Current Pharmaceutical Design - Online First

Intestinal permeability plays a crucial role in drug absorption, as it varies across different gastrointestinal regions, affecting the bioavailability of orally administered drugs. This variability, combined with dose-dependent absorption, influences the overall efficacy and pharmacokinetics of the drug.

This study aimed to investigate the impact of three intestinal regions (jejunum, ileum, and colon) along with two different doses of amlodipine (AML) (5 mg and 10 mg) on its permeability.

An optimized HPLC method was developed and validated for the simultaneous quantification of AML, metoprolol (MTP), and phenol red (PR), while a modified single-pass intestinal perfusion (SPIP) was used to assess AML permeability across different intestinal segments.

Net Water Flux (NWF) showed significant fluctuations, with high positive values in the colon, indicating distinct physiological responses in this region. The effective permeability (Peff) of AML varied across different intestinal segments and doses. In the jejunum and ileum, the Peff of AML decreased with increasing doses from 5 mg to 10 mg, while in the colon, Peff remained relatively stable. Peff values ranged from 
3.50 × 10⁻⁴ cm/s for the 5 mg dose to 1.80 × 10⁻⁴ cm/s for the 10 mg dose in the jejunum, from 3.30 × 10⁻⁴ cm/s (5 mg) to 2.41 × 10⁻⁴ cm/s (10 mg) in the ileum, and from 6.65 × 10⁻⁴ cm/s (5 mg) to 6.79 × 10⁻⁴ cm/s (10 mg) in the colon.

This study demonstrated significant segmental and dose-dependent variations in the intestinal permeability of AML using the SPIP model in rats.

Breast cancer remains a critical global health issue, particularly in patients with BRCA1/2 mutations, which lead to genomic instability and increased cancer susceptibility. While PARP inhibitors targeting PARP1 and PARP2 have shown clinical success through synthetic lethality, PARP15, a mono-ADP-ribosyltransferase involved in DNA repair and tumour progression, remains largely understudied.

A structure-based virtual screening approach was applied to identify potential PARP15 inhibitors. The screening was performed on a Bioactive Screening Compound Library consisting of over 12,200 drug-like small molecules. Using the MTiOpenScreen platform, 1,500 candidate compounds were initially shortlisted. Molecular docking was then conducted to identify top-binding compounds, followed by 500-nanosecond molecular dynamics simulations to assess complex stability. Principal component analysis (PCA), free energy landscape (FEL) evaluation, and absorption, distribution, metabolism, and excretion (ADME) profiling were also performed to characterise compound behaviour and drug-likeness.

Three compounds, F2002-0551, F2028-0309, and F1495-1822, emerged with docking scores surpassing the known PARP15 inhibitor, Niraparib. Molecular dynamics simulations confirmed their structural stability with low RMSD values and favourable FELs. PCA revealed consistent ligand dynamics, and ADME analysis showed high gastrointestinal absorption and other drug-like characteristics. Superimposition analysis demonstrated minimal deviation in docked poses, indicating strong and stable interactions with PARP15.

These results highlight the therapeutic potential of the selected compounds as novel PARP15 inhibitors. Their favourable binding stability and pharmacokinetic profiles support their candidacy for further development against BRCA-mutated breast cancer.

F2002-0551, F2028-0309, and F1495-1822 represent promising leads for PARP15 inhibition. This study offers a computational foundation for future experimental validation and therapeutic exploration in BRCA-associated breast cancer.

Despite significant advances in the comprehensive treatment of nasopharyngeal carcinoma (NPC), local recurrence or distant metastasis still occurs in a considerable proportion of patients, leading to poor outcomes and posing a significant clinical challenge. The current therapeutic agent, Triptonide (TN), has shown potential efficacy in modulating cellular autophagy, suggesting its therapeutic promise for treating NPC. However, the precise molecular targets and mechanisms underlying TN’s role in NPC remain to be elucidated.

Initially, relevant targets for TN in the treatment of NPC were identified through public databases. Next, network pharmacology and bioinformatics analyses were employed to pinpoint the top 15 hub targets and critical signaling pathways involved in TN’s therapeutic action. Finally, experimental validation, including a range of molecular assays, was conducted to investigate the cellular effects of TN treatment, such as apoptosis induction, migration inhibition, Caspase-3 activation, mitochondrial dysfunction, autophagy-related gene expression, and TFAM level detection, thereby confirming the essential genes and pathways.

A total of 31 potential molecular targets for TN in NPC were identified, with 27 genes confirmed through autophagy-related gene analysis. Among these, the top 15 hub genes included RELA, CASP8, NFKBIA, PPARG, PTGS2, MAPK14, MAPK8, HDAC1, ERBB2, CASP1, TERT, AR, CDK1, PGR, and HDAC6. TN was found to activate the MAPK signaling pathway. In vitro, TN induced NPC cell apoptosis via increased ROS, MAPK14 activation, and Caspase-3 cleavage. It disrupted mitochondrial function (reduced membrane potential, decreased copy number, enhanced fission), inhibited mTOR and RELA phosphorylation, and promoted autophagy. TN also caused S-phase arrest, reduced CDH3, and increased CDH1. Lipoic acid partially reversed TN-induced cytotoxicity.

TN exerts anti-NPC effects primarily through MAPK pathway activation and autophagy induction. Key targets mediating these effects include RELA, CASP8, PPARG, MAPK14, MAPK8, HDAC1, ERBB2, and CASP1. The reversal by lipoic acid implicates ROS in TN's mechanism. The disruption of mitochondrial function represents a critical facet of its action.

TN demonstrates potential as a therapeutic agent for NPC, primarily through activation of the MAPK signaling pathway and autophagy. Key targets, including RELA, CASP8, PPARG, MAPK14, MAPK8, HDAC1, ERBB2, and CASP1, have been identified as critical mediators of TN’s effects, highlighting its role in promoting autophagy and enhancing NPC treatment.

There is increasing evidence that environmental factors play an important role in the pathogenesis of hyperuricemia. However, the relationship between Brominated Flame Retardants (BFRs) and serum uric acid and hyperuricemia remains unclear.

This study used data from 7996 National Health and Nutrition Examination Survey (NHANES) participants from 2005 to 2016. Ten BFRs, including PBB153 and PBDE28, were included in the analysis. Multivariate logistic regression, subgroup analysis, Spearman correlation analysis, Weighted Quantile Sum (WQS), and Bayesian Kernel Machine Regression (BKMR) were used to assess the association between BFRs and hyperuricemia. We also evaluated the mediating role of the Systemic Immunoinflammatory Index (SII) in the relationship between BFRs and hyperuricemia.

Results show that, after adjusting for all covariates, PBDE47, PBDE99, PBDE100, and PBDE154 were significantly associated with hyperuricemia risk. The results of the WQS regression and BKMR model showed a significant positive correlation between exposure to mixed BFRs and hyperuricemia risk. PBDE183 (weight: 38%) was found to have the highest weight in the mixture. Further mediating analysis showed that the relationship between PBDE28 and PBDE183 exposure and hyperuricemia risk was mediated by SII.

Exposure to BFRs increases the risk of hyperuricemia, which may be mediated by inflammation. Therefore, future research should further explore the potential mechanisms underlying the association between BFR exposure and hyperuricemia risk.

Exposure to BFRs may increase the risk of hyperuricemia. Large-scale prospective cohort studies and experimental research are needed to confirm the relationship between BFRs and hyperuricemia.

This study aimed to synthesize and characterize copper oxide nanoparticles (CuO NPs) using Rhus punjabensis extract and chemical methodologies. The comparative nephrotoxicity of green-synthesized CuO NPs (G-CuO-NPs) and chemically synthesized CuO NPs (C-CuO NPs) were examined in Sprague-Dawley rats and their offspring following oral administration during pregnancy and lactation.

Fourier Transform Infrared Spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), and X-ray Diffraction (XRD) were employed to examine the morphology, dimensions, and functional groups of the fabricated CuO NPs. To assess the relative nephrotoxicity of G-CuO-NPs and C-CuO-NPs at doses of 50 and 100 mg/kg, twenty-five rats were randomly allocated to five groups (designated as G1, G2, G3, G4, and G5), with each group comprising one male and four female animals for mating purposes. Nephrotoxicity of both parental and offspring animals was evaluated by examining their antioxidant status, total protein content, lipid peroxidation, genotoxicity, serum biochemistry, and histopathology.

FT-IR confirmed the synthesis of CuO NPs, while TEM and SEM revealed that G-CuO NPs were spherical and C-CuO NPs were oval. The XRD analysis showed that both NPs had a monoclinic structure. The crystalline dimensions of G-CuO NPs were 36.6 nm, and 32.85 nm for C-CuO NPs. C-CuO NPs showed dose-dependent toxicity in both parents and pups, causing a disturbance in the antioxidant balance, reducing protein content, and inducing lipid peroxidation and genotoxicity in the renal tissues. The morphological architecture of the parents’ kidneys and renal function were evaluated. G-CuO NPs, on the other hand, showed mild toxicity only in the parents.

The findings indicate that G-CuO NPs exhibit biocompatibility and are suitable for biological applications. This study underscores the compatibility of plant-derived metallic nanoparticles with living systems and paves the way for investigating their potential applications in contexts where toxicity limits the use of nanoparticles.

Based on these findings, the biocompatibility of green-synthesized CuO NPs was determined, and they did not induce nephrotoxicity in both parents and their offspring. In contrast, chemically synthesized CuO NPs, when administered at higher concentrations, were found to cause nephrotoxicity, which may also be transmitted to the offspring through lactation.

The COVID-19 pandemic, caused by SARS-CoV-2, has highlighted the urgent need for effective antiviral and anti-inflammatory therapies. Spiropyridine derivatives containing a chalcone moiety have shown potential in targeting key enzymes involved in viral replication and inflammation.

To evaluate the inhibitory effects of synthesized spiropyridine derivatives on SARS-CoV-2 main protease (Mpro), secreted phospholipase A2 (sPLA2), and cytosolic phospholipase A2 (cPLA2), and to assess their impact on inflammatory and oxidative stress markers in LPS-treated lung cells.

To develop novel therapeutic agents that can effectively manage COVID-19 and related inflammatory conditions.

The synthesized compounds (1-3) were tested for their inhibitory activity against SARS-CoV-2 Mpro, sPLA2, and cPLA2 using in vitro assays to determine IC50 values. Inflammatory markers (COX-2, IL-2, IL-4, TGF-1β, TNF-α) and oxidative stress markers (GSH, SOD, GR, MDA) were measured in LPS-treated lung cells. Gene expression levels of sPLA2 and cPLA2 were also assessed. Molecular docking studies were conducted to analyze the binding affinities and interactions of the compounds with the target enzymes.

Compounds 1-3 showed significant inhibitory activity against SARS-CoV-2 Mpro with IC50 values of 19.85 µM, 7.31 µM, and 3.73 µM, respectively. For comparison, baicalein's IC50 value was 13.63 µM. Additionally, these compounds inhibited sPLA2 with IC50 values of 8.36 µM, 7.31 µM, and 3.73 µM, and cPLA2 with IC50 values of 20.44 µM, 6.02 µM, and 4.61 µM, respectively. Baicalein's IC50 values for sPLA2 and cPLA2 were 11.73 µM and 5.89 µM, respectively. In LPS-treated lung cells, compounds 1-3 significantly reduced COX-2 by up to 90.12%, IL-2 by 74.19%, IL-4 by 79.51%, TGF-1β by 44.57%, and TNF-α by 68.49%. They enhanced GSH by up to 194%, SOD by 357.19%, and GR by 445.87%, while reducing MDA by 77.90%. Gene expression of sPLA2 and cPLA2 was significantly downregulated by up to 82.31% and 64.59%, respectively. Molecular docking studies revealed binding affinities of -28.20, -28.20, and -28.07 kcal/mol for SARS-CoV-2 Mpro; -16.72, -17.21, and -15.89 kcal/mol for sPLA2; and -65.66, -66.95, and -79.24 kcal/mol for cPLA2, respectively.

The results demonstrate that the structural integration of a spiropyridine core with a chalcone moiety yields compounds with superior multi-target inhibitory activity. The potent antiviral, anti-inflammatory, and antioxidant effects are significantly correlated with their strong binding interactions with the active sites of Mpro, sPLA2, and cPLA2, as validated by molecular docking. These findings align with and extend current research on targeting host-inflammatory pathways alongside viral replication for COVID-19 management.

The synthesized spiropyridine derivatives containing a chalcone moiety exhibit potent antiviral, anti-inflammatory, and antioxidant properties. These findings suggest that these compounds could be promising therapeutic agents for managing COVID-19 and related inflammatory conditions. Future studies should focus on in vivo experiments, clinical trials, and structural optimization to further develop these compounds for clinical use.

Millions of people have died from zoonotic illnesses, like COVID-19 and Nipahvirus infection (NiV), throughout history. Fruit bats (Pteropus sp.) are the main reservoir host for NiV, an RNA virus belonging to the Henipavirus group, which causes extremely infectious illnesses, such as COVID-19. NiV outbreaks have posed significant public health concerns, especially in South and Southeast Asia. The Nipah virus (NiV) infection is caused by a virus that belongs to the Paramyxoviridae family's Henipavirus genus. It is the source of zoonosis, which causes respiratory and neurological symptoms.

This study has reviewed the epidemiology, pathophysiology, genetic diversity, and phylogenetics of NiV. It has explored NiV’s clinical features, cellular monitoring, infection factors, and the virus’ reservoir host.

Phylogenetic analysis has identified two circulating NiV lineages. Additionally, the study has examined the role of phytochemicals in combating viral infections. Despite the absence of a focused therapy for COVID-19, phytochemicals have been investigated for their potential antiviral properties. Evidence suggests that plants and their components may possess resistance against NiV by modulating the immune system and inhibiting viral replication.

The investigation into plant-derived compounds has offered a novel direction for NiV treatment, potentially enhancing viral resistance through immune modulation. Continued research on natural antivirals could bridge current gaps in therapeutic options for emerging zoonotic diseases.

The study has highlighted the transmission risk, detection challenges, and the potential of phytochemicals in managing NiV infections. The therapeutic potential of plants and their antiviral properties offer promising insights into future treatments for serious viral diseases, like NiV.