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The current study explored the effects of natural compounds, berbamine, bergapten, and carveol on paclitaxel-associated neuroinflammatory pain. Berbamine, an alkaloid obtained from BerberisamurensisRuprhas been previously researched for anticancer and anti-inflammatory potential. Bergapten is 5-methoxsalenpsoralen previously investigated in cancer, vitiligo, and psoriasis. Carveol obtained from caraway is a component of essential oil. The neuropathic pain model was induced by administering 2 mg/kg of paclitaxel (PTX) every other day for a week. After the final PTX injection, a behavioral analysis was conducted, and subsequently, tissue was collected for molecular analysis. Berbamine, bergapten, and carveol treatment attenuated thermal hypersensitivity, improved latency of falling, normalized the changes in body weight, and increased the threshold for pain sensation. The drugs increased the protective glutathione (GSH) and glutathione S-transferase (GST) levels in the sciatic nerve and spinal cord while lowering inducible nitric oxide synthase (iNOS) and lipid peroxidase (LPO). Hematoxylin and eosin (H and E) and immunohistochemistry (IHC) examinations confirmed that the medication reversed the abnormal alterations. The aforementioned natural substances inhibited cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-κb) overexpression, as evidenced by enzyme-linked immunosorbant assay (ELISA) and Western blot and hence provide neuroprotection in chronic constriction damage.

This present study aimed to delineate Rumex hastatus D. Don crude extract (Rh.Cr), n-Hexane, ethyl acetate, aqueous fractions (Rh.n-Hex, Rh.ETAC, Rh.Aq) and rutin for antidiarrheal, antisecretory effects, anti-spasmodic, gastrointestinal transient time, anti H. pylori, antiulcer effects, and toxicology. The preliminary phytochemical analysis of Rumex hastatus showed different phytoconstituents and shows different peaks in GC-MC chromatogram. Rumex hastatus crude extract (Rh.Cr), fractions, and rutin attributed dose-dependent (50–300 mg/kg) protection (0–100%) against castor oil-induced diarrhea and dose-dependently inhibited intestinal fluid secretions in mice. They decreased the distance traversed by charcoal in the gastrointestinal transit model in rats. In rabbit jejunum preparations, Rh.Cr and Rh.ETAC caused a concentration-dependent relaxation of both spontaneous and K+ (80 mM)-induced contractions at a similar concentration range, whereas Rh.n-Hex, rutin, and verapamil were relatively potent against K+-induced contractions and shifted the Ca2+ concentration–response curves (CRCs) to the right, Rh.Cr (0.3–1 mg/mL) and Rh.ETAC (0.1–0.3 mg/mL) shifted the isoprenaline-induced inhibitory CRCs to the left. Rh.n-Hex, Rh.ETAC and rutin showed anti-H. pylori effect, also shows an inhibitory effect against H+/K+-ATPase. Rumex hastatus showed gastroprotective and antioxidant effects. Histopathological evaluation showed improvement in cellular architecture and a decrease in the expression of inflammatory markers such as, cyclooxygenase (COX-2), tumor necrosis factor (TN,F-α) and phosphorylated nuclear factor kappa B (p-NFƙB), validated through immunohistochemistry and ELISA techniques. In RT-PCR it decreases H+/K+-ATPase mRNA levels. Rumex hastatus was found to be safe to consume up to a dose of 2000 mg/kg in a comprehensive toxicity profile. Docking studies revealed that rutin against H+/K+-ATPase pump and voltage-gated L-type calcium channel showed E-values of −8.7 and −9.4 Kcal/mol, respectively. MD simulations Molecular Mechanics Poisson Boltzmann surface area and molecular mechanics Generalized Born surface area (MMPBSA/GBSA) findings are consistent with the in-vitro, in-vivo and docking results.

The recombinant production of Pseudomonas aeruginosa exotoxin A (ETA), a critical component for immunotoxin development, remains hindered by its complex disulfide bond architecture, cytotoxicity, and aggregation propensity. Despite recent advancements in strain engineering, a systematic, data-driven approach integrating high-throughput screening with machine learning for ETA optimization has remained largely unexplored. We implemented a combinatorial optimization platform, screening 12 engineered E. coli strains across a matrix of four induction temperatures, three chaperone systems, and four redox-modulating additives. A high-throughput fluorescence-based solubility reporter was developed for rapid screening of 576 unique conditions, followed by training of an XGBoost machine learning model to predict soluble yield. The model was validated using 5-fold cross-validation with hyperparameter optimization to mitigate overfitting. Statistical analyses included one-way ANOVA with Tukey post-hoc test, Pearson correlation, and multiple regression. The disulfide-competent strain SHuffle T7, induced at 12°C with co-expression of the DnaKJE/GroEL chaperone system and supplementation with 2 mM oxidized glutathione, yielded 3.24 ± 0.4 mg/L of soluble, enzymatically active ETA. This represents a 15-fold improvement over conventional BL21(DE3) systems (F (11,24) = 45.32, p < 0.0001). Structural validation via redox-sensitive PAGE and nano-LC-MS/MS confirmed native disulfide pairing. The trained machine learning model demonstrated high predictive accuracy (R² = 0.92, RMSE = 0.24 mg/L) with consistent performance across cross-validation folds (average R² = 0.91 ± 0.02), and identified cytoplasmic redox potential and translational rate as the primary determinants of soluble expression. We present an integrated platform that synergizes experimental high-throughput screening with predictive machine learning to overcome the challenge of ETA production. While validation on additional protein targets is needed to fully establish generalizability, this work establishes an optimized, scalable protocol for therapeutic-grade ETA and provides a transferable computational framework for the rational optimization of other complex, disulfide-rich proteins.

•Polio is considered a serious threat to public health in Pakistan.•Online commenters show empathy for polio health care workers.•Misinformation on polio vaccine as an amplification of new polio cases.•Online commenters correct misinformation and false claims by providing factual information on polio.•Pakistan launches the Perception Management Initiative (PMI) to block anti-vaccination propaganda social media pages. Polio, which is caused by poliovirus, is a contagious, potentially crippling, and deadly disease. Pakistan is one of the countries in which polio is still endemic in the 21st century. In 2019, 146 polio cases were reported across the country with some resulting in deaths. Following the spread of rumors insinuating that children were falling sick after receiving an anti-polio vaccine, a mob attacked and set fire to a small hospital in the Peshawar district in April 2019. The present study investigates readers’ discussions that emerged from Dawn’s online readers’ comments on polio-related news stories in Pakistan. Using thematic analysis, we analyzed (N = 2216) comments made by readers in the polio-related news stories published on Dawn.com from January 1, 2012, to March 1, 2020. Seven major themes emerged from the analysis of the comments: 1) reasons for and challenges resulting in the failure to eradicate polio; 2) proposed solutions and policy changes to eradicate polio; 3) misinformation; 4) criticism, frustration, and shame; 5) comparison of Pakistan to other countries; 6) the internet as a public sphere; 7) suffering, empathy, and appreciation. Overall, our findings suggested that commenters are knowledgeable about polio vaccines and consider polio a serious threat to public health in Pakistan. Our study not only validated previous study findings such as reasons, challenges, and issues related to polio vaccination, but also found new challenges in online news sites concerning misinformation on polio and polio vaccination in Pakistan.

Pakistan is one of only three poliomyelitis-endemic countries in the world. Twelve wild poliovirus (WPV) cases were recorded in the country in 2018. Even though resistance to oral polio vaccine (OPV) has decreased over time, there are still pockets of communities, mostly ethnic Pakhtun living in the Khyber Pakhtunkhwa (KP) province, that resist OPV. Although local journalists may be important sources of health information, past studies have overlooked their role in this context. The purpose of this study was to examine Pakhtun health journalists’ beliefs regarding OPV and their views of the barriers and facilitators that influence OPV acceptance or hesitancy in their communities. We recruited and interviewed 33 Pakhtun journalists covering health issues for diverse media outlets in high-risk districts for WPV of the KP province. The semi-structured interviews were translated, transcribed, and analyzed for themes. The participants strongly supported OPV and advocated that children in their own families and communities get vaccinated against polio. At the same time, they felt that their communities faced more urgent health needs that were not addressed by the government. They identified barriers at the media organizational level operating against accurate coverage of OPV, including financial and time constraints, a lack of checks and balances, and limited health literacy. They regarded press releases issued by the officials associated with OPV campaigns as the main facilitators in the coverage of OPV. The participants perceived lack of community trust in the government, security concerns, and community members’ religious beliefs as the major impediments to increase in uptake of OPV. Pakhtun health journalists have the potential to be important partners in national polio eradication initiatives. They should receive culturally sensitive training in local languages at appropriate literacy levels. We also suggest direct involvement of journalists in community mobilization efforts.

Three-dimensional (3D) printing has become a potent production tool in the field of biomedical engineering over the past 20 years. Through layer-by-layer deposition of materials, proteins, and even living cells, it offers considerable advantages in the creation of sophisticated and individualized biomedical products with accuracy, efficiency, cost effectiveness, and reproducibility. Despite the tremendous advances made in 3D printing, more work needs to be done to improve the quality of biomedical goods created with this technology. To assure the creation of remarkable and ground-breaking goods that address patients’ demands, numerous challenges in 3D printing processes, materials, and applications must be addressed. It is necessary to incorporate developments in physics, materials science, engineering, biological sciences, and medicine to meet these problems. This article reviews a variety of 3D printing-related issues in the biomedical industry, including processes, post-processing techniques, applications, and related difficulties. It analyzes the difficulties 3D printing in biomedical engineering faces and makes suggestions for potential future advancements. It is obvious that 3D printing is becoming more and more important in this field and has the ability to provide a wide variety of useful biological items. This review seeks to identify future directions for research and development while also advancing understanding of the existing state of 3D printing and the effect of post-processing in biomedical engineering. Graphical Abstract

The recombinant production of Pseudomonas aeruginosa exotoxin A (ETA), a critical component for immunotoxin development, remains hindered by its complex disulfide bond architecture, cytotoxicity, and aggregation propensity. Despite recent advancements in strain engineering, a systematic, data-driven approach integrating high-throughput screening with machine learning for ETA optimization has remained largely unexplored. We implemented a combinatorial optimization platform, screening 12 engineered E. coli strains across a matrix of four induction temperatures, three chaperone systems, and four redox-modulating additives. A high-throughput fluorescence-based solubility reporter was developed for rapid screening of 576 unique conditions, followed by training of an XGBoost machine learning model to predict soluble yield. The model was validated using 5-fold cross-validation with hyperparameter optimization to mitigate overfitting. Statistical analyses included one-way ANOVA with Tukey post-hoc test, Pearson correlation, and multiple regression. The disulfide-competent strain SHuffle T7, induced at 12°C with co-expression of the DnaKJE/GroEL chaperone system and supplementation with 2 mM oxidized glutathione, yielded 3.24 ± 0.4 mg/L of soluble, enzymatically active ETA. This represents a 15-fold improvement over conventional BL21(DE3) systems (F (11,24) = 45.32, p < 0.0001). Structural validation via redox-sensitive PAGE and nano-LC-MS/MS confirmed native disulfide pairing. The trained machine learning model demonstrated high predictive accuracy (R² = 0.92, RMSE = 0.24 mg/L) with consistent performance across cross-validation folds (average R² = 0.91 ± 0.02), and identified cytoplasmic redox potential and translational rate as the primary determinants of soluble expression. We present an integrated platform that synergizes experimental high-throughput screening with predictive machine learning to overcome the challenge of ETA production. While validation on additional protein targets is needed to fully establish generalizability, this work establishes an optimized, scalable protocol for therapeutic-grade ETA and provides a transferable computational framework for the rational optimization of other complex, disulfide-rich proteins.

Background Selective serotonin reuptaker inhibitors, including fluoxetine, are widely studied and prescribed antidepressants, while their exact molecular and cellular mechanism are yet to be defined. We investigated the involvement of HDAC1 and eEF2 in the antidepressant mechanisms of fluoxetine using a lipopolysaccharide (LPS)-induced depression-like behavior model. Methods For in vivo analysis, mice were treated with LPS (2 mg/kg BW), fluoxetine (20 mg/kg BW), HDAC1 activator (Exifone: 54 mg/kg BW) and NH125 (1 mg/kg BW). Depressive-like behaviors were confirmed via behavior tests including OFT, FST, SPT, and TST. Cytokines were measured by ELISA while Iba-1 and GFAP expression were determined by immunofluorescence. Further, the desired gene expression was measured by immunoblotting. For in vitro analysis, BV2 cell lines were cultured; treated with LPS, exifone, and fluoxetine; collected; and analyzed. Results Mice treated with LPS displayed depression-like behaviors, pronounced neuroinflammation, increased HDAC1 expression, and reduced eEF2 activity, as accompanied by altered synaptogenic factors including BDNF, SNAP25, and PSD95. Fluoxetine treatment exhibited antidepressant effects and ameliorated the molecular changes induced by LPS. Exifone, a selective HDAC1 activator, reversed the antidepressant and anti-inflammatory effects of fluoxetine both in vivo and in vitro, supporting a causing role of HDAC1 in neuroinflammation allied depression. Further molecular mechanisms underlying HDAC1 were explored with NH125, an eEF2K inhibitor, whose treatment reduced immobility time, altered pro-inflammatory cytokines, and NLRP3 expression. Moreover, NH125 treatment enhanced eEF2 and GSK3β activities, BDNF, SNAP25, and PSD95 expression, but had no effects on HDAC1. Conclusions Our results showed that the antidepressant effects of fluoxetine may involve HDAC1-eEF2 related neuroinflammation and synaptogenesis.

PurposeNurses' turnover intention has become a major issue in developing countries with high power distance cultures. Therefore, the authors attempt to investigate how turnover intention among nurses' can be reduced through paternalistic leadership (PL). The authors further investigate the mediating role of job satisfaction between the associations of benevolent, moral and authoritarian dimensions of PL with turnover intention. Finally, the authors examined perceived organizational support (POS) as a conditional variable between job satisfaction and turnover intention.Design/methodology/approachThe authors collected data from 374 nurses working in public and private hospitals of high power distance culture using a questionnaire-based survey on convenience basis.FindingsStructural equation modeling confirms that benevolent and moral dimensions of PL positively affect nurses' job satisfaction which helps them reduce their turnover intention. While the authoritarian dimension of PL negatively affects job satisfaction to further enhance their turnover intention. In addition, the authors noted POS as a conditional variable to trigger the negative effect of job satisfaction on turnover intention.Research limitations/implicationsThe authors used a cross-sectional design to collect responses and ensured the absence of common method variance through Harman's Single factor test.Originality/valueThis study identified the mechanism (job satisfaction and POS) through which benevolent, moral and authoritative dimensions of PL predict turnover intention among nurses working in high power distance culture.

Ginkgo biloba extract possess several promising biological activities; currently, it is clinically employed in the management of several diseases. This research work aimed to extrapolate the antioxidant and anti-inflammatory effects of Ginkgo biloba (Gb) in methotrexate (MTX)-induced liver toxicity model. These effects were analyzed using different in vivo experimental approaches and by bioinformatics analysis. Male SD rats were grouped as follows: saline; MTX; Gb (pretreated for seven days with 60, 120, and 180 mg/kg daily dose before MTX treatment); silymarin (followed by MTX treatment); Gb 180 mg/kg daily only; and silymarin only. Histopathological results revealed that MTX induced marked hepatic injury, associated with a substantial surge in various hepatic enzymes such as alanine transaminase (ALT), aspartate transaminase (AST), and serum alkaline phosphatase (ALP). Furthermore, MTX caused the triggering of oxidative distress associated with a depressed antioxidant system. All these injury markers contributed to a significant release of apoptotic (caspase-3 and c-Jun N-terminal kinases (JNK)) and tumor necrosis factor (TNF-α)-like inflammatory mediators. Treatment with Gb counteracts MTX-mediated apoptosis and inflammation dose-dependently along with modulating the innate antioxidative mechanisms such as glutathione (GSH) and glutathione S-transferase (GST). These results were further supplemented by in silico study to analyze drug-receptor interactions (for several Gb constituents and target proteins) stabilized by a low energy value and with a good number of hydrogen bonds. These findings demonstrated that Gb could ameliorate MTX-induced elevated liver reactive oxygen species (ROS) and inflammation, possibly by JNK and TNF-α modulation.