Ferulic acid ameliorates concanavalin A-induced hepatic fibrosis in mice via suppressing TGF-ß/smad signaling.

BACKGROUND AND AIM: Hepatic fibrosis, one of the main reasons for death globally, is a serious complication of chronic liver disorders. However, the available therapies for liver fibrosis are limited, ineffective, and often associated with adverse events. Hence, seeking for a novel, effective therapy is warranted. Our objective was to investigate the potential efficacy of ferulic acid (FA), a phenolic phytochemical, at different doses in hindering the progress of concanavalin A (Con A)-induced hepatic fibrosis and explore the involved mechanisms. METHODS: Thirty-six mice were assorted into 6 groups (n = 6): Group I (control); group II received FA (20 mg/kg/day orally for 4 weeks); group III received Con A (6 mg/kg/week/i.v.) for 4 weeks; groups IV, V, and VI received Con A and were offered FA at 5, 10, and 20 mg/kg/day, respectively. RESULTS: The data showed the palliative effect of FA against Con A-induced fibrosis in a dose-dependent manner. This was obvious from the recovery of liver markers and hepatic architecture with the regression of fibrosis in FA-treated mice. FA abolished Con A-mediated oxidative insults and promoted the antioxidant enzyme activities, which run through the Nrf2/HO-1 signaling. Additionally, FA suppressed Con A-induced increase in NF-kB and IL-ß levels, and TNF-α immune-expression. The anti-fibrotic effect of FA was evident from the drop in TGF-ß, smad3 levels, α-SMA expression, and hydroxyproline content. CONCLUSION: FA attenuated Con A-induced liver fibrosis through stimulating Nrf2 signaling, suppressing NF-kB, and inhibiting the TGF-ß/smad3 signaling pathway. Thus FA can be considered as a promising therapy for combating liver fibrosis.

Exploring the interactive impacts of citronellol, thymol, and trans-cinnamaldehyde in broilers: moving toward an improved performance, immunity, gastrointestinal integrity, and Clostridium perfringens resistance.

AIMS: This study aimed to explore the effectiveness of dietary citronellol, thymol, and trans-cinnamaldehyde (CTC) essential oils blend on broilers' growth performance, immunity, intestinal microbial count, gut integrity, and resistance against Clostridium perfringens utilizing the necrotic enteritis (NE) challenge model. METHODS AND RESULTS: A total of 200 Ross 308 male broiler chicks received either a control diet or diet supplemented with three graded levels of CTC blend, including 300, 600, and 900 mg of CTC blend/kg diet and experimentally infected with C. perfringens strain at 23 days of age. Herein, dietary CTC blend fortifications significantly improved the broilers' growth performance, which was supported by upregulating the expression levels of MUC-2, occludin, and JAM-2 genes. Moreover, dietary CTC blend inclusion significantly enhanced the levels of blood phagocytic percentage and serum IgA, IgG, and MPO, and reduced the values of serum CRP, and NO at 5 days pre-infection, 10-, and 15 days post-infection (dpi) with C. perfringens. At 15 dpi, CTC blend inclusion significantly reduced the intestinal digesta pH, coliforms and C. perfringens loads, and the expression levels of genes related to C. perfringens virulence (cpe, cnaA, and nanI), proinflammatory cytokines (IL-1ß and TNF-α), and chemokines (CCL20), in addition to increasing the count of beneficial total Lactobacillus and total aerobic bacteria, and the expression levels of genes related to anti-inflammatory cytokines (IL-10) and chemokines (AvBD6 and AvBD612). CONCLUSION: Our results point to the growth-provoking, immunostimulant, antibacterial, anti-inflammatory, and antivirulence characteristics of the CTC blend, which improves the broilers' resistance to C. perfringens and ameliorates the negative impacts of NE.

Innovative next-generation therapies in combating multi-drug-resistant and multi-virulent Escherichia coli isolates: insights from in vitro, in vivo, and molecular docking studies.

Despite notable advances in vaccine and antimicrobial therapies, treatment failure has been increasingly reported worldwide. Of note, multi-drug-resistant (MDR) Escherichia coli (E. coli) strains have a considerable share in the evolution of this crisis. So, current practice guidelines are directed towards complementary and alternative therapies. Therefore, we evaluated the antibacterial and antivirulence activities of curcumin, thymol, and eugenol essential oils (EOs) as well as EOs-EOs and EOs-antibiotics interactions on MDR and multi-virulent E. coli isolates. Unfortunately, MDR E. coli could be isolated with a prevalence rate of 95.6% (86/90). Additionally, the majority of our isolates harbored both fimH (95.6%) and ompA (91.1%) genes, and half of them (45/90) were multi-virulent. Interestingly, all the tested EOs, especially curcumin, exhibited inhibitory activities against all MDR and multi-virulent E. coli isolates. The addition of thymol enhanced the antibacterial activities of curcumin and eugenol. Moreover, the activities of piperacillin/tazobactam and imipenem were increased by adding any one of the tested EOs. Regarding the antivirulence activities of the tested EOs, the cell surfaces of treated E. coli isolates under transmission electron microscope (TEM) were uneven. The cells appeared damaged and lost their appendages. Furthermore, EOs strongly reduced the transcription of ompA and fimH genes. The antibacterial and antivirulence activities of the used EOs were confirmed by in silico and mice protection assays. Hereby, we introduced the promising uses of curcumin, thymol, and eugenol oils as complementary and alternative therapies for combating MDR and multi-virulent E. coli isolates. KEY POINTS: • Our promising results confirmed that we were right for renewed interest of EOs. • The EOs, especially curcumin, can be used to prevent treatment failure. • We supposed a new pharmaceutical formulation of antibiotic powders dissolved in EOs.

Effects of verapamil on the pharmacokinetics of ivermectin in rabbits.

This study was aimed to investigate the influence of verapamil-mediated inhibition of P-glycoprotein (P-gp) on the pharmacokinetics of ivermectin (IVM) given orally and subcutaneously (SC) to rabbits. Twenty New Zealand rabbits were allotted to 4 groups (n = 5) and received IVM either orally or SC (0.4 mg/kg) alone or co-administered with verapamil (2 mg/kg SC, 3 times at a 12-hr interval). Plasma, fecal, and urine samples were collected over 30 days after medication to assess IVM concentrations in these samples. No significant differences were observed in the pharmacokinetic parameters of IVM between oral and SC administrations. The area under the plasma concentration-time curve was higher (p < .05) after IVM (oral)/verapamil treatment, compared with oral IVM alone. Moreover, the time to the Cmax of IVM was shorter (p < .05), whereas the elimination half-life and the mean residence time were longer (p < .05) in the presence of verapamil. The IVM/verapamil combination administered orally or SC reduced fecal IVM concentrations, compared with IVM alone. In conclusion, the significant changes by verapamil on the pharmacokinetics of IVM, likely due to the inhibition of a P-gp-mediated intestinal secretion, may change IVM's antinematodal activity.

Pharmacokinetics, tissue residues, and ex vivo pharmacodynamics of tylosin against Mycoplasma anatis in ducks.

The pharmacokinetics of tylosin were investigated in 3 groups of ducks (n = 6). They received a single dose of tylosin (50 mg/kg) by intravenous (IV), intramuscular (IM), and oral administrations, respectively. Plasma samples were collected at various time points to 24 hr post-administration to evaluate tylosin concentration over time. Additionally, tylosin residues in tissues and its withdrawal time were assessed using 30 ducks which received tylosin orally (50 mg/kg) once daily for 5 consecutive days. After IV administration, the volume of distribution, elimination half-life, area under the plasma concentration-time curve, and the total body clearance were 7.07 ± 1.98 L/kg, 2.04 hr, 19.47 µg hr/ml, and 2.82 L hr-1  kg-1 , respectively. After IM and oral administrations, the maximum plasma concentrations were 3.70 and 2.75 µg/ml achieved at 1 and 2 hr, and the bioavailability was 93.95% and 75.77%, respectively. The calculated withdrawal periods of tylosin were 13, 8, and 5 days for kidney, liver, and muscle, respectively. For the pharmacodynamic profile, the minimum inhibitory concentration for tylosin against M. anatis strain 1,340 was 1 µg/ml. The calculated optimal oral dose of tylosin against M. anatis in ducks based on the ex vivo pharmacokinetic/pharmacodynamic modeling was 61 mg kg-1  day-1 .

α-Bisabolol and royal jelly differentially mitigate thioacetamide-induced hepatic fibrosis in rats associated with the inhibition of TGF-ß1/FAK/α-SMA signaling.

Hepatic fibrosis is a global health burden that accounts for high mortality. No definitive therapy to suppress the fibrosis so far. Thus, looking for an effective remedy to address the unmet medical need is crucial. We aimed to scrutinize the efficacy of royal jelly (RJ) and/or α-Bisabolol (BISA) in the regression of fibrosis provoked by thioacetamide (TAA), focusing on their action on redox status, NF-κBp65, apoptosis, and TGF-ß1/FAK/α-SMA pathway. TAA was injected intraperitoneally twice weekly to trigger hepatic fibrosis. Rats were gavaged with RJ (100 mg/kg) and/or BISA (50 mg/kg) daily for 8 weeks. The findings elucidated that RJ and/or BISA alleviated TAA-provoked fibrosis mirrored by the improvement of hepatotoxicity serum indices, abolishing oxidative stress, and repair the morphological alterations. Additionally, RJ and BISA suppressed the hepatic inflammation induced by TAA through downregulating NF-κBp65 expression, reducing TNF-α and IL-6 concentrations, and elevating IL-10 level. Their anti-fibrotic effect was emphasized from the decline in FAK, Smad3, COL-III, hydroxyproline levels, and TGF-ß1, α-SMA immunoexpression. BISA displayed better ameliorative action than RJ. Conclusively, RJ and/or BISA possess a hepatoprotective activity against TAA-mediated fibrosis by enhancing antioxidant defense, inhibiting NF-κBp65, and modulating TGF-ß1/FAK/α-SMA signaling. RJ and BISA might be prospective candidates to combat hepatic fibrosis.

Pulmonary damage induction upon Acrylic amide exposure via activating miRNA-223-3p and miRNA-325-3p inflammasome/pyroptosis and fibrosis signaling pathway: New mechanistic approaches of A green-synthesized extract.

Exposure to acrylic amide (AD) has garnered worldwide attention due to its potential adverse health effects, prompting calls from the World Health Organization for intensified research into associated risks. Despite this, the relationship between oral acrylic amide (acrylamide) (AD) exposure and pulmonary dysfunction remains poorly understood. Our study aimed to investigate the correlation between internal oral exposure to AD and the decline in lung function, while exploring potential mediating factors such as tissue inflammation, oxidative stress, pyroptosis, and apoptosis. Additionally, we aimed to evaluate the potential protective effect of zinc oxide nanoparticles green-synthesized moringa extract (ZNO-MONPs) (10 mg/kg b.wt) against ACR toxicity and conducted comprehensive miRNA expression profiling to uncover novel targets and mechanisms of AD toxicity (miRNA 223-3 P and miRNA 325-3 P). Furthermore, we employed computational techniques to predict the interactions between acrylic amide and/or MO-extract components and tissue proteins. Using a rat model, we exposed animals to oral acrylamide (20 mg/kg b.wt for 2 months). Our findings revealed that AD significantly downregulated the expression of miRNA 223-3 P and miRNA 325-3 P, targeting NLRP-3 & GSDMD, respectively, indicating the induction of pyroptosis in pulmonary tissue via an inflammasome activating pathway. Moreover, AD exposure resulted in lipid peroxidative damage and reduced levels of GPX, CAT, GSH, and GSSG. Notably, AD exposure upregulated apoptotic, pyroptotic, and inflammatory genes, accompanied by histopathological damage in lung tissue. Immunohistochemical and immunofluorescence techniques detected elevated levels of indicative harmful proteins including vimentin and 4HNE. Conversely, concurrent administration of ZNO-MONPs with AD significantly elevated the expression of miRNA 223-3 P and miRNA 325-3 P, protecting against oxidative stress, apoptosis, pyroptosis, inflammation, and fibrosis in rat lungs. In conclusion, our study highlights the efficacy of ZNO-MONPs NPs in protecting pulmonary tissue against the detrimental impacts of foodborne toxin AD.

Should Airway Interstitial Fluid Be Used to Evaluate the Pharmacokinetics of Macrolide Antibiotics for Dose Regimen Determination in Respiratory Infection?

Macrolide antibiotics are important drugs to combat infections. The pharmacokinetics (PK) of these drugs are essential for the determination of their optimal dose regimens, which affect antimicrobial pharmacodynamics and treatment success. For most drugs, the measurement of their concentrations in plasma/serum is the surrogate for drug concentrations in target tissues for therapy. However, for macrolides, simple reliance on total or free drug concentrations in serum/plasma might be misleading. The macrolide antibiotic concentrations of serum/plasma, interstitial fluid (ISF), and target tissue itself usually yield very different PK results. In fact, the PK of a macrolide antibiotic based on serum/plasma concentrations alone is not an ideal predictor for the in vivo efficacy against respiratory pathogens. Instead, the PK based on drug concentrations at the site of infection or ISF provide much more clinically relevant information than serum/plasma concentrations. This review aims to summarize and compare/discuss the use of drug concentrations of serum/plasma, airway ISF, and tissues for computing the PK of macrolides. A better understanding of the PK of macrolide antibiotics based on airway ISF concentrations will help optimize the antibacterial dose regimen as well as minimizing toxicity and the emergence of drug resistance in clinical practice.

Novel Insights about Synergistic Effect of Zamzam Water with SGL2 Inhibitors on Wound Healing in STZ-Induced Diabetic Rats: The Role of anti-Inflammatory and Proangiogenic Effects.

Background: Hyperglycemia usually impairs wound healing by dysregulating the inflammatory response and angiogenesis. This study aimed to examine the synergistic effect of dapagliflozin and Zamzam water (ZW) on the healing of diabetic wounds and to explore their anti-inflammatory and proangiogenic effects.Materials and methods: A full-thickness excisional wound was made on the backs of all groups after two weeks of diabetes induction. Forty rats were divided into five groups, with eight rats per group; Group 1: Control non-diabetic rats; Group II: Untreated diabetic rats; Group III: Diabetic rats drinking ZW; Group IV: Diabetic rats receiving an oral dose of 1 mg/kg dapagliflozin; and Group V: Received both dapagliflozin and ZW. The healing of diabetic wounds was assessed by measuring wound closure, oxidative stress markers, immunohistochemical staining of NF-ßB, VEGF, CD34, CD45, Ki-67, and eNOS, gene expression of MMP-9, TGF-ß1, EGF-b1, FGF, and Col1A1, protein levels of TNFα, IL-1ß, IL6, Ang II, and HIF-1α by ELISA assay, and histological examination with H & E and Masson's trichrome. Combined treatment with dapagliflozin and ZW significantly (p < 0.05) enhanced the wound closure and antioxidant enzyme level, with apparent histological improvement, and shortened the inflammatory stage of the diabetic wound by decreasing the level of inflammatory markers NF-κB, TNF-α, IL-1ß, IL6, and CD45. Therefore, it improved angiogenesis markers VEGF, CD34, eNOS, EGF-ß1, FGF, Ang II, and HIF-1α, increasing Ki-67 cellular proliferation. Moreover, it enhanced the remodeling stage by increasing MMP-2, TGF-ß1, and Col1A1 levels compared to diabetic rats.

Palliative Role of Zamzam Water against Cyclosporine-Induced Nephrotoxicity through Modulating Autophagy and Apoptosis Crosstalk.

Cyclosporine (CsA) is considered one of the main components of treatment protocols for organ transplantation owing to its immunosuppressive effect. However, its use is very restricted due to its nephrotoxic effect. ZW is an alkaline fluid rich in various trace elements and has a great ability to stimulate antioxidant processes. This study aimed to investigate the possible mitigating effect of ZW on CsA-induced nephrotoxicity and its underlying mechanisms. Forty rats were allocated into four groups (n = 10): a control group, ZW group, cyclosporine A group (injected subcutaneously (SC) with CsA (20 mg/kg/day)), and cyclosporine A+ Zamzam water group (administered CsA (SC) and ZW as their only drinking water (100 mL/cage/day) for 21 days). Exposure to CsA significantly (p < 0.001) increased the serum creatinine level, lipid peroxidation marker level (malondialdehyde; MDA), and the expression of apoptotic markers procaspase-8, caspase-8, caspase- 9, calpain, cytochrome c, caspas-3, P62, and mTOR in renal tissues. Meanwhile, it markedly decreased (p< 0.001) the autophagic markers (AMPK, ULK-I, ATag5, LC3, and Beclin-1), antiapoptotic Bcl-2, and antioxidant enzymes. Moreover, the administration of CsA caused histological alterations in renal tissues. ZW significantly (p < 0.001) reversed all the changes caused by CsA and conclusively achieved a positive outcome in restraining CsA-induced nephrotoxicity, as indicated by the restoration of the histological architecture, improvement of renal function, inhibition of apoptosis, and enhancement of autophagy via the AMPK/mTOR pathway.

Impact of resveratrol-loaded liposomal nanocarriers on heat-stressed broiler chickens: Effects on performance, sirtuin expression, oxidative stress regulators, and muscle building factors.

Climate change is considered to be the primary cause of heat stress (HS) in broiler chickens. Owing to the unique properties of extracted polyphenols, resveratrol-loaded liposomal nanoparticles (Resv-Lipo NPs) were first explored to mitigate the harmful effects of HS. The dietary role of Resv-Lipo NPs in heat-stressed birds was investigated based on their growth performance, antioxidative potential, and the expression of heat shock proteins, sirtuins, antioxidant, immune, and muscle-building related genes. A total of 250 1-day-old Ross 308 broiler chickens were divided into five experimental groups (5 replicates/group, 10 birds/replicate) for 42 days as follows: the control group was fed a basal diet and reared in thermoneutral conditions, and the other four HS groups were fed a basal diet supplemented with Resv-Lipo NPsI, II, and III at the levels of 0, 50, 100, and 150 mg/kg diet, respectively. The results indicated that supplementation with Resv-Lipo NP improved the growth rate of the HS group. The Resv-Lipo NP group showed the most significant improvement in body weight gain (p < 0.05) and FCR. Additionally, post-HS exposure, the groups that received Resv-Lipo NPs showed restored functions of the kidney and the liver as well as improvements in the lipid profile. The restoration occurred especially at higher levels in the Resv-Lipo NP group compared to the HS group. The elevated corticosterone and T3 and T4 hormone levels in the HS group returned to the normal range in the Resv-Lipo NPsIII group. Additionally, the HS groups supplemented with Resv-Lipo NPs showed an improvement in serum and muscle antioxidant biomarkers. The upregulation of the muscle and intestinal antioxidant-related genes (SOD, CAT, GSH-PX, NR-f2, and HO-1) and the muscle-building genes (myostatin, MyoD, and mTOR) was observed with increasing the level of Resv-Lipo NPs. Heat stress upregulated heat shock proteins (HSP) 70 and 90 gene expression, which was restored to normal levels in HS+Resv-Lipo NPsIII. Moreover, the expression of sirtuin 1, 3, and 7 (SIRT1, SIRT3, and SIRT7) genes was increased (p < 0.05) in the liver of the HS groups that received Resv-Lipo NPs in a dose-dependent manner. Notably, the upregulation of proinflammatory cytokines in the HS group was restored in the HS groups that received Resv-Lipo NPs. Supplementation with Resv-Lipo NPs can mitigate the harmful impact of HS and consequently improve the performance of broiler chickens.

Phytochemical analysis of Origanum majorana L. extract and investigation of its antioxidant, anti-inflammatory and immunomodulatory effects against experimentally induced colitis downregulating Th17 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Origanum majorana L. is a member of the Lamiaceae family and is commonly used in Egyptian cuisine as a seasoning and flavor enhancer. It is also recognized as a well-known traditional medicine in Egypt and is widely used for treating abdominal colic due to its antispasmodic properties. However, the protective effects of Origanum majorana L. against ulcerative colitis and its underlying mechanisms remain unclear. AIM OF THE STUDY: This study aimed to identify the biologically active components present in methanol extracts of Origanum majorana L. using gas chromatography/mass spectrometry (GC/MS). Additionally, it aimed to investigate the therapeutic effects of these extracts on acetic acid-induced ulcerative colitis and elucidate the potential mechanisms involved. MATERIALS AND METHODS: We conducted a GC-MS analysis of the methanolic extract obtained from Origanum majorana L. Thirty-two male rats were included in the study and divided into four experimental groups, with eight rats in each group: sham, UC, UC + O. majorana, and UC sulfasalazine. After euthanizing the rats, colon tissue samples were collected for gross and microscopic examinations, assessment of oxidative stress, and molecular evaluation. GC-MS analysis identified 15 components in the extracts. Pretreatment with O. majorana L. extract and sulfasalazine significantly improved the disease activity index (DAI) and resulted in notable improvements in macroscopic and microscopic colon findings. Additionally, both treatments demonstrated preventive effects against colonic oxidative damage by reducing the levels of malondialdehyde (MDA) and increasing the levels of the antioxidant systems superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), which operate through the Nrf2/HO-1 signaling pathway. Moreover, these treatments downregulated the colonic inflammatory cascade by inhibiting NFκB, TNFα, IL-1ß, IL6, IL23, IL17, COX-2, and iNOS, subsequently leading to downregulation of the JAK2/STAT3 signaling pathway and a decrease in the Th17 cell response. Furthermore, a reduction in the number of apoptotic epithelial cells that expressed caspase-3 was observed. CONCLUSION: pretreatment with O. majorana L. extract significantly ameliorated acetic acid-induced ulcerative colitis. This effect could be attributed to the protective, antioxidant, anti-inflammatory, and anti-apoptotic properties of the extract.

Anxiolytic and antidepressant like effects of Zamzam water in STZ-induced diabetic rats, targeting oxidative stress, neuroinflammation, BDNF/ERK/CREP pathway with modulation of hypothalamo-pituitary-adrenal axis.

Introduction: Recent studies have reported a strong relationship between diabetes and anxiety- and depression-like behaviors; however, there is a lack of information on the underlying pathophysiology. Alkaline Zamzam water (ZW), which is rich in several trace elements, has neuroprotective properties. This study aimed to investigate the anxiolytic and antidepressant effects of ZW against diabetes-induced behavioral changes and shed light on the possible underlying mechanisms. Methods: Forty-eight rats were divided into four experimental groups (n = 12): group I (control group), group II (Zamzam water group), group III (diabetic group), and group IV (diabetic + Zamzam water group). Diabetes was induced by an intraperitoneal injection of 60 mg/kg streptozotocin (STZ). At the end of the experiment, the forced swimming test (FST) was used to assess depression-like effects. The elevated plus maze test (EPMT) and open field test (OFT) were performed to evaluate anxiety-like behavior. Blood levels of the hypothalamic-pituitary-adrenal (HPA) axis were measured, and prefrontal cortex and hippocampal tissue samples were removed for histological, immunohistochemical, ELISA, and Q-PCR analyses. Results: ZW significantly decreased the immobility time in the FST, indicating an antidepressant effect (p < 0.001). Additionally, ZW significantly improved the OFT and open field entry (OFE) percentages in the EPMT, increasing center crossing and decreasing grooming and fecal boli in the OFT. This indicated an anxiolytic-like effect in diabetic rats with histological improvement. Interestingly, ZW significantly increased prefrontal cortical and hippocampal levels of antioxidant enzymes and the Nrf2/HO-1 pathway. It also modulated the HPA axis by increasing cortisol and corticotropin-releasing hormone (CRH) levels, with a decrease in ACTH and an increase in monoamine neurotransmitters. Furthermore, diabetic rats that received ZW showed a decrease in the inflammatory markers TNF-α and GFAP by immunohistochemistry and in the mRNA levels of NFκB, IL-1ß, and IL6. In addition, ZW downregulated the expression of the BDNF/ERK2/CREP pathway. Conclusion: Our results suggested a neuroprotective effect of ZW against diabetes-induced anxiety- and depression-like behaviors and explored the underlying mechanisms. These findings suggest a promising therapeutic strategy for patients with diabetes who experience anxiety and depression.

Tackling strong biofilm and multi-virulent vancomycin-resistant Staphylococcus aureus via natural alkaloid-based porous nanoparticles: perspective towards near future eradication.

Introduction: As a growing direction, nano-based therapy has become a successful paradigm used to address the phytogenic delivery-related problems in overcoming multivirulent vancomycin-resistant Staphylococcus aureus (VRSA) infection. Methods: Hence, our aim was to develop and assess a novel nanocarrier system (mesoporous silica nanoparticles, MPS-NPs) for free berberine (Free-BR) as an antimicrobial alkaloid against strong biofilm-producing and multi-virulent VRSA strains using in vitro and in vivo mouse model. Results and discussion: Our outcomes demonstrated vancomycin resistance in 13.7% of Staphylococcus aureus (S. aureus) strains categorized as VRSA. Notably, strong biofilm formation was observed in 69.2% of VRSA strains that were all positive for icaA gene. All strong biofilm-producing VRSA strains harbored a minimum of two virulence genes comprising clfA and icaA with 44.4% of them possessing all five virulence genes (icaA, tst, clfA, hla, and pvl), and 88.9% being multi-virulent. The study findings affirmed excellent in vitro antimicrobial and antibiofilm properties of BR-loaded MPS-NPs. Real-time quantitative reverse transcription PCR (qRT-PCR) assay displayed the downregulating role of BR-loaded MPS-NPs on strong biofilm-producing and multi-virulent VRSA strains virulence and agr genes in both in vitro and in vivo mice models. Additionally, BR-loaded MPS-NPs supplementation has a promising role in attenuating the upregulated expression of pro-inflammatory cytokines' genes in VRSA-infected mice with attenuation in pro-apoptotic genes expression resulting in reduced VRSA-induced apoptosis. In essence, the current study recommends the future scope of using BR-loaded MPS-NPs as auspicious alternatives for antimicrobials with tremendous antimicrobial, antibiofilm, anti-quorum sensing (QS), and anti-virulence effectiveness against problematic strong biofilm-producing and multi-virulent VRSA-associated infections.

Antagonism of cadmium-induced liver injury in ducks by α-bisabolol.

Cadmium (Cd) is an ecological pollutant which causes hazardous effects in animals and humans. The aim of this study was to investigate the role of α-bisabolol (BISA) in antagonizing the Cd-induced hepatotoxicity in ducks. Two-week old ducks were allocated into 8 groups (10 ducks/group): Group I received basal diet and was gavaged with sunflower oil (BISA vehicle, 1.1 mL/kg/day); group II was administered BISA orally (50 mg/kg/day; diluted with sunflower oil); groups III, IV, and V were fed the basal diet mixed with CdCl2 at 37.5, 75, and 150 mg/kg diet, respectively, and were gavaged with sunflower oil; group VI, VII, and VIII were given basal diet containing CdCl2 at the aforementioned consecutive doses plus BISA. All treatments were provided daily for 4 weeks. Exposure to CdCl2 induced mortality in ducks, increased hepatic Cd content and serum levels of hepatopathic biomarkers, and caused oxidative stress and morphological alterations in ducks' liver. Furthermore, exposure to Cd caused upregulation of the mRNA of proinflammatory cytokine tumor necrosis factor-α and apoptotic gene Bax, and that of cyclooxygenase-2 protein in the liver. All effects of Cd were dose-dependent. BISA antagonized all of the aforementioned CdCl2-induced changes. These findings suggested that BISA exert the hepatoprotective effect against Cd toxicity through reducing the hepatic content of Cd as well as antagonizing oxidative insults, inflammation, and apoptosis. Thus, BISA has a great potential to be used as an antidote in the control of Cd poisoning.

Anti-Toxoplasma Activities of Some Egyptian Plant Extracts: An In Vitro Study.

PURPOSE: Toxoplasmosis is a globally widespread parasitic disease which causes major health problems in human and animals. This research was conducted to assess the effect of some Egyptian herbal extracts against Toxoplasma gondii (T. gondii) tachyzoites in vitro. METHODS: The methanol extracts of Withania somnifera, Cyper rotundus, Acacia nilotica, Chrysanthemum cinerariae folium, Anethum graveolens, Raphanus sativus, Ceratonia siliqua, Elettaria cardamomum and Cuminum cyminum were tested against T. gondii tachyzoites. RESULTS: Among the tested plants, the extracts from Raphanus sativus, Cuminum cyminum, and Ceratonia siliqua exhibited high anti-Toxoplasma activities at 50 µg/ml, relative to sulfadiazine. They showed low IC50 values on T. gondii (7.92, 9.47 and 13.52 µg/ml, respectively) and high selectivity index values (100.79, 59.19, and 29.05, respectively). Scanning electron microscopy (SEM) findings indicated evident morphological changes in tachyzoites treated with these three herbal extracts. CONCLUSION: Raphanus sativus, Ceratonia siliqua, and Cuminum cyminum methanol extracts could be promising sources of new medicament for toxoplasmosis.

Zamzam Water Ameliorates Gentamicin-Induced Testicular Toxicity in a Rat Model via Targeting Sperm Parameters, Testicular Tissue Oxidative Insult, Inflammation, Apoptosis, and Pituitary-Gonadal Axis.

Gentamicin is considered one of the most typical causes of testicular damage. Oxidative stress is a significant contributor to testicular tissue damage. Zamzam water (alkaline in nature) has an antioxidant effect. The purpose of this study was to assess the potential palliative effect of Zamzam water against gentamicin-induced testicular damage. Thirty Rats were separated into three groups, each with ten rats, as follows: The Control received only normal saline. The gentamicin group received 100 mg/kg/day of gentamicin intraperitoneally for six days from day 15 to the end of the experiment. The gentamicin +Zamzam Water group received a dose of gentamicin 100 mg/kg/day intraperitoneally with Zamzam water as their sole source of drinking from day one to day 21. Hormonal assay in serum, histological, immunohistochemical, and ultrastructural examination of testicular tissue with a molecular study were obtained. Pretreatment with Zamzam water significantly p < 0.001 increased serum levels of testosterone, FSH, and LH, as well as the percentage of sperm motility and progressive motility. It also upregulated SOD, CAT, GPx enzymatic activity, gene expression of Nrf2/HO-1, and immunoexpression of PCNA. While the percentage of dead sperm and abnormal sperm, immunoexpression of NFκB, Caspase 3, inflammatory cytokines TNFα, IL-1ß, IL-6, and MDA levels significantly (p < 0.001) declined with histological improvement. It was concluded that Zamzam water as alkaline water possesses antioxidant, anti-inflammatory, and antiapoptotic effects against gentamicin-induced testicular toxicity in vivo.

Multi-Strain-Probiotic-Loaded Nanoparticles Reduced Colon Inflammation and Orchestrated the Expressions of Tight Junction, NLRP3 Inflammasome and Caspase-1 Genes in DSS-Induced Colitis Model.

Gut modulation by multi-strain probiotics (MSPs) is considered an effective strategy for treating inflammatory bowel disease (IBD). The combination of nanomaterial-based MSPs can improve their viability and resistance and can allow their targeted release in the gastrointestinal tract to be achieved. Thus, our aim is to investigate the prospective role of MSP integration into nanomaterials (MSPNPs) and the underlying molecular mechanisms supporting their application as an alternative therapy for IBD using a colitis rat model. To induce the colitis model, rats received 5% DSS, and the efficacy of disease progression after oral administration of MSPNPs was assessed by evaluating the severity of clinical signs, inflammatory response, expressions of tight-junction-related genes and NLRP3 inflammasome and caspase-1 genes, microbial composition and histopathological examination of colonic tissues. The oral administration of MSPNPs successfully alleviated the colonic damage induced by DSS as proved by the reduced severity of clinical signs and fecal calprotectin levels. Compared with the untreated DSS-induced control group, the high activities of colonic NO and MPO and serum CRP levels were prominently reduced in rats treated with MSPNPs. Of note, colonic inflammation in the group treated with MSPNPs was ameliorated by downstreaming NLRP3 inflammasome, caspase-1, IL-18 and IL-1ß expressions. After colitis onset, treatment with MSPNPs was more effective than that with free MSPs in restoring the expressions of tight-junction-related genes (upregulation of occludin, ZO-1, JAM, MUC and FABP-2) and beneficial gut microbiota. Interestingly, treatment with MSPNPs accelerated the healing of intestinal epithelium as detected in histopathological findings. In conclusion, the incorporation of MPSs into nanomaterials is recommended as a perspective strategy to overcome the challenges they face and augment their therapeutic role for treating of colitis.

Activation of SIRT-1 Pathway by Nanoceria Sheds Light on Its Ameliorative Effect on Doxorubicin-Induced Cognitive Impairment (Chemobrain): Restraining Its Neuroinflammation, Synaptic Dysplasticity and Apoptosis.

Chemo fog is one of the most serious health concerns encountered by cancer survivors receiving doxorubicin (DOX)-based chemotherapy. Oxidative stress, neuroinflammation, apoptosis and impairment of synaptic plasticity are regarded as the key factors implicated in DOX-induced cognitive impairment. This research aimed to assess the possible neuroprotective effect of cerium oxide nanoparticles (CeNPs) against DOX-induced neurotoxicity. Forty-eight rats were divided into four groups (12 rats/group): control group, CeNPs group (received oral CeNPs solution (35 mg/kg) daily for 4 weeks), and DOX group (were administered DOX intraperitoneally (2 mg/kg, once/week for 4 weeks)) and DOX+ CeNPs group. The findings revealed that CeNPs mitigated behavioral alterations in DOX-induced cognitive deficit. Additionally, CeNPs alleviated the histopathological abnormalities in hippocampus and ameliorated DOX-induced neuroinflammation by downregulating the expression of NF-κB, TNF-α, IL-1ß and IL6. In addition, CeNPs antagonized the apoptosis through reducing the protein expression of cytochrome c and caspase 3. In addition, it stimulated the antioxidant defense, as indicated by upregulating the expression of the Nrf2, HO-1 and PGC-1α genes. CeNPs improved synaptic plasticity via acting on the BDNF. These actions were related through the modification of SIRT-1 expression. Based on the aforementioned results, CeNPs antagonized the doxorubicin-induced neurodegeneration by its antioxidant, anti-inflammatory and antiapoptotic effects, alongside its SIRT-1 mediated mechanisms.

Novel In Vivo Assessment of Antimicrobial Efficacy of Ciprofloxacin Loaded Mesoporous Silica Nanoparticles against Salmonella typhimurium Infection.

Salmonella enterica serovar Typhimurium (S. typhimurium) is known for its intracellular survival, evading the robust inflammation and adaptive immune response of the host. The emergence of decreased ciprofloxacin (CIP) susceptibility (DCS) requires a prolonged antibiotic course with increased dosage, leading to threatening, adverse effects. Moreover, antibiotic-resistant bacteria can persist in biofilms, causing serious diseases. Hence, we validated the in vitro and in vivo efficacy of ciprofloxacin-loaded mesoporous silica nanoparticles (CIP-MSN) using a rat model of salmonella infection to compare the oral efficacy of 5 mg/kg body weight CIP-MSN and a traditional treatment regimen with 10 mg/kg CIP postinfection. Our results revealed that mesoporous silica particles can regulate the release rate of CIP with an MIC of 0.03125 mg/L against DCS S. typhimurium with a greater than 50% reduction of biofilm formation without significantly affecting the viable cells residing within the biofilm, and a sub-inhibitory concentration of CIP-MSN significantly reduced invA and FimA gene expressions. Furthermore, oral supplementation of CIP-MSN had an insignificant effect on all blood parameter values as well as on liver and kidney function parameters. MPO and NO activities that are key mediators of oxidative stress were abolished by CIP-MSN supplementation. Additionally, CIP-MSN supplementation has a promising role in attenuating the elevated secretion of pro-inflammatory cytokines and chemokines in serum from S. typhimurium-infected rats with a reduction in pro-apoptotic gene expression, resulting in reduced S. typhimurium-induced hepatic apoptosis. This counteracted the negative effects of the S. typhimurium challenge, as seen in a corrected histopathological picture of both the intestine and liver, along with increased bacterial clearance. We concluded that, compared with a normal ciprofloxacin treatment regime, MSN particles loaded with a half-dose of ciprofloxacin exhibited controlled release of the antibiotic, which can prolong the antibacterial effect.