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Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks an actionable target with limited treatment options beyond conventional chemotherapy. Therapeutic failure is often encountered due to inherent or acquired resistance to chemotherapy. Previous studies implicated PI3K/Akt/mTOR signaling pathway in cancer stem cells (CSCs) enrichment and hence chemoresistance. The present study aimed at investigating the potential effect of piperine (PIP), an amide alkaloid isolated from Piper nigrum, on enhancing the sensitivity of TNBC cells to doxorubicin (DOX) in vitro on MDA-MB-231 cell line and in vivo in an animal model of Ehrlich ascites carcinoma solid tumor. Results showed a synergistic interaction between DOX and PIP on MDA-MB-231 cells. In addition, the combination elicited enhanced suppression of PI3K/Akt/mTOR signaling that paralleled an upregulation in this pathway's negative regulator, PTEN, along with a curtailment in the levels of the CSCs surrogate marker, aldehyde dehydrogenase-1 (ALDH-1). Meanwhile, in vivo investigations demonstrated the potential of the combination regimen to enhance necrosis while downregulating PTEN and curbing PI3K levels as well as p-Akt, mTOR, and ALDH-1 immunoreactivities. Notably, the combination failed to change cleaved poly-ADP ribose polymerase levels suggesting a pro-necrotic rather than pro-apoptotic mechanism. Overall, these findings suggest a potential role of PIP in decreasing the resistance to DOX in vitro and in vivo, likely by interfering with the PI3K/Akt/mTOR pathway and CSCs.
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Alcaloides , Benzodioxoles , Doxorrubicina , Células Madre Neoplásicas , Fosfatidilinositol 3-Quinasas , Piperidinas , Alcamidas Poliinsaturadas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Neoplasias de la Mama Triple Negativas , Doxorrubicina/farmacología , Alcamidas Poliinsaturadas/farmacología , Piperidinas/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Humanos , Alcaloides/farmacología , Benzodioxoles/farmacología , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Femenino , Línea Celular Tumoral , Serina-Treonina Quinasas TOR/metabolismo , Sinergismo Farmacológico , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Apoptosis/efectos de los fármacosRESUMEN
Schistosomiasis is a neglected tropical disease with considerable morbidity. The lone effective drug, praziquantel (PZQ), is showing emergence of drug resistance hence, searching for new supportive treatment is crucial. This study aimed to evaluate the efficacy of mucus and nucleoproteins (NPs) extracted from Biomphalaria alexandrina (B. alexandrina) snails on miracidia, cercariae and Schistosoma mansoni (S. mansoni) adults in vitro and assess their experimental in vivo effect through parasitological, histopathological, and biochemical parameters. The in vivo study included 90 male Swiss albino mice. Mice were grouped into 9 groups; G1-G5 were infected and treated with; GI: PZQ, GII: mucus, GIII: combined PZQ and mucus, GIV: NPs, GV: combined PZQ and NPs. Control groups; C1: Non infected non treated (negative control), C2: Infected non treated (positive control), C3: Non infected mucus treated and C4: Non infected NPs treated. The in vitro study proved that the mucus had a better lethal effect on cercariae than miracidia, while NPs had better lethal effect on miracidia. The mucus lethal effect on adults surpassed the NPs as 100% and 60%, respectively. The in vivo study proved that the combined NPs or mucus with PZQ added to the effect of individual PZQ resulting in 100% total worm burden (TWB) reduction. As regard oxidative stress markers, the lowest level of nitric oxide (NO) was shown with combined PZQ and NPs. While, the highest glutathione (GSH) level was produced by individual PZQ. The study concluded that mucus and NPs of B. alexandrina had cercaricidal, miracidicidal and anti-schistosomal effect in vitro and that their combination could be considered a contribution to PZQ potentiality in vivo.
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Sympathetic activation triggered by chronic stress afflicting cancer survivors is an emerging modulator of tumorigenesis. Adrenergic blockade was previously associated with improving response to doxorubicin (DOX) in triple-negative breast cancer (TNBC), yet the precise underlying mechanisms remain obscure. The resilience of cancer stem cells (CSCs) during chemotherapy fosters resistance and relapse. Hypoxia-inducible factor-1α (HIF-1α) and ß-catenin are intertwined transcriptional factors that enrich CSCs and evidence suggests that their expression could be modulated by systemic adrenergic signals. Herein, we aimed to explore the impact of adrenoreceptor blockade using carvedilol (CAR) on DOX and its potential to modulate CSCs overcoming chemoresistance. To achieve this aim, in vitro studies were conducted using adrenaline-preincubated MDA-MB-231 cells and in vivo studies using a chronic restraint stress-promoted solid tumor mouse model. Results revealed that adrenaline increased TNBC proliferation and induced a phenotypic switch reminiscent of CSCs, as evidenced by enhanced mammosphere formation. These results paralleled an increase in aldehyde dehydrogenase-1 (ALDH-1) and Nanog expression levels as well as HIF-1α and ß-catenin upsurge. In vivo, larger tumor volumes were observed in mice under chronic stress compared to their unstressed counterparts. Adrenergic blockade using CAR, however, enhanced the impact DOX had on halting TNBC cell proliferation and tumor growth via enhanced apoptosis. CAR also curbed HIF-1α and ß-catenin tumor levels subsequently suppressing ALDH-1 and SOX2. Our study unveils a central role for HIF-1α linking stress-induced sympathetic activation fueling CSC enrichment via the ß-catenin pathway. It also highlights novel insights into CAR's capacity in reversing DOX chemoresistance in TNBC.
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Gastric ulcer (GU) is a serious upper gastrointestinal tract disorder that affects people worldwide. The drugs now available for GU treatment have a high rate of relapses and drug interactions, as well as mild to severe side effects. As a result, new natural therapeutic medications for treating GU with fewer negative side effects are desperately needed. Because of quercetin's (QCT) diverse pharmacological effects and unique structural features, we decided to semi-synthesize new QCT derivatives and test them for antiulcer activity. Docking assays were performed on the synthesized compounds to determine their affinity for TLR-4/MD-2, MyD88/TIR, and NF-κB domains, an important inflammatory pathway involved in GU development and progression. Mice were given oral famotidine (40 mg/kg/day), QCT, QCT pentamethyl (QPM), or QCT pentaacetyl (QPA) (50 mg/kg/day) for 5 days before GU induction by a single intraperitoneal injection of indomethacin (INDO; 18 mg/kg). QPM and QPA have a stronger binding affinity for TLR-4/MD-2, MyD88/TIR and NF-κB domains than QCT. In comparison, they demonstrated the greatest reduction in ulcer score and index, gastric MDA and nitric oxide (NO) contents, MyD88 and NF-κB expressions, and gastric TLR-4 immunostaining. They also enhanced the levels of GSH, CAT, COX-1, and COX-2 in the gastric mucosa, as well as HO-1 and Nrf2 expression, with histological regression in gastric mucosal lesions, with QPA-treated mice demonstrating the best GU healing. QPA is safe against all of the target organs and adverse pathways studied, with good ADME properties. However, further in vitro experiments are necessary to demonstrate the inhibitory effects of QPM and QPA on the protein targets of interest. In addition, preclinical research on its bioavailability and safety is essential before clinical management can be undertaken. Overall, the new QPA derivative could one day serve as the basis for a new class of potential antiulcer drugs.
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Indometacina , Úlcera Gástrica , Humanos , Ratones , Animales , Indometacina/toxicidad , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/patología , Quercetina/farmacología , Quercetina/uso terapéutico , Simulación del Acoplamiento Molecular , Úlcera/metabolismo , Úlcera/patología , FN-kappa B/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Receptor Toll-Like 4/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologíaRESUMEN
Ulcerative colitis is a common type of inflammatory bowel disease that affects millions of individuals around the world. Traditional UC treatment has focused on suppressing immune responses rather than treating the underlying causes of UC, which include oxidative stress, inflammation, and microbiota dysbiosis. Diosmin (DIO), a naturally occurring flavonoid, possesses antioxidant and anti-inflammatory properties. This study aimed to assess the efficacy of DIO in treating dextran-sulfate sodium (DSS)-induced colitis, and to investigate some of its underlying mechanisms, with an emphasis on Akkermansia muciniphila abundance, inflammatory markers, and intestinal barrier function. C57BL/6 mice were given 4% (w/v) DSS to induce colitis. DSS-induced mice were administered DIO (100 and 200 mg/kg) or sulfasalazine orally for 7 days. Every day, the disease activity index (DAI) was determined by recording body weight, diarrhea, and bloody stool. Changes in fecal A. muciniphila abundance, colonic MUC1 and MUC2 expression, as well as oxidative stress and inflammatory markers were all assessed. Histopathological changes, colonic PIK3PR3 and ZO-1 levels, and immunohistochemical examinations of occludin and claudin-1, were investigated. DIO administration resulted in a dose-dependent decrease in DAI, as well as increase in A. muciniphila abundance and MUC2 expression while decreasing MUC1 expression. DIO also dramatically reduced colonic oxidative stress and inflammation by regulating the NF-κB and Nrf2 cascades, restored intestinal barrier integrity by inhibiting PIK3R3 and inducing ZO-1, and improved occludin/claudin-1 gene expression and immunostaining. This study provides the first evidence that DIO preserves intestinal barrier integrity and increases A. muciniphila abundance in DSS-induced colitis. However, more research is required to explore the impact of DIO on the overall composition and diversity of the gut microbiota. Likewise, it will be important to fully understand the molecular mechanisms by which A. muciniphila maintains intestinal barrier function and its potential use as an adjuvant in the treatment of UC.
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BACKGROUND: Trematode infections of the genus Schistosoma can induce physiological and behavioral changes in intermediate snail hosts. This is because the parasite consumes essential resources necessary for the host's survival, prompting hosts to adapt their behavior to maintain some level of fitness before parasite-induced mortality occurs. METHODS: In this study, the reproductive and biochemical parameters of Biomphalaria alexandrina and Bulinus truncatus were examined during the cercareal shedding stage of infection with Schistosoma mansoni and Schistosoma haematobium, respectively, compared with controls. RESULTS: The study revealed an infection rate of 34.7% for S. mansoni and 30.4% for S. haematobium. In B. alexandrina infected with S. mansoni, a survival rate of 65.2% was recorded, along with a mean prepatent period of 30.3 ± 1.41 days, a mean shedding duration of 14.2 ± 0.16 days, and a mean lifespan of 44.1 ± 0.24 days. Meanwhile, in B. truncatus infected with S. haematobium, a survival rate of 56.4% was observed, with a mean prepatent period of 44.3 ± 1.41 days, a mean shedding duration of 22.6 ± 2.7 days, and a mean lifespan of 66.9 ± 1.6 days. Feeding increased in both infected species of snails, while the net reproductive rate (Ro) of the infected snails decreased. Total antioxidant (TAO) and lipid peroxidation activity increased in the two infected snail species during shedding, while Glutathione-S-transferase levels decreased. Lipid peroxidase activity and nitrogen oxide levels significantly decreased in infected B. alexandrina and increased in infected Bulinus. Steroid hormone levels were elevated in infected Biomphalaria, whereas they were reduced in infected Bulinus. Comet assay parameters showed an increase in the two infected genera after infection compared to control snails, indicating genotoxic damage and histopathological damage was observed. CONCLUSIONS: These findings demonstrate that infection with larva species diverse biochemical, hormonal, genotoxic, and histopathological changes in the tissues responsible for fecundity and reproduction in B. alexandrina and B. truncates comparing with controls.
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Biomphalaria , Bulinus , Interacciones Huésped-Parásitos , Schistosoma mansoni , Animales , Biomphalaria/parasitología , Schistosoma mansoni/fisiología , Bulinus/parasitología , Schistosoma haematobium/genética , Schistosoma haematobium/fisiología , Conducta Alimentaria , Cercarias/fisiología , ReproducciónRESUMEN
Pyridine compounds are one of the most important heterocyclic derivatives showing wide ranges in biological and pharmacological activities. Green chemistry eliminates or reduces the generation of hazardous compounds. It prevents pollution at a molecular level. The microwave technique used in heterocyclic compound synthesis is also an important branch of green chemistry techniques. In this study, we report designing and synthesizing a new pyridine-bearing pentose moiety via a one-pot multicomponent reaction using D-glucose and also investigate its behavior and reactivity toward some simple and heterocyclic amino derivatives. The chemical structures of the synthesized compounds were characterized and tested for their cytotoxic activities. Some of the test compounds exhibited slight to high cytotoxic activities against Caco2 (colon cancer) cells, HepG2 (hepatocellular carcinoma) cells and MCF-7 (human breast cancer) cells by MTT assay. The results showed clearly that compound 4 and compound 8 displayed strongest to moderate cytotoxic activity against the HepG2, Caco2 and MCF-7 respectively and compound 1 showed good activity against MCF-7 in comparison to the standard anticancer drug doxorubicin. These data were by cytopathological examination. An in-vivo radioactive tracing study of compound 4 proved its targeting ability to sarcoma cells in a tumor-bearing mice model. Our findings suggest that the synthesized compounds may be promising candidates as novel anticancer agents.
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Antineoplásicos , Radioisótopos de Yodo , Humanos , Animales , Ratones , Radioisótopos de Yodo/farmacología , Células MCF-7 , Células CACO-2 , Proliferación Celular , Antineoplásicos/farmacología , Antineoplásicos/química , Piridinas/farmacología , Piridinas/química , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Diseño de Fármacos , Simulación del Acoplamiento MolecularRESUMEN
BACKGROUND: Cholestasis is an important predisposing factor for hepatocyte damage, liver fibrosis, primary biliary cirrhosis, and even liver failure. Silybum marianum L. (SM) plant is used in teas or eaten in some countries due to its antioxidant and hepatoprotective properties. Because of its low and poor oral bioavailability, so we improve the therapeutic activity of Silybum marianum L. extract (SM) by studying the potential effects of nanoformulation of Silybum marianium L. extract (nano-SM) on 17α-ethinylestradiol (EE)-induced intrahepatic cholestasis. METHODS: Thirty female Sprague-Dawley rats were divided into 5 groups (6 rats/group). Group I: Rats were received the treatment vehicle and served as normal group. Group II:Rats were injected daily with EE (10 mg/kg) for five successive days. Group III-V: Rats were injected daily with EE (10 mg/kg) and treated with either Ursodeoxycholic acid (UDCA) (40 mg/kg), SM (100 mg/kg) and nano-SM (100 mg/kg) orally once/day throughout the trialfor five successive days, respectively. RESULTS: Nano-SM greatly dampened the increase in serum levels of total and direct bilirubin, alanine aminotransaminase, aspartate aminotransaminase, and alkaline phosphatase caused by EE. Furthermore, nano-SM increased the hepatic contents of reduced glutathione (GSH) and catalase (CAT) and also upregulated the relative hepatic gene expressions of Rho-kinase (ROCK-1), myosin light chain kinase (MLCK), and myosin phosphatase target subunit (MYPT1) compared to the EE-induced group. Administration of nano-SM reduced hepatic lipid peroxidation and downregulated the relative hepatic expressions of the nuclear factor-kappa B (NF-Ò¡B) and interleukin-1ß (IL-1ß). In addition, nano-SM improved the histopathological changes induced by EE. CONCLUSION: Nano-SM possessed a superior effect over SM, which can be considered an effective protective modality against EE-induced cholestatic liver injury through its antioxidant, anti-inflammatory activities, and enhancing bile acid (BA) efflux.
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Asteraceae , Colestasis Intrahepática , Animales , Ratas , Ratas Sprague-Dawley , Silybum marianum , Etinilestradiol , Antioxidantes , Extractos VegetalesRESUMEN
Because of their low ecological impact, plant molluscicides have garnered much attention. The work aimed to find out if Annona squamosa (AS) seed extract has a molluscicidal impact on Biomphalaria alexandrina snails and enhances this extract by adding CuO nanoparticles (NPs). Using a scanning electron microscope (SEM), transmission electron microscope (TEM), and PANalytical X'Pert PRO X-ray diffractometer (XRD), the presence of the green A. squamosa-based CuO NPs (AS-CuO NPs) was confirmed. After 24 h of exposure, the half-lethal concentration (LC50) of AS-CuO NPs was more toxic to mature B. alexandrina than the aqueous extract of AS seeds (LC50: 119.25 mg/L vs. 169.03 mg/L). The results show that snails exposed to sublethal doses of AS-CuO NPs at LC10 or LC25 (95.4 or 106.7 mg/L, respectively) had much higher glucose levels and alkaline phosphatase activity than those not exposed. Nevertheless, there was no discernible change in the protein content in general or glycogen phosphorylase production. Histological and immunohistochemical analysis showed that snails exposed to A. squamosa-derived CuO NPs LC10 had shrinking digestive tubules and degeneration as well as vacuolation of many digestive, secretory, ova, and sperm cells, with PCNA expressing positively in the hermaphrodite gland and digestive tubule cells. The toxic profile of green CuO NPs produced by A. squamosa may damage the biological activity of B. alexandrina snails; thus, this compound could be used as a molluscicidal base. Furthermore, B. alexandrina proved to be a useful biomarker of nanomaterial contamination.
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Annona , Biomphalaria , Moluscocidas , Nanopartículas , Animales , Cobre/farmacología , Semillas , Moluscocidas/toxicidad , Extractos Vegetales/farmacología , Conducta Alimentaria , ÓxidosRESUMEN
Damage-associated molecular patterns released upon hepatocyte injury ensuing non-alcoholic steatohepatitis (NASH) can stimulate innate immunity by activating NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, thereby triggering pro-inflammatory cascades in the liver. Aberrant NLRP3 activation allied to compromised autophagic clearance of its components contributes to the progression of multiple inflammatory diseases. Such intricate interplay, however, was not fully deciphered in NASH. Prior studies have illuminated the ability of vitamin D3 to temper inflammasome activation in several contexts, prompting us to probe the impact of vitamin D3, particularly its active form, calcitriol (CAL), on NLRP3 overactivation in a high-fat diet (HFD)-based NASH model and its potential dependence on autophagy. Hydroxychloroquine (HCQ), an autophagy inhibitor, was co-administered with CAL to examine the likely modulation of the NLRP3/autophagy crosstalk. Our results showed that treatment with CAL countervailed the histopathological derangement reported in the livers of HFD-fed mice that paralleled a restoration of vitamin D receptor gene expression and reduction in sterol regulatory element binding protein 1c levels. Moreover, p62 was curtailed with CAL treatment indicating autophagy induction. CAL also prompted a reduction in NLRP3, caspase-1, gasdermin D, and IL-18 protein levels along with the apoptosis-associated speck-like protein (ASC) gene expression. Treatment with CAL also reduced IL-1ß and caspase-3 immunoreactivities compared to control. Intriguingly, CAL modulatory effects on inflammasome activation were curbed in the group that received HCQ, suggesting a potential autophagy dependency. Accordingly, the current study suggests that CAL was capable of ameliorating NASH via inhibiting NLRP3 inflammasome activation in an autophagy-dependent manner.
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Inflamasomas , Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Inflamasomas/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Colecalciferol/farmacología , Autofagia , Calcitriol/farmacologíaRESUMEN
This study investigated a 'de Novo' medicinal herb, Ferula asafetida (FA), against toxoplasma encephalitis either alone or combined with spiramycin (SP). Female Swiss-Webster mice (n = 72) were divided into three batches. Batch-I received no DMS to serve as an immunocompetent control, batch-II was immune-suppressed with the DMS (0.25 mg/g/day) for 14 days pre-infection, whilst batch-III was immune-suppressed with the DMS on the same day of infection. All experimental mice were inoculated with Toxoplasma gondii ME49 cysts (n = 75). Each batch was split into four subgroups: Mono-SP, mono-FA, combined drug (SP + FA), or neither. Therapies were administered on day zero of infection in batches (I and II) and 35 days post-infection in batch (III). Treatments lasted for 14 days, and mice were sacrificed 60 days post-infection. Histopathological changes, cysts load, and CD4 and CD8 T-cells were counted in brain tissues. The cyst-load count in mice receiving SP + FA was significantly (p < .0001) the least compared to the mono treatments in all protocols. Interestingly, the combined therapy demolished the T-cell subsets to zero in immunocompetent and immunocompromised infected mice. In conclusion, F. asafetida might be a powerfully natural, safe vehicle of SP in the digestive system and/or across the brain-blood barrier to control toxoplasmosis even through immunodeficient conditions.
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Encefalitis , Ferula , Espiramicina , Toxoplasma , Toxoplasmosis Animal , Toxoplasmosis Cerebral , Femenino , Ratones , Animales , Espiramicina/uso terapéutico , Encéfalo , Toxoplasmosis Animal/tratamiento farmacológico , Encefalitis/tratamiento farmacológico , Encefalitis/patologíaRESUMEN
Bacterial-associated wound infections are an obstacle for individuals and the medical industry. Developing versatile, antibiotic-free therapies helps heal wounds more quickly and efficiently. In the current study, fungal metabolites were employed as a reducing agent in fabricating selenium nanoparticles (SeNPs) for improved antibacterial and wound healing properties. Utilizing UV-visible spectroscopy, dynamic light scattering (DLS), zeta potential, X-ray diffraction (XRD), and electron microscopic examination, the properties of the synthesized nanoparticles were extensively evaluated. Myco-synthesized SeNPs demonstrated strong antibacterial activity against Staphylococcus aureus ATCC 6538 with a minimum inhibitory concentration of 0.3125 mg/mL, reducing cell number and shape distortion in scanning electron microscope (SEM) images. SeNPs' topical administration significantly reduced wound area and healing time, exhibiting the least bacterial load after six days compared to controls. After six and 11 days of treatment, SeNPs could decrease proinflammatory cytokines IL-6 and TNF-α production. The histopathological investigation showed a healed ulcer with moderate infiltration of inflammatory cells after exposing mice's skin to SeNPs for six and 11 days. The docking interaction indicated that SeNPs were highly efficient against the IL-6 and TNF-α binding receptors. These findings imply that myco-fabricated SeNPs might be used as topically applied antimicrobial agents for treating skin infections and wounds.
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The present investigation aimed to synthesize chitosangold nanocomposites (Ch-AuNPs) with gamma radiation, then to evaluate its toxic effect on the freshwater snails Biomphalaia alexandrina. Results showed that Ch-AuNPs is spherical shaped with average size 12 nm. It had a toxic effect against B. alexandrina snails with LC50 20.43 mg/l. Exposure of B. alexandrina snails to LC10 7.51 or LC25 13.63 mg/l of Ch-AuNPs, reduced the survival, reproductive and fecundity rates; total protein and albumin; both testosterone (T) and 17ß Estradiol (E) levels; SOD and CAT activities of exposed snails while increased the activities of transaminases (AST & ALT), uric acid, creatinine, TAC and MDA levels compared to the control group. Results were supported by histopathological and immunohistopathological alterations of the digestive and hermaphrodite glands. In conclusion B. alexandrina could be used as a model to screen the negative impact of nanomaterials. Also, Ch-AuNPs could be used as a molluscicidal agent.
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Biomphalaria , Quitosano , Nanopartículas del Metal , Nanocompuestos , Animales , Quitosano/farmacología , Oro , Estrés OxidativoRESUMEN
Cryptosporidiosis is a serious parasitic diarrheal disease linked to the occurrence of colorectal cancer in immunocompromised patients. The FDA-approved drug nitazoxanide (NTZ) achieved a temporary effect, and relapses occur. Annona muricata leaf is widely used in traditional medicine to treat a wide range of disorders, including antiparasitic and anticancer effects. So, this study aimed to investigate Annona muricata leaf antiparasitic and anticancer properties compared to NTZ in Cryptosporidium parvum (C. parvum) acutely and chronically infected immunosuppressed mice. A molecular docking analysis was performed to evaluate the effectiveness of some biologically active compounds that represented the pharmacological properties of Annona muricata leaf-rich extract toward C. parvum lactate dehydrogenase compared to NTZ. For the in vivo study, eighty immunosuppressed albino mice were classified into four groups as follows: group I: infected and treated with A. muricata; group II: infected and treated with nitazoxanide; group III: infected and received no treatment; and group IV: were neither infected nor treated. Furthermore, half of the mice in groups I and II received the drugs on the 10th day post-infection (dpi), and the other half received treatment on the 90th day post-infection. Parasitological, histopathological, and immunohistochemical evaluations were performed. The docking analysis showed that the lowest estimated free energy of binding of annonacin, casuarine, L-epigallocatechin, P-coumaric acid, and ellagic acid toward C. parvum LDH, were -6.11, -6.32, -7.51, -7.81, and -9.64 kcal/mol, respectively, while NTZ was -7.03 kcal/mol. Parasitological examination displayed a significantly high difference in C. parvum oocyst mean counts in groups I and II compared to group III (p-value < 0.001), with group I demonstrating the highest efficacy. The analyses of histopathological and immunohistochemical results revealed that group I showed restoration of the normal villous pattern without evidence of dysplasia or malignancy. A. muricata leaf has proved to be a reliable agent for Cryptosporidium treatment. This paper argues for its promising use as an antiparasitic agent and for the prevention of neoplastic sequels of Cryptosporidium infection.
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In the past three decades, a significant progress has been made in the prevention and treatment of gastric ulcers. The incidence of the disease has decreased, but gastric ulcer is still a medical problem. Currently, the available drugs for gastric ulcer treatment have many side effects; therefore, searching for new and safe therapeutic agents is mandatory. The present study aims to investigate the gastroprotective potential of Cornu aspersum (C. aspersum) mucin against gastric ulcers, and the mechanisms related to oxidative stress and inflammation. C. aspersum mucin was collected from 50 snails. The characteristics of C. aspersum mucin (chemical and microbiological) were evaluated. Mice were pretreated with famotidine and C. aspersum mucin (7.5 and 15 ml/kg b.w.) for 5 days, and then gastric ulcers were induced by indomethacin. Macroscopic examination, biochemical estimations, and Quantitative real-time PCR were carried out. Also, histopathological and immunohistopathological examinations were evaluated. We found that the high dose of the mucin significantly decreased the gastric mucosal malondialdehyde (MDA) and nitric oxide (NO) contents as well as interleukin 1ß (IL-1ß) and nuclear factor kappa ß (NF-Ò¡B) expression, and inducible nitric oxide synthase (iNOS) immunostaining. It also increased the gastric mucosal GSH and catalase contents as well as hemoxygenase-1 (HO-1) and nuclear factor-erythroid 2-related factor 2 (Nrf2) expressions with regressions in gastric mucosal lesions. In conclusion, C. aspersum mucin could be a potential therapeutic candidate to protect against gastric ulceration.
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OBJECTIVES: To evaluate DNA ploidy and S-phase fraction (SPF) in non-Lynch colonic adenocarcinoma, ulcerative colitis (UC), Crohn disease (CD) which are known as risk factors, and colitis. We correlated ploidy and SPF with tumor grading, staging and BRAF expression. METHODS: All studied adenocarcinomas have intact mismatch repair genes as proved by immunohistochemistry. All were assessed for ploidy by automated image-based DNA cytometry and histograms were drawn. Immunostaining by anti-BRAF V600E was performed. Diagnostic laparoscopy (DL) was done as a preliminary step for staging GI cancers. RESULTS: there is significant difference in DNA ploidy between groups; 77.5% and 17.5% of aneuploid cases are adenocarcinoma and UC. Groups are compared in terms of 2C, 4C, above 4C DNA content and SPF and significant difference is principally found between adenocarcinoma group and others. In adenocarcinomas, DNA ploidy is significantly correlated with tumor staging and grading. Regarding BRAF expression, there is significant difference between groups; all adenocarcinomas, 83.33% of UC were positive, while all cases of colitis, bilharzial colitis, CD were negative. There is significant relation between BRAF and SPF among all diploid cases including adenocarcinoma, and among non-neoplastic diploid cases. There is direct significant relation between BRAF intensity and adenocarcinoma staging. There is no significant difference between BRAF and ploidy among UC cases, although 75% of aneuploid UC are positive. DL helps in GI cancer staging. Routine laparoscopy before laparotomy, especially in cancers which have equivocal operability helps to avoid unnecessary laparotomies. CONCLUSION: Based on significant difference in ploidy between adenocarcinoma and UC and between SPF and ploidy, assessment of ploidy by DNA cytometry for UC and other colitis could therefore predict impending malignant transformation before development of colonic dysplasia. Also measuring SPF in adenocarcinoma helps to select patients who could greatly benefit from chemotherapy. DL has vital role in staging GI cancers.
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Adenocarcinoma , Colitis Ulcerosa , Neoplasias del Colon , Humanos , Adenocarcinoma/genética , Adenocarcinoma/patología , Aneuploidia , Colitis Ulcerosa/genética , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/genética , Neoplasias del Colon/patología , ADN , ADN de Neoplasias/genética , Citometría de Flujo , Inmunohistoquímica , Estadificación de Neoplasias , PloidiasRESUMEN
Daphnia magna and freshwater snails are used as delicate bioindicators of contaminated aquatic habitats. Due to their distinctive characteristics, selenium oxide nanoparticles (SeONPs) have received interest regarding their possible implications on aquatic environments. The current study attempted to investigate the probable mechanisms of fungal-mediated selenium nanoparticles' ecotoxicological effects on freshwater Biomphalaria alexandrina snails and Daphnia magna. SeONPs revealed a toxicological impact on D. magna, with a half-lethal concentration (LC50) of 1.62 mg/L after 24 h and 1.08 mg/L after 48 h. Survival, fecundity, and reproductive rate were decreased in B. alexandrina snails exposed to SeONPs. Furthermore, the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were markedly elevated, while albumin and total protein levels decreased. Histopathological damage in the hermaphrodite and digestive glands was detected by light, electron microscopy, and immunohistochemistry studies. The molecular docking study revealed interactions of selenium oxide with the ALT and AST. In conclusion, B. alexandrina snails and D. magna could be employed as bioindicators of selenium nanomaterial pollution in aquatic ecosystems. This study emphasizes the possible ecological effects of releasing SeONPs into aquatic habitats, which could serve as motivation for regulatory organizations to monitor and control the use and disposal of SeONPs in industry.
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Background: Phytochemicals have amazing biological effects in relation to age-related illnesses and are increasingly being studied in clinical trials. The goal of this study was to examine the effectiveness of the aqueous extracts of Rosmarinus officinalis L. (Rosemary) and Crocus sativus L. (Saffron) and their combinations as tau and ß-amyloid antagonists in an Alzheimer's rat model. Methods: AlCl3 and D-galactose (150 & 300 mg/kg) were used to create the Alzheimer's neuroinflammation rat model. The animals were subsequently given the two extracts and their combinations (500 mg/kg) along 15 days. The cognitive impairment, oxidative stress, tau & amyloid neuroproteins, acetylcholine, acetylcholinesterase neurotransmitters, proinflammatory cytokines, LC3 as an autophagy marker, computational analysis, and morphological alterations were all assessed. Results: When compared to the conventional donepezil and normal groups, the treated groups showed a significant improvement in all calculated parameters. The cortex and hippocampus have a better morphological appearance. In silico analysis found that these extracts may have an affinity for and impede the activity of some proteins thought to be essential regulators of disease progression. Conclusion: Rosemary and Saffron extracts by the power of their constituents were able to alleviate the neurotoxicity of AlCl3 & D-galactose and regulate the natural autophagy process.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Animales , Ratas , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/uso terapéutico , Autofagia , Galactosa/uso terapéutico , Proteínas tau/metabolismoRESUMEN
Experimental and clinical evidence implicate disrupted gut barrier integrity in provoking innate immune responses, specifically macrophages, towards the progression of non-alcoholic steatohepatitis (NASH). Peroxisome proliferator-activated receptors (PPARs), a subset of the nuclear receptor superfamily, act to fine-tune several metabolic and inflammatory processes implicated in NASH. As such, the current study was carried out to decipher the potential role of dual PPAR α/δ activation using elafibranor (ELA) on ileal macrophage polarization (MP) and its likely impact on the liver in a NASH setting. To achieve this aim, an in vitro NASH model using fat-laden HepG2 cells was first used to validate the impact of ELA on hepatic fat accumulation. Afterwards, ELA was used in a combined model of dietary NASH and chronic colitis analogous to the clinical presentation of NASH parallel with intestinal barrier dysfunction. ELA mitigated fat accumulation in vitro as evidenced by Oil Red-O staining and curbed triglyceride levels. Additionally, ELA restored the expression of tight junctional proteins, claudin-1 and occludin, along with decreasing intestinal permeability and inflammation skewing ileal macrophages towards the M2 phenotype, as indicated by boosted arginase-1 (Arg1) and curtailed inducible nitric oxide synthase (iNOS) expression levels. These changes were aligned with a modulation in hepatic toll-like receptor-4 (TLR4)/nuclear factor kappa B (NF-κB) along with ileal interleukin-10 (IL-10)/signal transducer and activator of transcription-3 (STAT3) axes. Overall, the present findings suggest that the dual PPAR α/δ agonist, ELA, may drive MP in the ileum towards the M2 phenotype improving intestinal integrity towards alleviating NASH.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , PPAR delta , Humanos , FN-kappa B/metabolismo , Interleucina-10/metabolismo , PPAR alfa/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Hígado/metabolismo , Macrófagos/metabolismo , PPAR delta/metabolismo , Receptor Toll-Like 4/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
Engineered nanoparticles have been recently utilized in numerous domains particularly, silver nanoparticles (AgNPs). Nonetheless, the possible side effects resulting from AgNPs exposure are not fully clarified. The present study was designed to clarify the toxicity of AgNPs on lung tissue. Furthermore, therapeutic impact of Glycosmis pentaphylla (G. pentaphylla) and Casimiroa edulis (C. edulis) leaves extracts in addition to mucilage and protein (the purified compounds from C. edulis) was investigated against AgNPs induced pulmonary toxicity. Male Swiss albino mice were administered AgNPs orally in two different particle sizes (20 nm and 100 nm) for one month and was further treated via G. pentaphylla, C. edulis, mucilage and protein in a dose of 500 mg/ kg for three weeks. Biochemical, molecular, immunohistochemistry, and histopathological investigations were further assessed. An obvious alteration in oxidative stress biomarkers as well as mRNA gene expression of both survivin and matrix metalloproteinase (MMP-9) was recorded in AgNPs intoxicated group. In addition to, exploration of positive nuclei for Ki-67 was also observed upon AgNPs intoxication. Data declared a significant improvement in the assessed parameters upon G. pentaphylla, C. edulis, mucilage and protein treatment. In conclusion; G. pentaphylla and C. edulis extracts could be considered as a promising candidate as therapeutic regimen against pulmonary toxicity induced via AgNPs due to their enrichment with different active constituents. Practical applications: Due to the expansion of AgNPs applications, it is urgent to investigate their toxic impact associated with release of free silver ions. Different particle sizes of AgNPs can induce various alterations in cellular biochemical parameters, mRNA gene expression, histopathological and immunohistopathological examination. Herein, this natural products extracts are used for the first time as promising therapeutic regimen to ameliorate the toxic effect in AgNPs intoxicated lung tissue in mice model as a result of the bioactive metabolites, especially flavonoids and polyphenolic compounds.