CC50 > 200 µg/ml). The IC50 values of DPPH-radical scavenging activity were 51.02 ± 0.94 and 62.91 ± 1.85 µg/ml for B. lyceum and F. indica, respectively. They also exhibited reducing power and total antioxidant capacity.The phytochemicals were identified as potent HCV NS5A inhibitors with good druglikeness and ADMET properties. Six of the docked phytochemicals exhibited higher binding scores (-17.9 to -19.2 kcal/mol) with HCV NS5A protein than the standard drug, daclatasvir (-17.2 kcal/mol). Molecular dynamics (MD) simulation confirmed the stability of two compounds, berbamine and paprafumine at 100 ns with active site of HCV NS5A protein. The identified compounds through molecular docking and MD simulation could have potential as HCV NS5A inhibitor after further validation.

Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung Cancer.

Targeting pentose phosphate pathway (PPP) enzymes has emerged as a promising strategy to combat cancer. 6-Phosphogluconate dehydrogenase (6-PGD), the third critical enzyme of the PPP, catalyzes oxidative decarboxylation of 6-phosphogluconate (6-PG) to produce ribulose-5-phosphate (Ru-5-P) and CO2. Overexpression of 6-PGD has been reported in multiple cancers and is recognized as a potential anticancer drug target. The current study is focused on the utilization of indispensable virtual screening tools for structure-based drug discovery. During the study, 17,000 natural compounds were screened against the 3-phosphoglycerate (3-PG) binding site of 6-PGD through a molecular operating environment (MOE), which revealed 115 inhibitors with higher selectivity and binding affinity. Out of the 115 best-fit compounds within the 6-PGD binding cavity, 15 compounds were selected and optimized through stringent in silico ADMET assessment models that justified the desirable pharmacokinetic, pharmacodynamic and physicochemical profiles of 5 ligands. Further protein−ligand stability assessment through molecular dynamics (MD) simulation illustrated three potential hits, secoisolariciresinol, syringaresinol and cleomiscosin A, with stable confirmation. Moreover, 6-PGD inhibitor validation was performed by an in vitro enzymatic assay using human erythrocytes purified 6-PGD protein and A549 cell lysate protein. The results of the in vitro assays supported the in silico findings. In order to gain insight into the anticancer activity of the aforementioned compounds, they were subjected to CLC-Pred, an in silico cytotoxicity browsing tool, which proved their anticancer activity against several cancer cell lines at Pa > 0.5. Additionally, a confirmation for in silico cytotoxicity was made by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for commercially available hits syringaresinol and cleomiscosin A against lung cancer (A549) cells. The results demonstrated that syringaresinol has an IC50 value of 36.9 µg/mL, while cleomiscosin A has an IC50 value of 133 µg/mL. After MTT, flow cytometry analysis confirmed that compounds induced apoptosis in A549 cells in a dose-dependent manner. This study suggested that the respective lignan compounds can serve as lead candidates for lung cancer therapy via 6-PGD inhibition. Furthermore, in vivo experiments need to be conducted to confirm their efficacy.