Even one dose of tocilizumab could hinder bad prognosis of cytokines storm in COVID-19 patients.

Severe COVID-19 pneumonia is a principal cause of death due to cascade of hyper inflammatory condition that leading to lung damage. Therefore, an effective therapy to countercurrent the surge of uncontrolled inflammation is mandatory to propose. Anti-interlukin-6 receptor antagonist monoclonal therapy, tocilizumab (TCZ) showed potential results in COVID-19 patients. This study aimed to emphasize the factors associated with mortality in COVID-19 patients that treated with tocilizumab and may influence the level of serum IL-6. A retrospective cohort study included all patients with clinical parameters that pointed to presence of cytokines storm and treated with one or more doses of TCZ beside the regular protocol of COVID-19 pneumonia. The factors that influence the mortality in addition to the level of serum IL-6 were analyzed. A total of 377 patients were included, 69.5 % of them received only one dose of TCZ which started mainly at the third day of admission. The mortality rate was 29.44 %. Regardless the time of starting TCZ, just one dose was fair enough to prevent bad consequence; OR = 0.04, P = 0.001.However, in spite of protective action of TCZ, older age and female sex were significant risk factors for mortality, P = 0.001 and 0.01 respectively, as well heart disease. Moreover, increasing the level of neutrophil, AST and IL-6 were associated with bad prognosis. In the same line, treatment with ivermectin, chloroquine and remdesivir inversely affect the level of IL-6. Early treatments of COVID-19 pneumonia with at least one dose of tocilizumab minimized the fatality rate.

In Vivo and in Vitro Mitigation of Salmonella Typhimurium Isolates by Fortunella Japonica Fruit Extract.

The vast dissemination of resistance to different antibiotics among bacterial pathogens, especially foodborne pathogens, has drawn major research attention. Thus, many attempts have been made to reveal novel alternatives to the current antibiotics. Due to their variable pharmacologically active phytochemicals, plants represent a good solution for this issue. This study investigated the antibacterial potential of Kumquat or Fortunella japonica methanol extract (FJME) against Salmonella typhimurium clinical isolates. Gas chromatography coupled with mass spectrometry (GC/MS) characterized 39 compounds in FJME. Palmitic acid (15.386%) and cis-vaccenic acid (15.012%) are the major active constituents detected by GC/MS. Remarkably, FJME had minimum inhibitory concentrations from 128 to 512 µg/mL in vitro. In addition, a systemic infection model revealed the in vivo antibacterial action of FJME. The antibacterial therapeutic activity of FJME was noticed by improving the histological features of the liver and spleen. Moreover, there was a perceptible lessening (p < 0.05) of the levels of the oxidative stress markers (nitric oxide and malondialdehyde) using ELISA. In addition, the gene expression of the proinflammatory cytokine (interleukin 6) was downregulated. On the other hand, there was an upregulation of the anti-inflammatory cytokine (interleukin 10). Accordingly, future clinical investigations should be done to reveal the potential antibacterial action of FJME on other food pathogens.

New investigation of anti-inflammatory activity of Polycladia crinita and biosynthesized selenium nanoparticles: isolation and characterization.

BACKGROUND: Marine macroalgae have gained interest recently, mostly due to their bioactive components. Polycladia crinita is an example of marine macroalgae from the Phaeophyceae class, also known as brown algae. They are characterized by a variety of bioactive compounds with valuable medical applications. The prevalence of such naturally active marine resources has made macroalgae-mediated manufacturing of nanoparticles an appealing strategy. In the present study, we aimed to evaluate the antioxidant and anti-inflammatory features of an aqueous extract of Polycladia crinita and biosynthesized P. crinita selenium nanoparticles (PCSeNPs) via a carrageenan-induced rat paw edema model. The synthesized PCSeNPs were fully characterized by UV-visible spectroscopy, FTIR, XRD, and EDX analyses. RESULTS: FTIR analysis of Polycladia crinita extract showed several sharp absorption peaks at 3435.2, 1423.5, and 876.4 cm-1 which represent O-H, C=O and C=C groups. Moreover, the most frequent functional groups identified in P. crinita aqueous extract that are responsible for producing SeNPs are the -NH2-, -C=O-, and -SH- groups. The EDX spectrum analysis revealed that the high percentages of Se and O, 1.09 ± 0.13 and 36.62 ± 0.60%, respectively, confirmed the formation of SeNPs. The percentages of inhibition of the edema in pretreated groups with doses of 25 and 50 mg/kg, i.p., of PCSeNPs were 62.78% and 77.24%, respectively. Furthermore, the pretreated groups with 25, 50 mg/kg of P. crinita extract displayed a substantial decrease in the MDA levels (P < 0.00, 26.9%, and 51.68% decrease, respectively), indicating potent antioxidant effect. Additionally, the pretreated groups with PCSeNPs significantly suppressed the MDA levels (P < 0.00, 54.77%, and 65.08% decreases, respectively). The results of immune-histochemical staining revealed moderate COX-2 and Il-1ß expressions with scores 2 and 1 in rats pre-treated with 25 and 50 mg/kg of free extract, respectively. Additionally, the rats pre-treated with different doses of PCSeNPs demonstrated weak COX-2 and Il-1ß expressions with score 1 (25 mg/kg) and negative expression with score 0 (50 mg/kg). Both antioxidant and anti-inflammatory effects were dose-dependent. CONCLUSIONS: These distinguishing features imply that this unique alga is a promising anti-inflammatory agent. Further studies are required to investigate its main active ingredients and possible side effects.

Anti-inflammatory potential of Penicillium brefeldianum endophytic fungus supported with phytochemical profiling.

Various factors contribute to the development of the acute inflammation process, like the pro-inflammatory cytokines, certain enzymes as well as oxidative stress mediators. The anti-inflammatory potential of the endophytic fungus Penicillium brefeldianum was explored in carrageenan-induced inflammation in rats. After isolation of the fungus from Acalypha hispida leaves, it was identified by 18S rRNA gene sequencing. Then, its phytochemical profile was elucidated using LC-ESI-MS/MS technique. There was a remarkable decrease in the edema weight in the endophytic fungi-treated group (200 mg/kg). Also, this group had few inflammatory cells and thickened epidermis with underlying moderate collagenosis when stained with haematoxylin and eosin. Besides, immunostaining with monoclonal antibodies of cyclooxygenase-2 and tumor necrosis factor alpha showed a decrease in the positive immune cells in the endophytic fungi treated group (200 mg/kg) in relation to the positive control. Interestingly, the levels of the inflammatory as well as oxidative stress markers, including prostaglandin E2, nitric oxide, and malondialdehyde, which are hallmarks of the inflammatory process, considerably diminished (p < 0.05) in this group. qRT-PCR was utilised to elucidate the impact of the endophytic fungi treatment on the expression of interleukins (IL-1ß and IL-6) genes, which decreased in comparison with the positive control group. Consequently, we can deduce that P. brefeldianum endophytic fungus has a promising anti-inflammatory potential and should be extensively studied on a broader range in the near future.

New Insight on the Cytoprotective/Antioxidant Pathway Keap1/Nrf2/HO-1 Modulation by Ulva intestinalis Extract and Its Selenium Nanoparticles in Rats with Carrageenan-Induced Paw Edema.

Currently, there is growing interest in exploring natural bioactive compounds with anti-inflammatory potential to overcome the side effects associated with the well-known synthetic chemicals. Algae are a rich source of bioactive molecules with numerous applications in medicine. Herein, the anti-inflammatory effect of Ulva intestinalis alone or selenium nanoparticles loaded with U. intestinalis (UISeNPs), after being fully characterized analytically, was investigated by a carrageenan-induced inflammation model. The pretreated groups with free U. intestinalis extract (III and IV) and the rats pretreated with UISeNPs (groups V and VI) showed significant increases in the gene expression of Keap1, with fold increases of 1.9, 2.27, 2.4, and 3.32, respectively. Similarly, a remarkable increase in the Nrf2 gene expression, with 2.09-, 2.36-, 2.59-, and 3.7-fold increases, was shown in the same groups, respectively. Additionally, the groups III, IV, V, and VI revealed a significantly increased HO-1 gene expression with a fold increase of 1.48, 1.61, 1.87, and 2.84, respectively. Thus, both U. intestinalis extract and the UISeNPs boost the expression of the cytoprotective/antioxidant pathway Keap1/Nrf2/HO-1, with the UISeNPs having the upper hand over the free extract. In conclusion, U. intestinalis and UISeNPs have proven promising anti-inflammatory activity through mediating different underlying mechanisms.

Prospective Antiviral Effect of Ulva lactuca Aqueous Extract against COVID-19 Infection.

Marine algal extracts exhibit a potent inhibitory effect against several enveloped and non-enveloped viruses. The infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has several adverse effects, including an increased mortality rate. The anti-COVID-19 agents are still limited; this issue requires exploring novel, effective anti-SARS-CoV-2 therapeutic approaches. This study investigated the antiviral activity of an aqueous extract of Ulva lactuca, which was collected from the Gulf of Suez, Egypt. The aqueous extract of Ulva lactuca was characterized by high-performance liquid chromatography (HPLC), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and Energy Dispersive X-ray (EDX) analyses. According to the HPLC analysis, the extract comprises several sugars, mostly rhamnose (32.88%). The FTIR spectra showed numerous bands related to the functional groups. EDX analysis confirmed the presence of different elements, such as oxygen (O), carbon (C), sulfur (S), magnesium (Mg), potassium (K), calcium (Ca), and sodium (Na), with different concentrations. The aqueous extract of U. lactuca (0.0312 mg/mL) exhibited potent anti-SARS-CoV-2 activity via virucidal activity, inhibition of viral replication, and interference with viral adsorption (% inhibitions of 64%, 33.3%, and 31.1%, respectively). Consequently, ulvan could be a promising compound for preclinical study in the drug development process to combat SARS-CoV-2.

Insight into Fucoidan-Based PEGylated PLGA Nanoparticles Encapsulating Methyl Anthranilic Acid: In Vitro Evaluation and In Vivo Anti-Inflammatory Study.

A potential fucoidan-based PEGylated PLGA nanoparticles (NPs) offering a proper delivery of N-methyl anthranilic acid (MA, a model of hydrophobic anti-inflammatory drug) have been developed via the formation of fucoidan aqueous coating surrounding PEGylated PLGA NPs. The optimum formulation (FuP2) composed of fucoidan:m-PEG-PLGA (1:0.5 w/w) with particle size (365 ± 20.76 nm), zeta potential (-22.30 ± 2.56 mV), % entrapment efficiency (85.45 ± 7.41), drug loading (51.36 ± 4.75 µg/mg of NPs), % initial burst (47.91 ± 5.89), and % cumulative release (102.79 ± 6.89) has been further investigated for the anti-inflammatory in vivo study. This effect of FuP2 was assessed in rats' carrageenan-induced acute inflammation model. The average weight of the paw edema was significantly lowered (p ≤ 0.05) by treatment with FuP2. Moreover, cyclooxygenase-2 and tumor necrosis factor-alpha immunostaining were decreased in FuP2 treated group compared to the other groups. The levels of prostaglandin E2, nitric oxide, and malondialdehyde were significantly reduced (p ≤ 0.05) in the FuP2-treated group. A significant reduction (p ≤ 0.05) in the expression of interleukins (IL-1ß and IL-6) with an improvement of the histological findings of the paw tissues was observed in the FuP2-treated group. Thus, fucoidan-based PEGylated PLGA-MA NPs are a promising anti-inflammatory delivery system that can be applied for other similar drugs potentiating their pharmacological and pharmacokinetic properties.

Antidiarrheal and Antibacterial Activities of Monterey Cypress Phytochemicals: In Vivo and In Vitro Approach.

Monterey cypress (Cupressus macrocarpa) is a decorative plant; however, it possesses various pharmacological activities. Therefore, we explored the phytochemical profile of C. macrocarpa root methanol extract (CRME) for the first time. Moreover, we investigated its antidiarrheal (in vivo), antibacterial, and antibiofilm (in vitro) activities against Salmonella enterica clinical isolates. The LC-ESI-MS/MS analysis of CRME detected the presence of 39 compounds, besides isolation of 2,3,2″,3″-tetrahydro-4'-O-methyl amentoflavone, amentoflavone, and dihydrokaempferol-3-O-α-l-rhamnoside for the first time. Dihydrokaempferol-3-O-α-l-rhamnoside presented the highest antimicrobial activity and the range of values of MICs against S. enterica isolates was from 64 to 256 µg/mL. The antidiarrheal activity of CRME was investigated by induction of diarrhea using castor oil, and exhibited a significant reduction in diarrhea and defecation frequency at all doses, enteropooling (at 400 mg/kg), and gastrointestinal motility (at 200, 400 mg/kg) in mice. The antidiarrheal index of CRME increased in a dose-dependent manner. The effect of CRME on various membrane characters of S. enterica was studied after typing the isolates by ERIC-PCR. Its impact on efflux and its antibiofilm activity were inspected. The biofilm morphology was observed using light and scanning electron microscopes. The effect on efflux activity and biofilm formation was further elucidated using qRT-PCR. A significant increase in inner and outer membrane permeability and a significant decrease in integrity and depolarization (using flow cytometry) were detected with variable percentages. Furthermore, a significant reduction in efflux and biofilm formation was observed. Therefore, CRME could be a promising source for treatment of gastrointestinal tract diseases.

Elucidation of the Metabolite Profile of Yucca gigantea and Assessment of Its Cytotoxic, Antimicrobial, and Anti-Inflammatory Activities.

The acute inflammation process is explained by numerous hypotheses, including oxidative stress, enzyme stimulation, and the generation of pro-inflammatory cytokines. The anti-inflammatory activity of Yucca gigantea methanol extract (YGME) against carrageenan-induced acute inflammation and possible underlying mechanisms was investigated. The phytochemical profile, cytotoxic, and antimicrobial activities were also explored. LC-MS/MS was utilized to investigate the chemical composition of YGME, and 29 compounds were tentatively identified. In addition, the isolation of luteolin-7-O-ß-d-glucoside, apigenin-7-O-ß-d-glucoside, and kaempferol-3-O-α-l-rhamnoside was performed for the first time from the studied plant. Inflammation was induced by subcutaneous injection of 100 µL of 1% carrageenan sodium. Rats were treated orally with YGME 100, 200 mg/kg, celecoxib (50 mg/kg), and saline, respectively, one hour before carrageenan injection. The average volume of paws edema and weight were measured at several time intervals. Levels of NO, GSH, TNF-α, PGE-2, serum IL-1ß, IL-6 were measured. In additionally, COX-2 immunostaining and histopathological examination of paw tissue were performed. YGME displayed a potent anti-inflammatory influence by reducing paws edema, PGE-2, TNF-α, NO production, serum IL-6, IL-1ß, and COX-2 immunostaining. Furthermore, it replenished the diminished paw GSH contents and improved the histopathological findings. The best cytotoxic effect of YGME was against human melanoma cell line (A365) and osteosarcoma cell line (MG-63). Moreover, the antimicrobial potential of the extract was evaluated against bacterial and fungal isolates. It showed potent activity against Gram-negative, Gram-positive, and fungal Candida albicans isolates. The promoting multiple effects of YGME could be beneficial in the treatment of different ailments based on its anti-inflammatory, antimicrobial, and cytotoxic effects.

Ehrlich ascites carcinoma as model for studying the cardiac protective effects of curcumin nanoparticles against cardiac damage in female mice.

While clinical innovation has improved, cancer or malignant growth stays a genuine medical issue and has been perceived as a significant factor in mortality and morbidity. Current work aimed to define the cardiac defensive effects of curcumin nanoparticles (Cur Nps) against EAC induced cardiac toxicity, injury, and alterations in apoptosis, proliferation, and cytokines immunoreactivity. Forty female mice were aimlessly and equally divided into four groups [Gp1, Control; Gp2, Cur NPs; Gp3, Ehrlich ascites carcinoma (EAC); Gp4, Co-treatment of EAC with Cur NPs (Cur NPs + EAC)]. Serum lactate dehydrogenase (LDH), phosphocreatine kinase (CPK), creatine kinase myoglobin (CK-MB), alkaline phosphatase (ALP), glutamic oxaloacetic transaminase (GOT), cholesterol, triglycerides, potassium ions, cardiac injury, P53, vascular endothelial growth factor protein (VEGF), Bax, and tumor necrosis factor alpha (TNFα) expressions were significantly elevated while sodium ions levels were significantly depleted in EAC when compared to control. Co-treatment of EAC with Cur NPs (Cur NPs + EAC) improved these parameters as compared with EAC group. So, our results indicate that; Cur NPs induced protection to the blood and heart tissue during Ehrlich ascites carcinoma.

In Vitro and In Vivo Antitumor Activity of Indolo[2,3-b] Quinolines, Natural Product Analogs from Neocryptolepine Alkaloid.

Neocryptolepine (5-methyl-5H-indolo[2,3-b] quinoline) analogs were synthesized and evaluated in vitro and in vivo for their effect versus Ehrlich ascites carcinoma (EAC). The analogs showed stronger cytotoxic activity against EAC cells than the reference drug. The in vivo evaluation of the target compounds against EAC-induced solid tumor in the female albino Swiss mice revealed a remarkable decrease in the tumor volume (TV) and hepatic lipid peroxidation. A noticeable increase of both superoxide dismutase (SOD) and catalase (CAT) levels was reported (p < 0.001), which set-forth proof of their antioxidant effect. In addition, the in vitro antioxidant activity of the neocryptolepine analogs was screened out using the DPPH method and showed promising activities activity. The histopathological investigations affirmed that the tested analogs have a remarkable curative effect on solid tumors with minimal side-effect on the liver. The study also includes illustrated mechanism of the antitumor activity at the cell level by flow cytometry. The cell cycle analysis showed that the neocryptolepine analogs extensively increase the aggregation of tumor cells in three phases of the cell cycle (G0/G1, S and G2/M) with the emergence of a hypo-diploid DNA content peak (sub-G1) in the cell cycle experiments, which is a clear-cut for the apoptotic cell population. Furthermore, the immunological study manifested a significant elevation in splenic lymphocyte count (p < 0.001) with the elevation of the responsiveness of lymphocytes to phytohemagglutinin (PHA). These results indicate that these naturally-based neocryptolepine alkaloids exhibit marked antitumor activity in vivo and represent an important lead in the development of natural-based anticancer drugs.

Potential therapeutic effects of avenanthramide-C against lung toxicity caused by silver nanoparticles injection in rats.

Most clinical investigations about the impact of nanoparticles on cells and tissues show that nanoparticles may enter the human body by means of respiratory tracts. Humans, animals, plants and environments are continually presented to a wide scope of business items containing silver nanoparticles (Ag NPs) in their piece. Ag NPs, utilized in various consumer products as room showers, surface cleaners, wound dressings, food storage containers and many textiles. The current examination planned to explore the defensive role of Avenanthramide-C (Avns) contrary to the lung toxicity initiated by Ag NPs injection in rats. 40 male Wistar rats were separated into 4 groups (Gp1, control; Gp2, Avns; Gp3, Ag NPs; Gp4, Ag NPs+Avns). Current results revealed that; Ag NPs induced a significant depletion in RBCs count, hemoglobin, platelets counts and a significant increase in total WBCs, lung injury, cyclooxygenase-2 (COX2) and TNFα expressions as compared to control. Treatments of Ag NPs with Avenanthramide-C extract (Ag NPs+Avns) improved the lung structure and blood complete pictures as compared to Ag NPs group.

Therapeutic effects of rocket seeds (Eruca sativa L.) against testicular toxicity and oxidative stress caused by silver nanoparticles injection in rats.

Silver nanoparticles (AgNPs), one of the most well-known nanomaterials, are regularly utilized in everyday consumer products. The present study aimed to investigate the testicular toxicity and oxidative stress by AgNPs and the therapeutic role of the rocket seeds (Eruca sativa) in treatments. Forty male Wistar rats were divided into four equivalent groups (group 1, control; group 2, rocket seeds extract [RS]; group 3, AgNPs; group 4, AgNPs+RS). Our results showed that AgNPs induced a significant decrease in serum total testosterone, FSH (follicle-animating hormone), prolactin and LH (luteinizing hormone), testicular glutathione (GSH), superoxide dismutase (SOD), and glutathione S-transferase (GST). In contrast, a significant increase in testicular DNA, injury, testicular thiobarbituric acid, proliferating cell nuclear antigen, and tumor necrosis factor-α (TNFα) expressions after treatments with AgNPs when contrasted with the control group. Treatments of AgNPs with rocket seeds extract (AgNPs+RS) improved testicular functions and structure. Rocket seeds extract might offer benefits against the toxic nature of AgNPs.

Therapeutic effect of rocket seeds (Eruca sativa L.) against hydroxyapatite nanoparticles injection induced cardiac toxicity in rats.

Hydroxyapatite is bio-ceramic materials with a calcium to phosphorus proportion like to that of normal bone and teeth. The current study meant to examine the cardiac toxicity by hydroxyapatite nanoparticles (HAP NPs) and the protective effect of the rocket seeds in treatments. An aggregate of 40 male Wistar rodents were partitioned into 4 equal groups [Gp1, control; Gp2, rocket seeds extract (RS); Gp3, HAP NPs; Gp4, HAP NPs+RS]. Current results exhibit that; HAP NPs induce a significant increase in myoglobin, LDH (lactate dehydrogenase), CK-MB (creatinine kinase) and CK (creatinine kinase) levels, cardiac thiobarbituric acid-reactive substances (TBARS), injury and P53 expressions. In contrast; a significant reduction in cardiac catalase, reduced glutathione (GSH) and superoxide dismutase (SOD) as compared to control group. Post treatment of rat with HAP NPs and rocket seeds extract (HAP NPs+RS) improved the cardiac functions and structure. Rocket seeds extract may offer advantages against the harmful effects of hydroxyapatite nanoparticles.

The therapeutic and antineoplastic effects of vitamin B17 against the growth of solid-form Ehrlich tumours and the associated changes in oxidative stress, DNA damage, apoptosis and proliferation in mice.

Many cancer therapies indirectly activate apoptosis by chemical or physical damage of DNA. This study was performed to evaluate protective potential of vitamin B17 (VitB17) against Ehrlich solid tumor (EST) induced changes in the oxidative stress, DNA damage, apoptosis and proliferation in mice. In the experiment, 60 female CD1 mice were randomly and allocated to the following four equal-sized groups [G1, negative control; G2, positive control (VitB17); G3, untreated EST; G4, EST treated with VitB17 (EST+VitB17)]. The untreated EST group displayed major increases in tumor volume, significant increase in the levels of MDA, H2O2, NO, PCNA, TNF-α, AFP and dsDNA and notable reductions in the catalase, GSH, P53 and SOD activities. By contrast, reduced levels of TNF-α, AFP, MDA, H2O2, NO, PCNA and dsDNA, along with enhanced levels of P53 and the antioxidant indicators catalase, GSH and SOD were observed in the EST+VitB17 group. These results indicate the antineoplastic and antioxidant properties of vitamin B17 with the potential to decrease the oxidative stress associated with ESTs by augmenting the antioxidant defence system.

Trifluoperazine mitigates cyclophosphamide-induced hepatic oxidative stress, inflammation, and apoptosis in mice by modulating the AKT/mTOR-driven autophagy and Nrf2/HO-1 signaling cascades.

AIM: This study aims to investigate the hepatoprotective effect of the antipsychotic drug trifluoperazine (TFP) against cyclophosphamide (CPA)-induced hepatic injury by exploring its effect on autophagy and the Nrf2/HO-1 signaling pathway. MAIN METHODS: The hepatotoxicity of CPA was assessed by biochemical analysis of the serum hepatotoxicity markers (ALT, AST, and direct bilirubin), histopathological examination, and ultrastructure analysis by transmission electron microscopy (TEM). The ELISA technique was used to assess the hepatic content of oxidative stress (MDA and SOD) and inflammatory markers (IL-1ß and TNF-α). Immunohistochemical assessment was used to investigate the hepatic expression of NF-κB, Nrf2, caspase-3, as well as autophagy flux markers (p62 and LC3B). The mRNA expression of HO-1 was assessed using RT-qPCR. Western blot assay was used to determine the expression of p-AKT and p-mTOR. KEY FINDINGS: TFP improved CPA-induced hepatotoxicity by reducing the elevated hepatotoxicity markers, and alleviating the histopathological changes with improving ultrastructure alterations. It also reduced oxidative stress by reducing MDA content and upregulating SOD activity. In addition, it exhibited anti-inflammatory and anti-apoptotic effects by decreasing NF-κB expression, IL-1ß, TNF-α levels, and caspase-3 expression. Furthermore, TFP-induced hepatoprotection was mediated by favoring Nrf2 expression and increasing the mRNA level of HO-1. As well, it improved autophagy by increasing LC3B expression concurrently with reducing p62 expression. Moreover, TFP modulated the AKT/mTOR pathway by reducing the expression of p-AKT and p-mTOR. SIGNIFICANCE: TFP significantly protected against CPA-induced hepatotoxicity by upregulating Nrf2/HO-1 signaling along with enhancement of protective autophagy via inhibition of the AKT/mTOR signaling pathway.

Antibacterial potential of Euphorbia canariensis against Pseudomonas aeruginosa bacteria causing respiratory tract infections.

The widespread dissemination of bacterial resistance has led to great attention being paid to finding substitutes for traditionally used antibiotics. Plants are rich in various phytochemicals that could be used as antibacterial therapies. Here, we elucidate the phytochemical profile of Euphorbia canariensis ethanol extract (EMEE) and then elucidate the antibacterial potential of ECEE against Pseudomonas aeruginosa clinical isolates. ECEE showed minimum inhibitory concentrations ranging from 128 to 512 µg/mL. The impact of ECEE on the biofilm-forming ability of the tested isolates was elucidated using crystal violet assay and qRT-PCR to study its effect on the gene expression level. ECEE exhibited antibiofilm potential, which resulted in a downregulation of the expression of the biofilm genes (algD, pelF, and pslD) in 39.13% of the tested isolates. The antibacterial potential of ECEE was studied in vivo using a lung infection model in mice. A remarkable improvement was observed in the ECEE-treated group, as revealed by the histological and immunohistochemical studies. Also, ELISA showed a noticeable decrease in the oxidative stress markers (nitric oxide and malondialdehyde). The gene expression of the proinflammatory marker (interleukin-6) was downregulated, while the anti-inflammatory biomarker was upregulated (interleukin-10). Thus, clinical trials should be performed soon to explore the potential antibacterial activity of ECEE, which could help in our battle against resistant pathogenic bacteria.

Potential Antitumor Activity of Combined Lycopene and Sorafenib against Solid Ehrlich Carcinoma via Targeting Autophagy and Apoptosis and Suppressing Proliferation.

An FDA-approved kinase inhibitor called sorafenib (SOR) is used to treat primary kidney and liver cancer as well as to stop the spread of advanced breast cancer. Side effects from SOR, such as palmar-plantar erythrodysesthesia syndrome, can negatively impact an individual's quality of life. There are a lot of data supporting the importance of lycopene (LYC) in preventing cancer. The antitumor properties of the combination of sorafenib and lycopene were examined in this study. A viability test against MDA-MB-231 was used to assess the anticancer efficacy of sorafenib, lycopene, and their combination in vitro. Moreover, a cell cycle analysis and Annexin-V/PI double staining were performed by using flow cytometry. In addition, the protein level of JNK-1, ERK-1, Beclin-1, P38, and P53 of the MDA-MB-231 cell line was estimated using ELISA kits. In addition, mice with SEC were divided into four equal groups at random (n = 10) to investigate the possible processes underlying the in vivo antitumor effect. Group IV (SEC-SOR-LYC) received SOR (30 mg/kg/day, p.o.) and LYC (20 mg/kg/day, p.o.); Group I received the SEC control; Group II received SEC-SOR (30 mg/kg/day, p.o.); and Group III received SEC-LYC (20 mg/kg/day, p.o.). The findings demonstrated that the combination of sorafenib and lycopene was superior to sorafenib and lycopene alone in causing early cell cycle arrest, suppressing the viability of cancer cells, and increasing cell apoptosis and autophagy. Likewise, the combination of sorafenib and lycopene demonstrated inhibition of the levels of Bcl-2, Ki-67, VEGF, IL-1ß, and TNF-α protein. Otherwise, the quantities of the proteins BAX, P53, and caspase 3 were amplified. Furthermore, the combined treatment led to a substantial increase in TNF-α, caspase 3, and VEGF gene expression compared to the equivalent dosages of monotherapy. The combination of sorafenib and lycopene enhanced apoptosis and reduced inflammation, as seen by the tumor's decreased weight and volume, hence demonstrating its potential anticancer effect.

New insights into the potential cardioprotective effects of telmisartan and nanoformulated extract of Spirulina platensis via regulation of oxidative stress, apoptosis, and autophagy in an experimental model.

Background: Cardiotoxicity is one of the limiting side effects of the commonly used anticancer agent cyclophosphamide (Cyclo). Materials and methods: The possible protective effects of telmisartan and nanoformulated Spirulina platensis (Sp) methanolic extract against Cyclo-induced cardiotoxicity were examined in this study. Experimental groups of rats were randomly divided into nine groups as control vehicle, control polymer, telmisartan (TEL, 10 mg/kg), free Sp extract (300 mg/kg), nano Sp extract (100 mg/kg), Cyclo (200 mg/kg), TEL + Cyclo, free Sp + Cyclo, and nano Sp + Cyclo. The groups with Cyclo combinations were treated in the same manner as their corresponding ones without Cyclo, with a single dose of Cyclo on day 18. Results: The results indicate that Cyclo causes significant cardiotoxicity, manifesting in the form of notable increases of 155.49%, 105.74%, 451.76%, and 826.07% in the serum levels of glutamic oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), and cardiac troponin I (cTnI) enzyme activities, respectively, as compared to the control. In addition, the cardiac glutathione (GSH) content and activity of glutathione peroxidase-1 (GPX-1) enzyme decreased by 65.94% and 73.85%, respectively. Treatment with nano Sp extract showed the most prominent restorations of the altered biochemical, histopathological, and immunohistochemical features as compared with those by TEL and free Sp; moreover, reductions of 30.64% and 43.02% in the p-AKT content as well as 60.43% and 75.30% of the endothelial nitric oxide synthase (eNOS) immunoreactivity were detected in the TEL and free Sp treatment groups, respectively. Interestingly, nano Sp boosted the autophagy signal via activation of beclin-1 (36.42% and 153.4%), activation of LC3II (69.13% and 195%), downregulation of p62 expressions (39.68% and 62.45%), and increased gene expressions of paraoxonase-1 (PON-1) (90.3% and 225.9%) compared to the TEL and free Sp treatment groups, respectively. Conclusion: The findings suggest the protective efficiency of telmisartan and nano Sp extract against cardiotoxicity via activations of the antioxidant, antiapoptotic, and autophagy signaling pathways.

Fabrication of Nanocrystals for Enhanced Distribution of a Fatty Acid Synthase Inhibitor (Orlistat) as a Promising Method to Relieve Solid Ehrlich Carcinoma-Induced Hepatic Damage in Mice.

BACKGROUND: Orlistat (ORL) is an effective irreversible inhibitor of the lipase enzyme, and it possesses anticancer effects and limited aqueous solubility. This study was designed to improve the aqueous solubility, oral absorption, and tissue distribution of ORL via the formulation of nanocrystals (NCs). METHODS: ORL-NC was prepared using the liquid antisolvent precipitation method (bottom-up technology), and it demonstrated significantly improved solubility compared with that of the blank crystals (ORL-BCs) and untreated ORL powder. The biodistribution and relative bioavailability of ORL-NC were investigated via the radiolabeling technique using Technetium-99m (99mTc). Female Swiss albino mice were used to examine the antitumor activity of ORL-NC against solid Ehrlich carcinoma (SEC)-induced hepatic damage in mice. RESULTS: The prepared NCs improved ORL's solubility, bioavailability, and tissue distribution, with evidence of 258.70% relative bioavailability. In the in vivo study, the ORL-NC treatment caused a reduction in all tested liver functions (total and direct bilirubin, AST, ALT, and ALP) and improved modifications in liver sections that were marked using hematoxylin and eosin staining (H&E) and immunohistochemical staining (Ki-67 and ER-α) compared with untreated SEC mice. CONCLUSIONS: The developed ORL-NC could be considered a promising formulation approach to enhance the oral absorption tissue distribution of ORL and suppress the liver damage caused by SEC.