The multifaceted role of beta-blockers in overcoming cancer progression and drug resistance: Extending beyond cardiovascular disorders.

Beta-blockers are commonly used medications that antagonize ß-adrenoceptors, reducing sympathetic nervous system activity. Emerging evidence suggests that beta-blockers may also have anticancer effects and help overcome drug resistance in cancer treatment. This review summarizes the contribution of different isoforms of beta-adrenoceptors in cancer progression, the current preclinical and clinical data on associations between beta-blockers use and cancer outcomes, as well as their ability to enhance responses to chemotherapy and other standard therapies. We discuss proposed mechanisms, including effects on angiogenesis, metastasis, cancer stem cells, and apoptotic pathways. Overall, results from epidemiological studies and small clinical trials largely indicate the beneficial effects of beta-blockers on cancer progression and drug resistance. However, larger randomized controlled trials are needed to firmly establish their clinical efficacy and optimal utilization as adjuvant agents in cancer therapy.

Urgent need for a non-discriminatory and non-stigmatizing nomenclature for monkeypox virus.

We propose a novel, non-discriminatory classification of monkeypox virus diversity. Together with the World Health Organization, we named three clades (I, IIa and IIb) in order of detection. Within IIb, the cause of the current global outbreak, we identified multiple lineages (A.1, A.2, A.1.1 and B.1) to support real-time genomic surveillance.

Prognostic value of single-subject grey matter networks in early multiple sclerosis.

The identification of prognostic markers in early multiple sclerosis (MS) is challenging and requires reliable measures that robustly predict future disease trajectories. Ideally, such measures should make inferences at the individual level to inform clinical decisions. This study investigated the prognostic value of longitudinal structural networks to predict 5-year Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting MS (RRMS). We hypothesized that network measures, derived from MRI, outperform conventional MRI measurements at identifying patients at risk of developing disability progression. This longitudinal, multicentre study within the Magnetic Resonance Imaging in MS (MAGNIMS) network included 406 patients with RRMS (mean age = 35.7 ± 9.1 years) followed up for 5 years (mean follow-up = 5.0 ± 0.6 years). EDSS was determined to track disability accumulation. A group of 153 healthy subjects (mean age = 35.0 ± 10.1 years) with longitudinal MRI served as controls. All subjects underwent MRI at baseline and again 1 year after baseline. Grey matter atrophy over 1 year and white matter lesion load were determined. A single-subject brain network was reconstructed from T1-weighted scans based on grey matter atrophy measures derived from a statistical parameter mapping-based segmentation pipeline. Key topological measures, including network degree, global efficiency and transitivity, were calculated at single-subject level to quantify network properties related to EDSS progression. Areas under receiver operator characteristic (ROC) curves were constructed for grey matter atrophy and white matter lesion load, and the network measures and comparisons between ROC curves were conducted. The applied network analyses differentiated patients with RRMS who experience EDSS progression over 5 years through lower values for network degree [H(2) = 30.0, P < 0.001] and global efficiency [H(2) = 31.3, P < 0.001] from healthy controls but also from patients without progression. For transitivity, the comparisons showed no difference between the groups [H(2) = 1.5, P = 0.474]. Most notably, changes in network degree and global efficiency were detected independent of disease activity in the first year. The described network reorganization in patients experiencing EDSS progression was evident in the absence of grey matter atrophy. Network degree and global efficiency measurements demonstrated superiority of network measures in the ROC analyses over grey matter atrophy and white matter lesion load in predicting EDSS worsening (all P-values < 0.05). Our findings provide evidence that grey matter network reorganization over 1 year discloses relevant information about subsequent clinical worsening in RRMS. Early grey matter restructuring towards lower network efficiency predicts disability accumulation and outperforms conventional MRI predictors.

The significance of caloric restriction mimetics as anti-aging drugs.

Aging is an intricate process characterized by the gradual deterioration of the physiological integrity of a living organism. This unfortunate phenomenon inevitably leads to a decline in functionality and a heightened susceptibility to the ultimate fate of mortality. Therefore, it is of utmost importance to implement interventions that possess the capability to reverse or preempt age-related pathology. Caloric restriction mimetics (CRMs) refer to a class of molecules that have been observed to elicit advantageous outcomes on both health and longevity in various model organisms and human subjects. Notably, these compounds offer a promising alternative to the arduous task of adhering to a caloric restriction diet and mitigate the progression of the aging process and extend the duration of life in laboratory animals and human population. A plethora of molecular signals have been linked to the practice of caloric restriction, encompassing Insulin-like Growth Factor 1 (IGF1), Mammalian Target of Rapamycin (mTOR), the Adenosine Monophosphate-Activated Protein Kinase (AMPK) pathway, and Sirtuins, with particular emphasis on SIRT1. Therefore, this review will center its focus on several compounds that act as CRMs, highlighting their molecular targets, chemical structures, and mechanisms of action. Moreover, this review serves to underscore the significant relationship between post COVID-19 syndrome, antiaging, and importance of utilizing CRMs. This particular endeavor will serve as a comprehensive guide for medicinal chemists and other esteemed researchers, enabling them to meticulously conceive and cultivate novel molecular entities with the potential to function as efficacious antiaging pharmaceutical agents.

Ultrafast Brain MRI with Deep Learning Reconstruction for Suspected Acute Ischemic Stroke.

Background Deep learning (DL)-accelerated MRI can substantially reduce examination times. However, studies prospectively evaluating the diagnostic performance of DL-accelerated MRI reconstructions in acute suspected stroke are lacking. Purpose To investigate the interchangeability of DL-accelerated MRI with conventional MRI in patients with suspected acute ischemic stroke at 1.5 T. Materials and Methods In this prospective study, 211 participants with suspected acute stroke underwent clinically indicated MRI at 1.5 T between June 2022 and March 2023. For each participant, conventional MRI (including T1-weighted, T2-weighted, T2*-weighted, T2 fluid-attenuated inversion-recovery, and diffusion-weighted imaging; 14 minutes 18 seconds) and DL-accelerated MRI (same sequences; 3 minutes 4 seconds) were performed. The primary end point was the interchangeability between conventional and DL-accelerated MRI for acute ischemic infarction detection. Secondary end points were interchangeability regarding the affected vascular territory and clinically relevant secondary findings (eg, microbleeds, neoplasm). Three readers evaluated the overall occurrence of acute ischemic stroke, affected vascular territory, clinically relevant secondary findings, overall image quality, and diagnostic confidence. For acute ischemic lesions, size and signal intensities were assessed. The margin for interchangeability was chosen as 5%. For interrater agreement analysis and interrater reliability analysis, multirater Fleiss κ and the intraclass correlation coefficient, respectively, was determined. Results The study sample consisted of 211 participants (mean age, 65 years ± 16 [SD]); 123 male and 88 female). Acute ischemic stroke was confirmed in 79 participants. Interchangeability was demonstrated for all primary and secondary end points. No individual equivalence indexes (IEIs) exceeded the interchangeability margin of 5% (IEI, -0.002 [90% CI: -0.007, 0.004]). Almost perfect interrater agreement was observed (P > .91). DL-accelerated MRI provided higher overall image quality (P < .001) and diagnostic confidence (P < .001). The signal properties of acute ischemic infarctions were similar in both techniques and demonstrated good to excellent interrater reliability (intraclass correlation coefficient, ≥0.8). Conclusion Despite being four times faster, DL-accelerated brain MRI was interchangeable with conventional MRI for acute ischemic lesion detection. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Haller in this issue.

Saroglitazar mitigated NASH-associated hepatic injury in dexamethasone-treated rats via modulating autophagy, apoptosis, and necroptosis.

This study aimed to evaluate the possible ameliorative effects of saroglitazar (SAR) on aspects of hepatic injury in dexamethasone (DEX)-induced nonalcoholic steatohepatitis (NASH) in rats. Wistar rats received SAR (2 or 4 mg/kg/day, orally) or metformin (MET, 500 mg/kg/day, orally) for one week before and concurrently with DEX administration (8 mg/kg/day, i.p., for 6 days. Control and drug control groups received vehicle or the higher dose of SAR, respectively. At the end of the experiment, an oral glucose tolerance test (OGTT) was conducted, serum hepatic function parameters and lipid profile were assessed, and hepatic histological changes were evaluated. Moreover, hepatic p-Akt/Akt ratios, malondialdehyde (MDA) content, SREBP-1, FOXO1, LC3, cleaved caspase-3, and p-MLKL protein levels were determined. Furthermore, hepatic immunohistochemical expressions of FOXO1, caspase-3, Bcl-2, LC3, and P62 were examined. SAR (mainly at 4 mg/kg/day) significantly improved Area under the OGTT curve (P < 0.0001), hepatic function parameters, lipid profile, and hepatic histopathological features in DEX-administered rats. Moreover, SAR significantly attenuated DEX-induced increases in hepatic MDA content (P < 0.05), SREBP-1 levels (P < 0.0001), and nuclear FOXO1, caspase-3, LC3, P62, and p-MLKL protein expressions (P < 0.0001). Furthermore, SAR significantly enhanced hepatic p-Akt/Akt ratio and Bcl-2 protein expression in DEX-administered rats (P < 0.0001). The higher dose of SAR showed greater hepatoprotective effects compared to its corresponding lower dose and MET in most assessments, approaching levels similar to the control group. SAR mitigated hepatic injury associated with DEX-induced NASH in rats, suggesting it might be a potential hepatoprotective drug for patients with or at high risk of NASH.

Fenpropathrin provoked kidney damage via controlling the NLRP3/Caspase-1/GSDMD-mediated pyroptosis: The palliative role of curcumin-loaded chitosan nanoparticles.

This study assessed the ability of formulated curcumin-loaded chitosan nanoparticles (CU-CS-NPs) to reduce the kidney damage resulting from fenpropathrin (FPN) in rats compared to curcumin (CU) in rats. Sixty male Sprague Dawley rats were separated into six groups and orally administered 1 mL/kg b.wt corn oil, 50 mg CU/kg b.wt, 50 mg CU-CS-NPs /kg b.wt., 15 mg FPN /kg b.wt, CU+ FPN or CU-CS-NPs + FPN for 60 days. Then, serum renal damage products were assessed. Total antioxidant capacity, reactive oxygen species, interleukin 1ß (IL-1ß), malondialdehyde, NF-κB P65, cleaved-Caspase-1, and Caspase-8 were estimated in kidney homogenates. The cleaved Caspase-3 and TNF-α immunoexpression and pyroptosis-related genes were determined in renal tissues. The results showed that CU-CS-NPS significantly repressed the FPN-induced increment in kidney damage products (urea, uric acid, and creatinine). Moreover, the FPN-associated hypo-proteinemia, renal oxidative stress and apoptotic reactions, and impaired renal histology were considerably repaired by CU and CU-CS-NPs. Additionally, compared to FPN-exposed rats, CU, and CU-CS-NPs-treated rats had considerably lower immunoexpression of cleaved Caspase-3 and TNF-α in renal tissue. The pyroptosis-related genes NLRP3, GSDMD, IL-18, Caspase-3, Caspase-1, IL-1ß, Caspase-8, TNF-α, and NF-κB dramatically upregulated by FPN exposure in the renal tissues. Yet, in CU and CU-CS-NPs-treated rats, the gene above expression deviations were corrected. Notably, CU-CS-NPs were superior to CU in preventing oxidative damage and inflammation and regulating pyroptosis in the renal tissues of the FPN-exposed group. The results of the present study conclusively showed the superior favorable effect of CU-CS-NPs in counteracting renal impairment linked to environmental pollutants.

Unraveling the miRNA Puzzle in Atherosclerosis: Revolutionizing Diagnosis, Prognosis, and Therapeutic Approaches.

PURPOSE OF REVIEW: To eradicate atherosclerotic diseases, novel biomarkers, and future therapy targets must reveal the burden of early atherosclerosis (AS), which occurs before life-threatening unstable plaques form. The chemical and biological features of microRNAs (miRNAs) make them interesting biomarkers for numerous diseases. We summarized the latest research on miRNA regulatory mechanisms in AS progression studies, which may help us use miRNAs as biomarkers and treatments for difficult-to-treat diseases. RECENT FINDINGS: Recent research has demonstrated that miRNAs have a regulatory function in the observed changes in gene and protein expression during atherogenesis, the process that leads to atherosclerosis. Several miRNAs play a role in the development of atherosclerosis, and these miRNAs could potentially serve as non-invasive biomarkers for atherosclerosis in various regions of the body. These miRNAs have the potential to serve as biomarkers and targets for early treatment of atherosclerosis. The start and development of AS require different miRNAs. It reviews new research on miRNAs affecting endothelium, vascular smooth muscle, vascular inflammation, lipid retention, and cholesterol metabolism in AS. A miRNA gene expression profile circulates with AS everywhere. AS therapies include lipid metabolism, inflammation reduction, and oxidative stress inhibition. Clinical use of miRNAs requires tremendous progress. We think tiny miRNAs can enable personalized treatment.

Advances in endoscopic management of colonic diverticular bleeding.

PURPOSE OF REVIEW: This review is focused on diagnostic and management strategies for colonic diverticular bleeding (CDB). It aims to present the current state of the field, highlighting the available techniques, and emphasizing findings that influence the choice of therapy. RECENT FINDINGS: Recent guidelines recommend nonurgent colonoscopy (>24 h) for CDB. However, factors such as a shock index ≥1, which may warrant an urgent colonoscopy, remain under investigation.The standard approach to detecting the source of CDB requires a water-jet scope equipped with a cap. Innovative diagnostic techniques, such as the long-cap and tapered-cap, have proven effective in identifying stigmata of recent hemorrhage (SRH). Furthermore, the water or gel immersion methods may aid in managing massive hemorrhage by improving the visualization and stabilization of the bleeding site for subsequent intervention. Innovations in endoscopic hemostasis have significantly improved the management of CDB. New therapeutic methods such as endoscopic band ligation and direct clipping have substantially diminished the incidence of recurrent bleeding. Recent reports also have demonstrated the efficacy of cutting-edge techniques such as over-the-scope clips, which have significantly improved outcomes in complex cases that have historically necessitated surgical intervention. SUMMARY: Currently available endoscopic diagnostic and hemostatic methods for CDB have evolved with improved outcomes. Further research is necessary to refine the criteria for urgent colonoscopy and to confirm the effectiveness of new endoscopic hemostasis techniques.

Concurrent inflammation-related brain reorganization in multiple sclerosis and depression.

BACKGROUND: Neuroinflammation affects brain tissue integrity in multiple sclerosis (MS) and may have a role in major depressive disorder (MDD). Whether advanced magnetic resonance imaging characteristics of the gray-to-white matter border serve as proxy of neuroinflammatory activity in MDD and MS remain unknown. METHODS: We included 684 participants (132 MDD patients with recurrent depressive episodes (RDE), 70 MDD patients with a single depressive episode (SDE), 222 MS patients without depressive symptoms (nMS), 58 MS patients with depressive symptoms (dMS), and 202 healthy controls (HC)). 3 T-T1w MRI-derived gray-to-white matter contrast (GWc) was used to reconstruct and characterize connectivity alterations of GWc-covariance networks by means of modularity, clustering coefficient, and degree. A cross-validated support vector machine was used to test the ability of GWc to stratify groups according to their depression symptoms, measured with BDI, at the single-subject level in MS and MDD independently. FINDINGS: MS and MDD patients showed increased modularity (ANOVA partial-η2 = 0.3) and clustering (partial-η2 = 0.1) compared to HC. In the subgroups, a linear trend analysis attested a gradient of modularity increases in the form: HC, dMS, nMS, SDE, and RDE (ANOVA partial-η2 = 0.28, p < 0.001) while this trend was less evident for clustering coefficient. Reduced morphological integrity (GWc) was seen in patients with increased depressive symptoms (partial-η2 = 0.42, P < 0.001) and was associated with depression scores across patient groups (r = -0.2, P < 0.001). Depressive symptoms in MS were robustly classified (88 %). CONCLUSIONS: Similar structural network alterations in MDD and MS exist, suggesting possible common inflammatory events like demyelination, neuroinflammation that are caught by GWc analyses. These alterations may vary depending on the severity of symptoms and in the case of MS may elucidate the occurrence of comorbid depression.

A comparative study of the risk assessment and heavy metal contamination of coastal sediments in the Red sea, Egypt, between the cities of El-Quseir and Safaga.

This study aimed to assess the influence of pollution on the quality of sediments and the risks associated with El-Qusier and Safaga Cities, Red Sea, Egypt, during 2021, divided into four sectors, using multiple pollution indices. To achieve that, we evaluated the metal pollution index (MPI), contamination factor (Cf), pollution load index (PLI), contamination security index (CSI), and anthropogenicity (Anp%). Moreover, carcinogenic and non-carcinogenic risks are used for human health hazards. Results indicated that Mn and Fe recorded the highest concentrations, whereas Cd had the lowest. El-Quseir City sediments were found the following metal ions: Fe > Mn > Ni > Zn > Cu > Co > Pb > Cd, where the order in the Safaga City was: Fe > Mn > Zn > Ni > Cu > Pb > Co > Cd. MPI > 1, this is alarming in the study area due to heavy metal pollution. In addition, Cf < 1 in all metals except Cd with contamination degree CD ranged from low to considerable contamination in El-Qusier city. In contrast, contamination ranged from significant to very high in Safaga city. PLI < 1 is lower than the reference at all monitored stations. CSI values ranged from relatively low to moderate. Besides Cd, data reflect each element's low environmental danger (EriMe40). This study's risk index (RI) is low to moderate in Sector 1 and high to extremely high in Sector 2. HQ and HI index < 1 means it is safe for human health in order: HI ingestion > HI dermal. CSR for different pathways was recorded as dermal > ingestion, in which total CSR for all paths is considered harmful, and the cancer risk is troublesome and higher than the reference ranges of 1 × 10-6-1 × 10-4. In conclusion, the examined heavy metals provide environmental hazards across the assessed locations.

Gender differences in self-assessed performance and stress level during training of basic interventional radiology maneuvers.

OBJECTIVES: Gender differences have been reported to influence medical training. We investigated gender differences encountered during training in interventional radiology maneuvers. METHODS: Catheter handling was analyzed under standardized conditions in 64 participants naïve to endovascular procedures (26 women, 38 men). Objective (e.g., catheter pathway, catheter movements, required time) and subjective parameters (stress level) were recorded. The NASA-Task Load Index (NASA-TLX; 1-20 points) was used to assess participants' stress levels and perceived workload. RESULTS: In the easier tasks, no significant differences between male and female participants regarding catheter handling were observed. In the most complex task, female participants took themselves more time (688 ± 363 vs. 501 ± 230 s; p = 0.02), asked for help more frequently (n = 19 vs. n = 8) and earlier than men (203 ± 94 vs. 305 ± 142 s; p = 0.049), whereas men stood out by more agitated catheter handling (6.0 ± 1.8 vs. 4.8 ± 1.6 movements/s; p = 0.005). Overall, female participants perceived tasks to be more difficult (11.5 ± 4.2 vs. 9.6 ± 3.3; p = 0.016), perceived higher stress levels (8.9 ± 4.9 vs. 6.3 ± 4.4; p = 0.037), and rated their own performance lower (9.12 ± 3.3 vs. 11.3 ± 3.3; p = 0.009). However, female participants were able to correlate self-assessed with objective parameters correctly (r between -0.555 and -0.469; p = 0.004-0.018), whereas male participants failed to correctly rate their performance (p between 0.34 and 0.73). Stress levels correlated with objective parameters in males (r between 0.4 and 0.587; p < 0.005), but not in female participants. CONCLUSION: Perceived stress levels, self-evaluation skills, and catheter handling differ greatly between untrained male and female participants trying to solve interventional radiological tasks. These gender-specific differences should be considered in interventional radiology training. CLINICAL RELEVANCE STATEMENT: As psychological aspects may influence individual working strategies gender-specific differences in self-perception while learning interventional radiology maneuvers could be essential regarding success in teaching and treatment outcomes. KEY POINTS: • After performing standardized training, 38 male and 26 female volunteers showed significant differences regarding objective and self-assessed performance, as well as in perceived workload while performing simulated endovascular catheter maneuvers. • After solving simulated endovascular radiological tasks, female participants were able to self-assess their objective performance much more accurately than male participants. • Women took more time to solve simulated endovascular tasks and asked earlier and more frequently for help than men.

Ecologically mediated differences in electric organ discharge drive evolution in a sodium channel gene in South American electric fishes.

Active electroreception-the ability to detect objects and communicate with conspecifics via the detection and generation of electric organ discharges (EODs)-has evolved convergently in several fish lineages. South American electric fishes (Gymnotiformes) are a highly species-rich group, possibly in part due to evolution of an electric organ (EO) that can produce diverse EODs. Neofunctionalization of a voltage-gated sodium channel gene accompanied the evolution of electrogenic tissue from muscle and resulted in a novel gene (scn4aa) uniquely expressed in the EO. Here, we investigate the link between variation in scn4aa and differences in EOD waveform. We combine gymnotiform scn4aa sequences encoding the C-terminus of the Nav1.4a protein, with biogeographic data and EOD recordings to test whether physiological transitions among EOD types accompany differential selection pressures on scn4aa. We found positive selection on scn4aa coincided with shifts in EOD types. Species that evolved in the absence of predators, which likely selected for reduced EOD complexity, exhibited increased scn4aa evolutionary rates. We model mutations in the protein that may underlie changes in protein function and discuss our findings in the context of gymnotiform signalling ecology. Together, this work sheds light on the selective forces underpinning major evolutionary transitions in electric signal production.

Benzimidazole-oxindole hybrids as multi-kinase inhibitors targeting melanoma.

In the current study, a series of benzimidazole-oxindole conjugates 8a-t were designed and synthesized as type II multi-kinase inhibitors. They exhibited moderate to potent inhibitory activity against BRAFWT up to 99.61 % at 10 µM. Notably, compounds 8e, 8k, 8n and 8s demonstrated the most promising activity, with 99.44 to 99.61 % inhibition. Further evaluation revealed that 8e, 8k, 8n and 8s exhibit moderate to potent inhibitory effects on the kinases BRAFV600E, VEGFR-2, and FGFR-1. Additionally, compounds 8a-t were screened for their cytotoxicity by the NCI, and several compounds showed significant growth inhibition in diverse cancer cell lines. Compound 8e stood out with a GI50 range of 1.23 - 3.38 µM on melanoma cell lines. Encouraged by its efficacy, it was further investigated for its antitumor activity and mechanism of action, using sorafenib as a reference standard. The hybrid compound 8e exhibited potent cellular-level suppression of BRAFWT, VEGFR-2, and FGFR-1 in A375 cell line, surpassing the effects of sorafenib. In vivo studies demonstrate that 8e significantly inhibits the growth of B16F10 tumors in mice, leading to increased survival rates and histopathological tumor regression. Furthermore, 8e reduces angiogenesis markers, mRNA expression levels of VEGFR-2 and FGFR-1, and production of growth factors. It also downregulated Notch1 protein expression and decreased TGF-ß1 production. Molecular docking simulations suggest that 8e binds as a promising type II kinase inhibitor in the target kinases interacting with the key regions in their kinase domain.

Identification of new anti-mycobacterial agents based on quinoline-isatin hybrids targeting enoyl acyl carrier protein reductase (InhA).

Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 µg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 µM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.

Environmental epigenetics: Exploring phenotypic plasticity and transgenerational adaptation in fish.

Epigenetics plays a vital role in the interaction between living organisms and their environment by regulating biological functions and phenotypic plasticity. Considering that most aquaculture activities take place in open or natural habitats that are vulnerable to environmental changes. Promising findings from recent research conducted on various aquaculture species have provided preliminary evidence suggesting a link between epigenetic mechanisms and economically valuable characteristics. Environmental stressors, including climate changes (thermal stress, hypoxia, and water salinity), anthropogenic impacts such as (pesticides, crude oil pollution, nutritional impacts, and heavy metal) and abiotic factors (infectious diseases), can directly trigger epigenetic modifications in fish. While experiments have confirmed that many epigenetic alterations caused by environmental factors have plastic responses, some can be permanently integrated into the genome through genetic integration and promoting rapid transgenerational adaptation in fish. These environmental factors might cause irregular DNA methylation patterns in genes related to many biological events leading to organs dysfunction by inducing alterations in genes related to oxidative stress or apoptosis. Moreover, these environmental issues alter DNA/histone methylation leading to decreased reproductive competence. This review emphasizes the importance of understanding the effects of environmentally relevant issues on the epigenetic regulation of phenotypic variations in fish. The goal is to expand our knowledge of how epigenetics can either facilitate or hinder species' adaptation to these adverse conditions. Furthermore, this review outlines the areas that warrant further investigation in understanding epigenetic reactions to various environmental issues.

Microfluidics for adaptation of microorganisms to stress: design and application.

Microfluidic systems have fundamentally transformed the realm of adaptive laboratory evolution (ALE) for microorganisms by offering unparalleled control over environmental conditions, thereby optimizing mutant generation and desired trait selection. This review summarizes the substantial influence of microfluidic technologies and their design paradigms on microbial adaptation, with a primary focus on leveraging spatial stressor concentration gradients to enhance microbial growth in challenging environments. Specifically, microfluidic platforms tailored for scaled-down ALE processes not only enable highly autonomous and precise setups but also incorporate novel functionalities. These capabilities encompass fostering the growth of biofilms alongside planktonic cells, refining selection gradient profiles, and simulating adaptation dynamics akin to natural habitats. The integration of these aspects enables shaping phenotypes under pressure, presenting an unprecedented avenue for developing robust, stress-resistant strains, a feat not easily attainable using conventional ALE setups. The versatility of these microfluidic systems is not limited to fundamental research but also offers promising applications in various areas of stress resistance. As microfluidic technologies continue to evolve and merge with cutting-edge methodologies, they possess the potential not only to redefine the landscape of microbial adaptation studies but also to expedite advancements in various biotechnological areas. KEY POINTS: • Microfluidics enable precise microbial adaptation in controlled gradients. • Microfluidic ALE offers insights into stress resistance and distinguishes between resistance and persistence. • Integration of adaptation-influencing factors in microfluidic setups facilitates efficient generation of stress-resistant strains.

Dietary lysozyme and avilamycin modulate gut health, immunity, and growth rate in broilers.

BACKGROUND: Attempts to use dietary lysozyme (LYZ) as an alternative to antibiotics in broilers have been successful, but further research is needed for effective use. Here, we compared the differences between LYZ and avilamycin (AVI) feed additives for growth performance, gut health and immunity of broilers. One-day old, one hundred and twenty broiler chicks (Ross 308) were randomly allocated into three groups consisting forty birds in each group. Standard diet without supplementation was applied as the control group (I), while the chicks of the other groups were supplemented with 100 mg of AVI per kg diet (AVI, group II), and 90 mg LYZ per kg diet (LYZ, group III) for five consecutive weeks. RESULTS: Body weight, feed conversion ratio, body weight gain, and European production efficiency factor were markedly (p < 0.05) increased in both AVI and LYZ groups in relation to CON group, but the feed intake and protein efficiency ratio were not affected. Both AVI and LYZ significantly (p < 0.001) upregulated the mRNA expression of ileal interleukin-18 (IL-18), interferon-gamma (IFN-γ), and interleukin-10 (IL-10), interleukin-2 (IL-2), and glutathione peroxidase (GSH-PX) genes compared to CON group. However, IL-2, IL-10, IL-18, and GSH-PX genes were markedly (p < 0.01) upregulated in LYZ compared to the AVI group. LYZ treated group had a significant increase (p < 0.05) in the serological haemagglutination inhibition titers of H5N1 vaccination and a significant decrease (p < 0.0001) in coliform counts compared to control and AVI groups, but all growth parameters were nearly similar between AVI and LYZ groups. The VH and VH/CD were markedly higher in LYZ than AVI and control groups. CONCLUSION: Exogenous dietary lysozyme supplementation by a dose of 90 mg/kg broilers' diet induced better effects on intestinal integrity, fecal bacterial counts, immune response, and growth performance which were comparable to avilamycin. Therefore, dietary lysozyme could safely replace avilamycin in the broiler chickens' diet. However, further experimental studies regarding the use of lysozyme in commercial broilers, both in vitro and in vivo, targeting more communities of intestinal microbiome and explaining more details about its beneficial effects need to be conducted.

Cinnamon nanoemulsion mitigates acetamiprid-induced hepatic and renal toxicity in rats: biochemical, histopathological, immunohistochemical, and molecular docking analysis.

Acetamiprid (ACDP) is a widely used neonicotinoid insecticide that is popular for its efficacy in controlling fleas in domestic settings and for pets. Our study aims to offer a comprehensive examination of the toxicological impacts of ACDP and the prophylactic effects of cinnamon nanoemulsions (CMNEs) on the pathological, immunohistochemical, and hematological analyses induced by taking ACDP twice a week for 28 days. Forty healthy rats were divided into four groups (n = 10) at random; the first group served as control rats; the second received CMNEs (2 mg/Kg body weight); the third group received acetamiprid (ACDP group; 21.7 mg/Kg body weight), and the fourth group was given both ACDP and CMNEs by oral gavage. Following the study period, tissue and blood samples were extracted and prepared for analysis. According to a GC-MS analysis, CMNEs had several bioactive ingredients that protected the liver from oxidative stress by upregulating antioxidant and anti-inflammatory agents. Our findings demonstrated that whereas ACDP treatment considerably boosted white blood cells (WBCs) and lymphocytes, it significantly lowered body weight gain (BWG), red blood cells (RBCs), hemoglobin (Hb), hematocrit (HCT), and platelets (PLT). ACDP notably reduced antioxidant enzyme activities: superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) and elevated hydrogen peroxide and malondialdehyde levels compared with other groups. ACDP remarkably raised alanine aminotransferase (ALT), aspartate amino transaminase (AST), and alkaline phosphatase (ALP) levels.Moreover, the histopathological and immunohistochemistry assays discovered a severe toxic effect on the liver and kidney following ACDP delivery. Furthermore, cyclooxygenase 2 (COX-2) + immunoexpression was enhanced after treatment with CMNEs. All of the parameters above were returned to nearly normal levels by the coadministration of CMNEs. The molecular docking of cinnamaldehyde with COX-2 also confirmed the protective potential of CMNEs against ACDP toxicity. Our findings highlighted that the coadministration of CMNEs along with ACDP diminished its toxicity by cutting down oxidative stress and enhancing antioxidant capacity, demonstrating the effectiveness of CMNEs in lessening ACDP toxicity.

Factor XI: structure, function and therapeutic inhibition.

Arterial and venous thromboembolism is a major medical concern that requires therapeutic anticoagulation in various medical fields to prevent its drastic consequences. Despite significant advances in anticoagulant therapy, thrombosis remains a leading cause of morbidity and mortality worldwide. Traditional anticoagulants like heparin and vitamin K antagonists (VKAs) have shown efficacy in preventing and treating thrombosis but come with an inherent risk of bleeding due to their non-specific inhibition of multiple coagulation factors. Subsequent direct oral anticoagulants (DOACs), targeting specific factors such as Xa or thrombin, demonstrated improved safety profiles compared to VKAs, yet bleeding remains a concern. Accordingly, research is focused on developing anticoagulants with improved safety profiles. A safer class of anticoagulants would have broad appeal. The intrinsic pathway of coagulation, involving factor XI (FXI), has attracted attention as a potential target for safer anticoagulants. Preclinical studies and epidemiological data indicate that FXI deficiency or inhibition protects against thrombosis with minimal bleeding. Current research involves evaluating various FXI-directed strategies, and phase 2 studies have shown promising results in orthopedic surgery, atrial fibrillation, end-stage renal disease (ESRD), myocardial infarction, and ischemic stroke. Several agents, such as antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers, have been developed to inhibit FXI at different stages, offering potentially safer alternatives to traditional anticoagulants. However, the optimal balance between preventing thrombosis and the risk of bleeding associated with FXI inhibitors requires validation through extensive phase 3 clinical trials using definite clinical endpoints. Several of such trials are currently underway or planned to define the role of FXI inhibitors in clinical practice and determine the most suitable FXI inhibitor for each specific indication. The current review highlights the rationale behind developing FXI inhibitors, presenting the most advanced agents in development, summarizing completed clinical trials, and discussing ongoing research efforts.