Mechanistic insights into carvedilol's potential protection against doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is an anthracycline chemotherapy drug widely employed in the treatment of various cancers, known for its potent antineoplastic properties but often associated with dose-dependent cardiotoxicity, limiting its clinical use. This review explores the complex molecular details that determine the heart-protective effectiveness of carvedilol in relation to cardiotoxicity caused by DOX. The harmful effects of DOX on heart cells could include oxidative stress, DNA damage, iron imbalance, disruption of autophagy, calcium imbalance, apoptosis, dysregulation of topoisomerase 2-beta, arrhythmogenicity, and inflammatory responses. This review carefully reveals how carvedilol serves as a strong protective mechanism, strategically reducing each aspect of cardiac damage caused by DOX. Carvedilol's antioxidant capabilities involve neutralizing free radicals and adjusting crucial antioxidant enzymes. It skillfully manages iron balance, controls autophagy, and restores the calcium balance essential for cellular stability. Moreover, the anti-apoptotic effects of carvedilol are outlined through the adjustment of Bcl-2 family proteins and activation of the Akt signaling pathway. The medication also controls topoisomerase 2-beta and reduces the renin-angiotensin-aldosterone system, together offering a thorough defense against cardiotoxicity induced by DOX. These findings not only provide detailed understanding into the molecular mechanisms that coordinate heart protection by carvedilol but also offer considerable potential for the creation of targeted treatment strategies intended to relieve cardiotoxicity caused by chemotherapy.

Efficacy and safety of infliximab and adalimumab in inflammatory bowel disease patients.

INTRODUCTION: Inflammatory bowel disease (IBD), consists of two primary types: Ulcerative Colitis (UC) and Crohn's Disease (CD). Infliximab (IFX) and Adalimumab (ADA) are frequently utilized in the management of moderate to severe cases of IBD. AIM: This study aimed to assess the efficacy and safety of IFX and ADA in individuals diagnosed with moderate to severe IBD. METHOD: This study is a prospective open-labeled randomized parallel study that included moderate to severe IBD patients treated with either IFX or ADA. A total of 56 patients participated, with 34 patients received IFX and 22 patients received ADA. Various measures, including Crohn's Disease Activity Index (CDAI), Mayo Score/ Disease Activity Index (DAI), and C-reactive protein (CRP) levels, were taken at baseline and week 14 to assess the efficacy of the treatments. In addition, the levels of drugs and sTREM-1 were measured at 14 weeks. Patient safety was monitored throughout the study period. RESULTS: In the group received IFX, there was a notable decrease in CDAI (P = 0.045), DAI (P = 0.026), and CRP (P = 0.023 for CD, and P = 0.021 for UC) levels. In addition, the group received ADA experienced a significant reduction in CDAI (P = 0.001), DAI (P = 0.032), and CRP (P < 0.018 for CD and P = 0.003 for UC) levels. Responders had higher drug concentrations than non-responders, notably IFX concentration was higher in responders with CD (P = 0.001) and UC (P < 0.001). ADA concentration was higher in UC (P <= 0.001) and all CD patients responded to the treatment. The same trend was observed for sTREM-1 levels in CD and UC patients (P = 0.042, and P = 0.015, respectively) in the IFX group. In UC patients treated with ADA, the level of sTREM-1 was significantly low (P = 0.002). CONCLUSION: Both IFX and ADA have a good safety profile and deliver a beneficial clinical and laboratory response in moderate-severe IBD patients. CLINICAL TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov under the identifier NCT05291039. (You can access the study at https://clinicaltrials.gov/study/NCT05291039 (First Posted: March 22, 2022).

Region-specific gene expression profile in the epididymis of high- and low-fertile dromedary camels.

The scenario of the fertile spermatozoa with high fertilizing capability is basically dependent on gene expression-based epididymal function. The current investigation aimed to declare the varied expression of different candidate genes (PLA2G4D, LCN15, CLUAP1, SPP1, AQP12B, DEFB110 and ESR1) relevant to spermatozoa features between the different epididymal segments in the mature dromedary camels (n = 30). Scrotal contents were collected post-slaughtering, during the breeding season and the epididymis was separated from the testicles and divided into three segments (caput, corpus and cauda) based on its morphology and anatomical characteristics. Epididymal spermatozoa were harvested from each epididymal portion and evaluated for motility, count, viability and morphology. Samples were grouped depending on their epididymal sperm cells features into high-fertile (n = 15) and low-fertile (n = 15) groups. The gene expression of the candidate genes was defined in the isolated RNA from each epididymal portion tissue. The segmental sperm motion and count were significantly (p < .05 and p < .01) higher in the three epididymal parts of high-fertile camels than the lower ones. There were some candidate genes markedly up-regulated in its expression in epididymal head of high-fertile camels (PLA2G4D and LCN15) and low fertile (CLUAP1), while others in the body region of the high-fertile group (SPP1, AQP12B and DEFB110). Nevertheless, ER1 did not differ in the expression among the epididymal segments. In conclusion, the variant expression patterns of these epididymal genes in relation to the regional spermatozoa features might suggest important roles of these genes in sperm maturation process in the epididymis and focusing more interest on their potential utility as markers for male camel fertility prediction.

Methylation of Interleukin-1 receptor-associated kinase-3 and the risk of multiple sclerosis relapse/activity.

This study retrospectively investigated the impact of interleukin-1 receptor-associated kinase-3 (IRAK-3/IRAK-M) silencing by methylation on the likelihood of multiple sclerosis (MS) activity. This cross-sectional study included 90 patients with MS: 45 with active disease (Group 1), 45 in remission (Group 2), and 45 healthy controls. The study included quantitation of IRAK-3 methylation index (MI%), IRAK-3 mRNA, and myeloid differentiation factor88 (MyD88) and assessment of NF-κB activity. IRAK-3 MI% was significantly higher in group 1 compared to group 2, accompanied by lower IRAK-3 mRNA expression, elevated circulating MyD88, and increased NF-κB activity. IRAK-3 MI% correlated negatively with its transcript and positively with MyD88 and NF-κB activity. A logistic regression model was created to predict active demyelination. The C-index was 0.924, which indicates a very strong prediction model. Within the limitations of current work, IRAK-3 methylation level seems to be a promising candidate biomarker for identifying MS patients at risk of relapse.

The influence of potassium nanoparticles as a foliar fertilizer on onion growth, production, chemical content, and DNA fingerprint.

Potassium is an important macro-fertilizer for plant growth but can be lost from the soil after application via irrigation. Slow-release nano-fertilizers can achieve sustainable crop cultivation and production, so this study evaluated the influence of potassium nanoparticles (K-NPs) with various concentrations (0, 50, 100, and 200 mg/l) on onion development, production, pigments, chemical content, and DNA fingerprint during two sequential agriculture seasons in 2021 and 2022 at a private farm in Zagazig, Sharkia Governorate, Egypt. Spraying onion plants with K-NPs (200 mg/l) significantly improved the vegetative characteristics of onion plant growth and production, as well as increasing the plant pigments and the content of carbohydrate, oil, total indole, and phosphorus in onion bulbs. Similarly, 50 mg/l of K-NPs considerably increased the content of nitrogen, potassium, protein, antioxidant activity, and phenols in the onion bulbs. The content of total flavonoids and anthocyanin was increased with 100 mg/l of K-NPs. In conclusion, the foliar application of K-NPs improves the onion plant yield and quality and can achieve agricultural sustainability.

Unveiling therapeutic frontiers: DON/DRP-104 as innovative Plasma kallikrein inhibitors against carcinoma-associated hereditary angioedema shocks - a comprehensive molecular dynamics exploration.

Human plasma kallikrein (PKa) is a member of the serine protease family and serves as a key mediator of the kallikrein-kinin system (KKS), which is known for its regulatory roles in inflammation, vasodilation, blood pressure, and coagulation. Genetic dysregulation of KKS leads to Hereditary Angioedema (HAE), which is characterized by spontaneous, painful swelling in various body regions. Importantly, HAE frequently coexists with various cancers. Despite substantial efforts towards the development of PKa inhibitors for HAE, there remains a need for bifunctional agents addressing both anti-cancer and anti-HAE aspects, especially against carcinoma-associated comorbid HAE conditions. Consequently, we investigated the therapeutic potential of the anti-glutamine prodrug, isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate (DRP-104), and its active form, 6-Diazo-5-oxo-l-norleucine (DON), recognized for their anti-cancer properties, as novel PKa inhibitors. Utilizing structure-based in silico methods, we conducted a comparative analysis with berotralstat, a clinically approved HAE prophylactic, and sebetralstat, an investigational HAE therapeutic agent, in Phase 3 clinical trials. Inhibiting PKa with DON resulted in relatively heightened structural stability, rigidity, restricted protein folding, and solvent-accessible loop exposure, contributing to increased intra-atomic hydrogen bond formation. Conversely, PKa inhibition with DRP-104 induced restricted residue flexibility and significantly disrupted the critical SER195-HIS57 arrangement in the catalytic triad. Both DON and DRP-104, along with the reference drugs, induced strong cooperative intra-residue motion and bidirectional displacement in the PKa architecture. The results revealed favorable binding kinetics of DON/DRP-104, showing thermodynamic profiles that were either superior or comparable to those of the reference drugs. These findings support their consideration for clinical investigations into the management of carcinoma-associated HAE.

MicroRNA-141-regulated KLK10 and TNFSF-15 gene expression in hepatoblastoma cells as a novel mechanism in liver carcinogenesis.

Liver cancer is one of the most pivotal global health problems, leading hepatocellular carcinoma (HCC) with a significant increase in cases worldwide. The role of non-coding-RNA in cancer proliferation and carcinogenesis has attracted much attention in the last decade; however, microRNAs (miRNAs), as non-coding RNA, are considered master mediators in various cancer progressions. Yet the role of miR-141 as a modulator for specific cellular processes in liver cancer cell proliferation is still unclear. This study identified the role of miR-141 and its potential functions in liver carcinogenesis. The level of miR-141 in HepG2 and HuH7 cells was assessed using quantitative real-time PCR (qRT-PCR) and compared with its expression in normal hepatocytes. A new miR-141 construct has been performed in a CMV promoter vector tagged with GFP. Using microarray analysis, we identified the potentially regulated genes by miR-141 in transfected HepG2 cells. The protein profile of the kallikrein-related peptidase 10 (KLK10) and tumor necrosis factor TNFSF-15 was investigated in HepG2 cells transfected with either an inhibitor, antagonist miR-141, or miR-141 overexpression vector using immunoblotting and flow cytometry assay. Finally, ELISA assay has been used to monitor the produced inflammatory cytokines from transfected HepG2 cells. Our findings showed that the expression of miR-141 significantly increased in HepG2 and HuH7 cells compared to the normal hepatocytes. Transfection of HepG2 cells with an inhibitor, antagonist miR-141, showed a significant reduction of HepG2 cell viability, unlike the transfection of miR-141 overexpression vector. The microarray data of HepG2 cells overexpressed miR-141 provided a hundred downregulated genes, including KLK10 and TNFSF-15. Furthermore, the expression profile of KLK10 and TNFSF-15 markedly depleted in HepG2 cells transfected with miR-141 overexpression accompanied by a decreasing level of interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α), indicating the role of miR-141 in HepG2 cell proliferation and programmed cell death. Interestingly, the experimental rats with liver cancer induced by Diethylnitrosamine injection further confirmed the upregulation of miR-141 level, IL-10, and TNF-α and the disturbance in KLK10 and TNFSF-15 gene expression compared with their expression in normal rats. The in-silico online tools, IntaRNA and miRWalk were used to confirm the direct interaction and potential binding sites between miR-141 and identified genes. Thus, the seeding regions of potential targeted sequences was cloned upstream of luciferase reporter gene in pGL3 control vector. Interestingly, the luciferase activities of constructed vectors were significantly decreased in HepG2 cells pre-transfected with miR-141 overexpression vector, while increasing in cells pre-transfected with miR-141 specific inhibitor. In summary, these data suggest the crucial role of miR-141 in liver cancer development via targeting KLK10 and TNFSF-15 and provide miR-141 as an attractive candidate in liver cancer treatment and protection.

Postcolonoscopy Diverticulitis.

Colonoscopy, generally safe but not devoid of risks, can lead to rare complications. We present 2 cases of postcolonoscopy diverticulitis (PCD). Case 1 was a 63-year-old woman, following colonoscopy, who developed acute sigmoid diverticulitis, despite a Diverticular Inflammation and Complication Assessment (DICA) score of 2, indicating extensive diverticulosis without inflammation. Conservative management with antibiotics led to recovery. Remarkably, she experienced a recurrent episode. Case 2 was a 74-year-old woman who had 2 colonoscopies, revealing pancolonic diverticulosis (DICA score: 2) without inflammation. After the second procedure, she developed severe sigmoid diverticulitis, managed conservatively with antibiotics. Discussion highlights PCD's rarity (prevalence: 0.04%-0.08%) and unclear pathogenesis. Both cases had DICA scores ≥2, suggesting a potential risk factor. Clinicians should recognize PCD, as it can mimic more common postcolonoscopy complications. Early recognition and management are vital.

A novel combination therapy targets sonic hedgehog signaling by the dual inhibition of HMG-CoA reductase and HSP90 in rats with non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is characterized by liver inflammation, fat accumulation, and collagen deposition. Due to the limited availability of effective treatments, there is a pressing need to develop innovative strategies. Given the complex nature of the disease, employing combination approaches is essential. Hedgehog signaling has been recognized as potentially promoting NASH, and cholesterol can influence this signaling by modifying the conformation of PTCH1 and SMO activity. HSP90 plays a role in the stability of SMO and GLI proteins. We revealed significant positive correlations between Hedgehog signaling proteins (Shh, SMO, GLI1, and GLI2) and both cholesterol and HSP90 levels. Herein, we investigated the novel combination of the cholesterol-lowering agent lovastatin and the HSP90 inhibitor PU-H71 in vitro and in vivo. The combination demonstrated a synergy score of 15.09 and an MSA score of 22.85, as estimated by the ZIP synergy model based on growth inhibition rates in HepG2 cells. In a NASH rat model induced by thioacetamide and a high-fat diet, this combination therapy extended survival, improved liver function and histology, and enhanced antioxidant defense. Additionally, the combination exhibited anti-inflammatory and anti-fibrotic potential by influencing the levels of TNF-α, TGF-ß, TIMP-1, and PDGF-BB. This effect was evident in the suppression of the Col1a1 gene expression and the levels of hydroxyproline and α-SMA. These favorable outcomes may be attributed to the combination's potential to inhibit key Hedgehog signaling molecules. In conclusion, exploring the applicability of this combination contributes to a more comprehensive understanding and improved management of NASH and other fibrotic disorders.

PCSK9 inhibitors as safer therapeutics for atherosclerotic cardiovascular disease (ASCVD): Pharmacophore design and molecular dynamics analysis.

Cardiovascular disorders are still challenging and are among the deadly diseases. As a major risk factor for atherosclerotic cardiovascular disease, dyslipidemia, and high low-density lipoprotein cholesterol in particular, can be prevented primary and secondary by lipid-lowering medications. Therefore, insights are still needed into designing new drugs with minimal side effects. Proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme catalyses protein-protein interactions with low-density lipoprotein, making it a critical target for designing promising inhibitors compared to statins. Therefore, we screened for potential compounds using a redesigned PCSK9 conformational behaviour to search for a significantly extensive chemical library and investigated the inhibitory mechanisms of the final compounds using integrated computational methods, from ligand essential functional group screening to all-atoms MD simulations and MMGBSA-based binding free energy. The inhibitory mechanisms of the screened compounds compared with the standard inhibitor. K31 and K34 molecules showed stronger interactions for PCSK9, having binding energy (kcal/mol) of -33.39 and -63.51, respectively, against -27.97 of control. The final molecules showed suitable drug-likeness, non-mutagenesis, permeability, and high solubility values. The C-α atoms root mean square deviation and root mean square fluctuation of the bound-PCSK9 complexes showed stable and lower fluctuations compared to apo PCSK9. The findings present a model that unravels the mechanism by which the final molecules proposedly inhibit the PCSK9 function and could further improve the design of novel drugs against cardiovascular diseases.

Orexins in apoptosis: a dual regulatory role.

The orexins, also referred to as hypocretins, are neuropeptides that originate from the lateral hypothalamus (LH) region of the brain. They are composed of two small peptides, orexin-A, and orexin-B, which are broadly distributed throughout the central and peripheral nervous systems. Orexins are recognized to regulate diverse functions, involving energy homeostasis, the sleep-wake cycle, stress responses, and reward-seeking behaviors. Additionally, it is suggested that orexin-A deficiency is linked to sleepiness and narcolepsy. The orexins bind to their respective receptors, the orexin receptor type 1 (OX1R) and type 2 (OX2R), and activate different signaling pathways, which results in the mediation of various physiological functions. Orexin receptors are widely expressed in different parts of the body, including the skin, muscles, lungs, and bone marrow. The expression levels of orexins and their receptors play a crucial role in apoptosis, which makes them a potential target for clinical treatment of various disorders. This article delves into the significance of orexins and orexin receptors in the process of apoptosis, highlighting their expression levels and their potential contributions to different diseases. The article offers an overview of the existing understanding of the orexin/receptor system and how it influences the regulation of apoptosis.

The Evaluation of Artificial Intelligence Technology for the Differentiation of Fresh Human Blood Cells From Other Species' Blood in the Investigation of Crime Scenes.

OBJECTIVES: The current study used the deep machine learning approach to differentiate human blood specimens from cow, goat, and chicken blood stains based on cell morphology. METHODS: A total of 1,955 known Giemsa-stained digitized images were acquired from the blood of humans, cows, goats, and chickens. To train the deep learning models, the well-known VGG16, Resnet18, and Resnet34 algorithms were used. Based on the image analysis, confusion matrices were generated. RESULTS: Findings showed that the F1 score for the chicken, cow, goat, and human classes were all equal to 1.0 for each of the three algorithms. The Matthews correlation coefficient (MCC) was 1 for chickens, cows, and humans in all three algorithms, while the MCC score was 0.989 for goats by ResNet18, and it was 0.994 for both ResNet34 and VGG16 algorithms. The three algorithms showed 100% sensitivity, specificity, and positive and negative predictive values for the human, cow, and chicken cells. For the goat cells, the data showed 100% sensitivity and negative predictive values with specificity and positive predictive values ranging from 98.5% to 99.6%. CONCLUSION: These data showed the importance of deep learning as a potential tool for the differentiation of the species of origin of fresh crime scene blood stains.

Assessment of Academic Resilience and Its Associated Factors Among Pharmacy Students in Twelve Countries.

OBJECTIVE: Academic resilience, a critical determinant of academic achievement, is affected by various factors. There is a paucity of large-scale international assessments of academic resilience among pharmacy students. Therefore, this study aimed to assess academic resilience among pharmacy students in 12 countries and to evaluate factors associated with their academic resilience levels. METHODS: A cross-sectional online survey-based study was conducted among randomly selected pharmacy students in 12 countries: Egypt, Türkiye, Indonesia, Pakistan, Bangladesh, Iraq, Jordan, Nigeria, Malaysia, Saudi Arabia, Sudan, and the United Arab Emirates. After pilot testing, the validated 30-item academic resilience scale (ARS) was used for the assessment. The data were collected between November 1, 2022 and April 15, 2023. Descriptive and inferential statistics were performed, as appropriate. RESULTS: A total of 3950 were received from the 12 participating countries. The mean age was 21.68 ± 2.62 years. About two-thirds of the responses were from female participants and those studying for Bachelor of Pharmacy degrees. Overall, the findings show moderate academic resilience, which varied across countries. The median (IQR) of the total ARS-30 was 114 (103-124). Females exhibited lower negative affective and emotional response subscale levels than males. There were significant cross-country variations in the ARS-30 and all subscales. The highest overall levels were reported for Sudan, Pakistan, and Nigeria and the lowest were reported for Indonesia and Türkiye. Students in private universities tended to have higher overall ARS levels than public university students. Higher academic performance was significantly associated with ARS levels, whereas those with excellent performance exhibited the highest ARS levels. Students with exercise routines had higher ARS levels than those without exercise routines. Finally, students who were engaged in extracurricular activities had higher ARS levels than those who did not participate in these activities. CONCLUSION: The study offers insights into the factors affecting academic resilience in pharmacy students across several countries. The findings could guide interventions and support activities to improve resilience and academic outcomes.

Tracking the therapeutic efficacy of a ketone mono ester and ß-hydroxybutyrate for ulcerative colitis in rats: New perspectives.

Ulcerative colitis (UC) is an inflammatory condition that affects the colon's lining and increases the risk of colon cancer. Despite ongoing research, there is no identified cure for UC. The recognition of NLRP3 inflammasome activation in the pathogenesis of UC has gained widespread acceptance. Notably, the ketone body ß-hydroxybutyrate inhibits NLRP3 demonstrating its anti-inflammatory properties. Additionally, BD-AcAc 2 is ketone mono ester that increases ß-hydroxybutyrate blood levels. It has the potential to address the constraints associated with exogenous ß-hydroxybutyrate as a therapeutic agent, including issues related to stability and short duration of action. However, the effects of ß-hydroxybutyrate and BD-AcAc 2 on colitis have not been fully investigated. This study found that while both exogenous ß-hydroxybutyrate and BD-AcAc 2 produced the same levels of plasma ß-hydroxybutyrate, BD-AcAc 2 demonstrated superior effectiveness in mitigating dextran sodium sulfate-induced UC in rats. The mechanism of action involves modulating the NF-κB signaling, inhibiting the NLRP3 inflammasome, regulating antioxidant capacity, controlling tight junction protein expression and a potential to inhibit apoptosis and pyroptosis. Certainly, BD-AcAc 2's anti-inflammatory effects require more than just increasing plasma ß-hydroxybutyrate levels and other factors contribute to its efficacy. Local ketone concentrations in the gastrointestinal tract, as well as the combined effect of specific ketone bodies, are likely to have contributed to the stronger protective effect observed with ketone mono ester ingestion in our experiment. As a result, further investigations are necessary to fully understand the mechanisms of BD-AcAc 2 and optimize its use.

Assessment of burnout, resilience, and thriving among academic health professionals: findings from an international study.

Introduction: Burnout, resilience, and thriving significantly impact academics, particularly in health professions, where responsibilities are extensive. This study aimed to explore these constructs among academic health professionals, examining sociodemographic and work-related factors influencing these outcomes. Methods: A cross-sectional study was conducted among academic health professionals via web-based professional networks from August 2022 to February 2023. Validated tools were used, and descriptive and inferential statistics were applied. Results: 505 participants were included, predominantly female (63%), with a mean age of 38.15 ± 9.6 years. High burnout was reported by 10.9%, 13.7% experienced exhaustion, and 6.3% were disengaged. Resilience and thriving were moderate at 59.2 and 51.9%, respectively. Age correlated negatively with burnout (r = -0.131, p = 0.003) but positively with resilience (r = 0.178, p < 0.001). Females reported higher exhaustion (p = 0.014), while males showed greater resilience (p = 0.016). Instructors exhibited lower resilience compared to assistant professors (p < 0.001) and associate professors (p < 0.001). Those at public universities reported higher exhaustion than those at private universities (p < 0.001). Conclusion: Variable levels of burnout, resilience, and thriving were observed among academic health professionals, influenced by sociodemographic and work-related factors. Interventions targeting resilience and thriving may mitigate burnout risk and enhance engagement among academics in health professions.

Very Early Onset of Fistulizing Inflammatory Bowel Disease With RIPK1 Mutation: A Case Report.

Infantile inflammatory bowel disease (IBD) is a very rare subgroup of IBD that develops in children younger than two years with genetic susceptibility, especially in those with monogenic defects. This type, when compared with IBD in older children, is more resistant to conventional medical treatment and presents with more complications that require more surgical interventions. Our patient is a male with first-degree consanguineous parents. He was 16 months old when he presented with multiple perianal fistulas, fissures, abscesses, diarrhea, fever, and failure to thrive. He underwent a protective double-barrel ileostomy and surgical repair of the perianal disease. Crohn's disease was confirmed after endoscopy and biopsy. A genetic workup was done and revealed receptor-interacting protein kinase 1 (RIPK1) mutations. Conventional pediatric IBD treatment was initiated after surgery, including tumor necrosis factor antagonist adalimumab 40 mg subcutaneously weekly for five months. Despite treatment, he presented with dysuria and a colovesical fistula. The patient underwent secondary surgical repair.

Novel green-based polyglycerol polymeric nanoparticles loaded with ferulic acid: A promising approach for hepatoprotection.

In the pursuit of eco-friendly and sustainable materials, polyglycerol diacid polymers hold immense promise for drug delivery compared to those derived from fossil fuels. Harnessing this potential, we aimed to prepare nanoparticles (NPs) derived from sustainable polymers, loaded with ferulic acid (FA), a natural polyphenolic compound known for its shielding effect against liver-damaging agents, including carbon tetrachloride (CCl4). Glycerol was esterified with renewable monomers, such as succinic acid, adipic acid, and/or FA, resulting in the creation of a novel class of polyglycerol diacid polymers. Characterization via Fourier-transform infrared spectroscopy and nuclear magnetic resonance confirmed the successful synthesis of these polymers with <7 % residual monomers. FA-loaded NPs were fabricated using the newly synthesized polymers. To further augment their potential, the NPs were coated with chitosan. The chitosan-coated NPs boasted an optimal PS of 290 ± 5.03 nm, showing superior physical stability, and a commendable EE% of 58.79 ± 0.43%w/v. The cytotoxicity was examined on fibroblast cells using the SRB assay. In-vivo experiments employing a CCl4-induced liver injury model yielded compelling evidence of the heightened hepatoprotective effects conferred by chitosan-coated particles. This demonstrates the benefits of incorporating sustainable polymers into innovative composites for efficient drug delivery, indicating their potential for creating versatile platforms for various therapeutic applications.

Changes in Milk Protein Functionality at Low Temperatures and Rennet Concentrations.

This study aimed to evaluate the influence of low-concentration rennet on the chemical, rheological characteristics, and protein fractions of skim milk (SM) at 4 ± 1 °C. Skimmed milk (SM) was divided into four lots of 500 mL, and diluted rennet (1:10,000) was added at different levels at 4 ± 1 °C. The treatments included control (no rennet), T1 (0.001 mL/rennet), T2 (0.01 mL rennet), and T3 (0.1 mL rennet) treatments, which were incubated for 24 h. The sampling was performed at 0, 1, 2, 6, 12, and 24 h, and the SM after incubation time was heated to 73 °C/16 s to denature the rennet enzyme. Skim milk samples (SMS) (control and rennet-added samples) were evaluated for proximate composition, capillary gel electrophoresis (CGE), hydrodynamic diameter, zeta potential, and rheology at 0, 1, 2, 6, 12, and 24 h. Foaming ability, foaming stability, water-holding capacity (WHC), oil emulsifying activity (OEA), and emulsion stability (ES) were performed at 0, 12, and 24 h of incubation time. There was a significant (p < 0.05) increase in non-proteins by 0.50% and in non-casein nitrogen by 0.81% as incubation progressed. The results showed that aggregation or curd was not formed during storage time. The CGE data indicated that increasing the rennet concentration had a significant (p < 0.05) effect on decreasing κ-CN, and breakdown increased at higher levels of rennet usage. There was a significant (p < 0.05) increase in the hydrodynamic diameter and a decrease in the zeta potential values in rennet-added samples at the end of the incubation time (24 h). The rheological results showed no changes in the storage modulus (G'), loss modulus (G″), or viscosity values. Increasing the rennet amount and storage time led to a significant (p < 0.05) decrease in the foaming ability and foaming stability and a significant (p < 0.05) increase in the oil emulsifying activity and emulsion stability of rennet-added SMS. This study concluded that milk protein functionality can be changed without aggregating or curd formation, and rennet milk can be processed.

DON/DRP-104 as potent serine protease inhibitors implicated in SARS-CoV-2 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach.

Human transmembrane serine protease 2 (TMPRSS2) is an important member of the type 2 transmembrane serine protease (TTSP) family with significant therapeutic markings. The search for potent TMPRSS2 inhibitors against severe acute respiratory syndrome coronavirus 2 infection with favorable tissue specificity and off-site toxicity profiles remains limited. Therefore, probing the anti-TMPRSS2 potential of enhanced drug delivery systems, such as nanotechnology and prodrug systems, has become compelling. We report the first in silico study of TMPRSS2 against a prodrug, [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] also known as DRP-104 synthesized from 6-Diazo-5-oxo-l-norleucine (DON). We performed comparative studies on DON and DRP-104 against a clinically potent TMPRSS2 inhibitor, nafamostat, and a standard serine protease inhibitor, 4-(2-Aminoethyl) benzenesulfonyl fluoride (AEBSF) against TMPRSS2 and found improved TMPRSS2 inhibition through synergistic binding of the S1/S1' subdomains. Both DON and DRP-104 had better thermodynamic profiles than AEBSF and nafamostat. DON was found to confer structural stability with strong positive correlated inter-residue motions, whereas DRP-104 was found to confer kinetic stability with restricted residue displacements and reduced loop flexibility. Interestingly, the Scavenger Receptor Cysteine-Rich (SRCR) domain of TMPRSS2 may be involved in its inhibition mechanics. Two previously unidentified loops, designated X (270-275) and Y (293-296) underwent minimal and major structural transitions, respectively. In addition, residues 273-277 consistently transitioned to a turn conformation in all ligated systems, whereas unique transitions were identified for other transitioning residue groups in each TMPRSS2-inhibitor complex. Intriguingly, while both DON and DRP-104 showed similar loop transition patterns, DRP-104 preserved loop structural integrity. As evident from our systematic comparative study using experimentally/clinically validated inhibitors, DRP-104 may serve as a potent and novel TMPRSS2 inhibitor and warrants further clinical investigation.

Chemically reacted blood Cu O nanofluid flow through a non-Darcy porous media with radially varying viscosity.

The study investigates the flow of a Newtonian Cu O nanofluid through a non-Darcy porous medium with radially varying viscosity, which is crucial for various industries such as pharmaceuticals, chemicals, nuclear, solar, and solar technologies. The peristaltic motion of the nanofluid is studied with thermal radiation and chemical reaction effects, and the viscosity varies with both radius and axial coordinates. The study assumes low Reynolds and long wavelength assumptions and uses the homotopy perturbation technique to obtain a semi-analytical solution of velocity, temperature, nanoparticle concentration, and skin friction. The results show that axial velocity increases with the increase of slip velocity and viscosity parameters, while wave amplitude and chemical reaction parameters increase while nanoparticle concentration decreases. High viscosity parameters allow fluid nanoparticles to gain more active energy and move more freely, which is the main idea behind crude oil refinement. This physical modeling is essential for physiological flows, such as stomach juice flow during endoscope insertion.