Kg-1 Day-1 Research Articles

Carnosine Remedial Effect on Fertility of Male Rats Receiving Cyclophosphamide, Hydroxydaunomycin, Oncovin and Prednisone (CHOP).

Chemotherapeutic agents can impair gonadal function triggering infertility. Here, we probed the properties of carnosine as an antioxidant in reproductive disorders caused by the combination of cyclophosphamide, hydroxydaunomycin (doxorubicin), oncovin (vincristine) and prednisone (CHOP); this combination is mostly used in treating non-Hodgkin lymphoma. Animals were distributed into four groups: Group I was the control. Group II received carnosine (250mgkgday-1 , i.p.); Group III received CHOP: cyclophosphamide (27mg/kg/cycle), doxorubicin (1.8mg/kg/cycle) and vincristine (0.05mg/kg /cycle) by i.p. plus oral prednisone (1.47mgkg-1 day-1 /cycle) for five days. Group IV received carnosine plus CHOP. The study involved 4 cycles each of 3weeks. Also, we explored the effect of combining carnosine with CHOP on the development of solid Ehrlich carcinoma in mice. CHOP lowered genitals weight, sperm count and motility, testicular function marker enzymes, serum testosterone level and gene expression of 3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase and steroidogenic acute regulatory protein. Furthermore, CHOP elevated testicular oxidative stress, serum follicle-stimulating hormone, luteinising hormone and triggered DNA damage. Morphometric and histopathological examinations of testicular tissues buttressed the biochemical results. Importantly, administration of carnosine ameliorated CHOP-induced alterations without diminishing CHOP's antineoplastic action. These results indicated that carnosine may ameliorate reproductive disorders induced by CHOP.

Protective effects of Lepidium draba L. leaves extract on testis histopathology, oxidative stress indicators, serum reproductive hormones and inflammatory signalling in oxymetholone-treated rat.

This study was aimed to investigate the protective effects of Lepidium draba L. (L.draba) extract on oxymetholone (OM)-induced testicular injury in rat. Six groups of n=5 adult male rats were used as; 1: control, 2: OM (5mg/kg OM orally), 3, 4 and 5: L.draba extract (100, 200 and 400mgkg-1 day-1 ) +OM (5mgkg-1 day-1 OM) and 6:400mg/kg/d L.draba extract for 30days. Serum testosterone (T), follicle-stimulating hormone (FSH) and luteinising hormone (LH), inflammatory cytokines (IL-6, IL-10, TNF-α, IL-1β), oxidative stress (OS) indicators [superoxide dismutase, catalase, glutathione peroxidase and nitric oxide (NO)], apoptotic related genes (Bcl-2, p53, caspase-3 (c3) and Bax) were investigated. OM significantly increased the serum levels of T, proinflammatory cytokines and pro-apoptotic genes expression. Also, it decreased LH and FSH, sperm viability, count and motility. L.draba extract especially could markedly normalise the serum levels of LH and FSH, and T, restore serum antioxidant enzymes and suppressed the pro-inflammatory cytokines. Also, germ cells apoptosis was inhibited against via downregulating the p53, c3, Bax and upregulating Bcl-2. It concluded that L.draba extract could protect the function and structure of testis against OM-induced testicular toxicity via its antioxidant and anti-inflammatory properties.

Lycopene ameliorates propionic acid-induced autism spectrum disorders by inhibiting inflammation and oxidative stress in rats.

This study was conducted to study lycopene efficacy in brain-behavior, pro-inflammatory and apoptotic markers, and antioxidant levels in a rodent model. Rats were administered with propionic acid (PPA) (500mg/kg BW) to induce autism-like disorders, then treated with different lycopene (L) concentrations (5, 10, 20mgkg-1 day-1 ) for 35days. The groups were: (i);control, (ii);PPA, (iii);PPA + L5, (iv);PPA + L10, and (v);PPA + L20. In this study, serum and brain malondialdehyde (MDA) levels decreased with lycopene supplements compared to the PPA group, similarly to the brain levels of inflammatory factors (IL-1α, IL-8, NF-κB, TNF-α; p<.05). Besides, brain levels of anti-apoptotic Bcl-2 decreased, whereas pro-apoptotic Bax, antioxidant Nrf2, and HO-1 levels in brain increased compared with PPA (p<.05). This study showed that lycopene might have therapeutic value to improve the dysfunctions in learning and memory in a dose-dependent way, along with the antioxidant, anti-inflammatory, and antiapoptotic molecular responses in a rat model of ASD-like disorders. PRACTICAL APPLICATIONS: This study suggested that lycopene can reduce propionic acid (PPA)-induced learning and memory impairment and oxidative damage by participating in multiple biological activities such as antioxidant, and anti-inflammatory effects. Lycopene protects serum and brain tissues against PPA induced oxidative damage in rats. These effects may be realized through up-regulation of the brain Nrf2/HO-1 pathway and down-regulation of the IL-1α, IL-8, TNF-α, and NF-κB levels. Lycopene may also contribute to memory and learning function, apoptotic/antiapoptotic modulation, and antioxidant and possible therapeutic efficacy in PPA-induced- Autism spectrum disorder cases.

Assessment of sexual behavior and neuromodulation of Cyperus esculentus L. and Tetracarpidium conophorum Müll. Arg dietary supplementation regulating the purinergic system in the cerebral cortex of L-NAME-challenged rats.

This study examined the behavioral responses, purinergic receptor densities, ectonucleotidases (E-NTPDase), adenosine deaminase (ADA) activity, and nitric oxide (NO) levels along with the parameters of oxidative stress-related to erectile function in the cerebral cortex (CC) of L-NAME-challenged rats pretreated with tigernut (TN) and walnut (WN) dietary supplementation. Wistar rats (male) of 70 total animals (250-300g) were used in this research and hence separated into seven groups (n=10): Group I: normal control-fed basal diet; Group II: positive control-fed basal diet/L-NAME/Sildenafil citrate (5mgkg-1 day-1 ); Group III: ED-induced (placed on a basal diet/L-NAME); Group IV: diet supplemented with processed TN (20%)/L-NAME; Group V: diet supplemented with raw TN (20%)/L-NAME; Group VI: diet supplemented with processed WN (20%)/L-NAME; and Group VII placed on a diet supplemented with raw WN (20%)/L-NAME. The rats were pretreated for 2weeks before the L-NAME (40mgkg-1 day-1 ) challenge on their respective diet. L-NAME brought about a decrease in the sexual behaviors evaluated while the effect was significantly reversed by supplemented diets containing TN and WN. L-NAME increased the levels of reactive oxygen species and malondialdehyde, E-NTPDase as well as ADA activities, and caused the level of NO in the CC as well as the purinoreceptor densities to be downregulated. Treatments with enriched diets, however, greatly reverse these effects. The behavioral responses and neuromodulatory capacity of the nuts displayed on the CC can, therefore, further support their aphrodisiac property. PRACTICAL APPLICATIONS: The results revealed the ability of tigernut (TN; Cyperus esculentus L.) and walnut (WN; Tetracarpidium conophorum Müll. Arg.) to enhance behavioral responses; modulate purinergic receptor densities, E-NTPDase, and ADA activities; increase NO levels; and prevent oxidative stress related to erectile function in the CC of L-NAME-challenged Wistar rats. The results show that these nuts are useful feeds for both animal and human nutrition.

Erianin inhibits human lung cancer cell growth via PI3K/Akt/mTOR pathway in vitro and in vivo.

Erianin is a small-molecule compound that is isolated from Dendrobium chrysotoxum Lindl. In recent years, it has been found to have evident antitumor activity in various cancers, such as bladder cancer, cervical cancer, and nasopharyngeal carcinoma. In this study, we assessed the effect of erianin on lung cancer in terms of cell growth inhibition and the related mechanism. First, erianin at a concentration of less than 1 nmol/L exhibited cytotoxicity in H1975, A549, LLC lung cancer cells, did not cause marked growth inhibition in normal lung and kidney cells, induced obvious apoptosis and G2/M phase arrest of cells, and inhibited the migration and invasion of lung cancer cells in vitro. Second, in a mouse xenograft model of lewis lung cancer (LLC), oral administration of erianin (50, 35, and 10 mg kg-1 day-1 for 12 days) substantially inhibited nodule growth, reduced the fluorescence counts of lewis cells and the percentage vascularity of tumor tissues, increased the number of apoptotic tumor cells, the thymus indices, up-regulated the levels of interleukin (IL)-2 and tumor necrosis factor-α (TNF-α), decreased IL-10 levels and the spleen index, and enhanced immune function. Lastly, the possible targets of erianin were determined by molecular docking and verified via western blot assay. The results indicated that erianin may achieve the above effects via inhibiting the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in vitro and vivo. Taken together, the results showed that erianin had obvious antitumor effects via inhibiting the PI3K/Akt/mTOR pathway in vitro and vivo and may have potential clinical value for the treatment of lung cancer.

Analysis and health risk assessment of phthalate esters (PAEs) in indoor dust of preschool and elementary school centers in city of Tehran, Iran.

Individuals spend a lot of time indoors; thus they are generally exposed to phthalates used in consumer products. Therefore, those exposed to phthalates as indoor contaminants are at high risks. The present study was conducted to evaluate the carcinogenic and non-carcinogenic hazard of phthalate esters (PAEs), like dimethyl phthalate, diethyl phthalate, di(nbutyl) phthalate, butyl benzyl phthalate, dioctyl phthalate, and di(2-ethylhexyl) phthalate in the dust obtained from 21 schools in Tehran, in 2019. A total of 63 indoor dust specimens were obtained by a vacuum cleaner. After transferring dust samples to the laboratory, 100 mg of each sample was centrifuged and mixed with 20 ml acetone and kept through a night and ultrasonicated within 30 min. Eventually, PAEs' contents were measured via gas chromatography-mass spectrometry. Based on the findings, median concentrations of DMP, DEP, DnBP, BBP, DEHP, and DnOP were 0.90, 0.10, 6.0, 0.20, 118.30, and 4.10 mg kg-1 respectively. Moreover, the overall average daily exposure doses (ADD) of phthalate esters via dust ingestion, skin contact, and inhalation were 1.56E-03, 1.70E-06, and 1.56E-07 mg kg-1 day-1, respectively, and the lifetime average daily exposure doses (LADD) were 1.83E-04, 2.34E-08, and 2.46E-08 mg kg-1 day-1, respectively; thus ingestion of dust particles was found to be the main pathway of exposure to phthalate for non-carcinogenic and carcinogenic risks. Although based on the results, the studied samples were below the US Environmental Protection Agency threshold of 1.00E-06, due to the disadvantages of phthalates in human safety, these kinds of investigations are helpful in understanding the main ways of exposure to PAEs and providing a science-based framework for the future attempts for mitigating the PAEs indoor emissions.

Maternal Garlic Oil Supplementation Prevents High-Fat Diet-Induced Hypertension in Adult Rat Offspring: Implications of H2S-Generating Pathway in the Gut and Kidneys.

Perinatal high-fat (HF) diet induces hypertension in adult offspring. Garlic, a naturally dietary source of Hydrogen sulfide (H2 S) donor, has been shown benefits in hypertension. The article examines whether maternal garlic oil supplementation can prevent hypertension induced by HF diet and elucidate its protective effects. Pregnant rats are given either a normal diet or HF diet. Rat dams are given garlic oil or vehicle daily by oral gavage at 100mg kg-1 day-1 during pregnancy and lactation. Male offspring are sacrificed at 16 weeks of age. Garlic oil supplementation during pregnancy and lactation protected against hypertension induced by HF diet in adult male offspring. The beneficial effects of garlic oil are associated with increased renal mRNA expression and activity of H2 S-generating enzymes, increased NO bioavailability, increased plasma short chain fatty acid levels, and alterations of gut microbiota composition. Garlic oil supplementation increases abundance of genus Lactobacillus, but decreases genera Turicibacter and Staphylococcus. The data reveals associations between H2 S-generating pathway in the gut and kidneys, NO system, gut microbiota, and microbiota-derived metabolites in hypertension induced by HF intake and provide insight to garlic oil as a hypertension reprogramming strategy for further translational research.

Low‐dose lithium supplementation augments mitochondrial biogenesis in murine skeletal muscle after high fat feeding

Promotion of oxidative metabolism in skeletal muscle improves muscle performance, fatigue resistance, and may help combat the obesogenic effects of a high fat diet. Lithium is a well-known glycogen synthase kinase (GSK3) inhibitor and we have recently shown that low-dose lithium supplementation (10 mg kg-1 day-1) augments skeletal muscle oxidative capacity in mice. In the soleus muscle, lithium mediated GSK3 inhibition increased the expression of oxidative markers such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) and myosin heavy chain I (MHCI) leading to improvements in muscle contractility and fatigue resistance. Interestingly, this same dose of lithium (10 mg kg-1 day-1) has been previously shown to attenuate high fat diet induced weight gain and metabolic efficiency (weight gained per calories consumed). However, the impact of lithium supplementation on muscle oxidative phenotype after high fat feeding has yet to be investigated. In this study, 36 wild-type male C57BL/6J mice were randomly assigned to low-fat standard chow diet (LFD, 4% kcal fat), high-fat diet (HFD, 60% kcal fat), or HFD with lithium chloride (HFD + Li; 10 mg kg-1 day-1) treatment groups for 12 weeks. Soleus muscles were collected at the end for Western blot analysis of total and phosphorylated GSK3 (inhibitory sites serine9 for GSK3b and serine21 for GSK3a), PGC-1a, cytochrome c oxidase subunit IV (COXIV), and MHCI protein content. Our results showed that the level of phosphorylated GSK3a and GSK3b (relative to total GSK3) were significantly lower after the HFD (-41 and -44%, respectively, p < 0.05), but in the HFD + Li group levels were similar to the LFD group. Therefore, the HFD enhanced soleus muscle GSK3 activation, and lithium supplementation was able to reduce this effect. No significant changes in MHCI content were observed. When examining PGC-1a, we found that the HFD + Li group had protein levels that were nearly 2-fold higher vs LFD, albeit only trending towards significance (p = 0.06). Further, COXIV content progressively increased from LFD, to HFD, and to HFD + Li (linear trend, r2=0.26, p = 0.002) with both HFD and HFD + Li groups having significantly higher COXIV content when compared to LFD. Altogether, our data shows that GSK3 inhibition via low dose lithium supplementation can augment mitochondrial biogenesis in the presence of a HFD. Future studies will further examine whether GSK3 inhibition via lithium can augment muscle oxidative metabolism after high fat feeding.

Losartan improved hippocampal long-term potentiation impairment induced by repeated LPS injection in rats.

Cognitive impairment has been known as a common consequence of brain inflammation. Long‐term potentiation (LTP), the generally accepted cellular mechanism for memory formation in the mammalian brain, has been shown to be suppressed by inflammation. Studies have shown that angiotensin II (Ang II) through the Ang II type 1 receptor (AT1R) has a role in brain and peripheral immune system communication and brain inflammation. Here, the effect of AT1R blockade on hippocampal LTP in rats undergoing repeated lipopolysaccharide (LPS) injection was investigated. Rats received intraperitoneal (ip) injections of LPS (250 μg kg−1 day−1) for seven days. Treatment with losartan (ip; 3 mg kg−1 day−1) was started 3 days before LPS injection and continued during the LPS injections. Rats were anesthetized, and field excitatory postsynaptic potential (fEPSP) was recorded from the stratum radiatum of the CA1 area of the hippocampus in response to stimulation of the Schaffer collateral pathway. Results showed that LTP was suppressed in the LPS‐injected rats as no significant differences were found in the fEPSP slope and amplitude before and after the LTP induction. AT1R blockade by losartan restored fEPSP to the control levels. These findings indicate that Ang II, through AT1R, has a role in LTP suppression induced by systemic inflammation.

Algal Oil Rich in Docosahexaenoic Acid Alleviates Intestinal Inflammation Induced by Antibiotics Associated with the Modulation of the Gut Microbiome and Metabolome.

In this study, the effect of algal oil rich in docosahexaenoic acid on the mucosal injury with gut microbiota disorders caused by ceftriaxone sodium (CS) was evaluated. The results showed that algal oil treatment (500 mg kg-1 day-1) significantly reduced the levels of pro-inflammatory cytokines, including interleukin 6 , interleukin 1β, and tumor necrosis factor α, in the colon. Algal oil restored the CS-induced gut microbiota dysbiosis by elevating some short-chain-fatty-acid-producing bacteria, e.g., Ruminococcus and Blautia. The CS-induced metabolic disorder was also regulated by algal oil, which was characterized by the modulations of tryptophan metabolism, phospholipid metabolism, and bile acid metabolism. Our results suggested that supplementation of algal oil could alleviate inflammation and promote mucosal healing, which could be a functional food ingredient to protect aganist antibiotic-induced alteration of gut microbiota and metabolic dysbiosis.

Cyclophosphamide suppresses spermatogenesis in the testis of mice through downregulation of miR-34b and miR-34c.

Cyclophosphamide (CP) is commonly used as an anticancer agent but has been associated with high toxicity in several organs, including the testes. In this study, we aimed to evaluate the effects of CP-induced testicular toxicity, using glial cell line-derived neurotrophic factor (GDNF), occludin and transforming growth factor beta 3 (TGF-β3) primary antibodies, and miR-34b and miR-34c expressions. Eighteen young Balb/c male mice were divided into three groups. The control group received no treatment. The mice of CP group were injected 100mgkg-1 day-1 CP for 5days, and the same amount of saline was injected in the sham group. The animals were sacrificed 24hr after the last injection. Immunohistochemical analysis of testicular tissues showed a decrease in both spermatogenic germ cell count and also GDNF, occludin expressions, but an increase in TGF-β3 expression in the CP group compared to the others group. The expressions of miR-34b and miR-34c were examined by qPCR technique, a significant decrease was observed in tissue samples in the CP-treated group. The expression of GDNF, occludin and TGF-β3 plays an important role in testicular injury caused by CP, and the decrease in the expression of miR-34b/c in tissue samples may be an important marker for the detection of testicular damage.

Total mercury and methylmercury in river dolphins (Cetacea: Iniidae: Inia spp.) in the Madeira River Basin, Western Amazon.

In the Amazon, mercury (Hg) contamination comes from ASGM operations along with soil remobilization processes associated with deforestation. The objective of this study was to evaluate the exposure to methylmercury (MeHg) and total mercury (THg) in 88 samples of skin and blubber tissue obtained from live captured river dolphins (Inia boliviensis, Inia geoffrensis, and Inia spp.) in the Madeira River Basin. THg and MeHg measurements were performed by CV-AAS and GC-AFS, respectively. We also calculated the daily intake rate (DIR) of THg (wet weight) by Inia spp. THg levels in blubber tissue of adult river dolphins (Inia spp.) ranged from 0.015 to 3.804 mg kg-1, while MeHg concentrations in blubber tissue varied from 0.04 to 2.65 mg kg-1 and in skin tissue from 0.09 to 0.66 mg kg-1. There were no significant differences in MeHg concentration in blubber (p = 0.616) and skin (p = 0.498) tissue samples between adult males and females in the different sampling locations. The adult animals showed differences in THg and MeHg concentrations significantly higher than in the calves. The estimate of the DIR of the genus Inia ranged from 1.17 to 12.35 μg kg-1 day-1 (bw), from the consumption of fish species with herbivorous to piscivorous habits, respectively. More biological and ecological data, such as the precise determination of age, mediated length, weight, and diet of river dolphins, are necessary to verify the Hg biomagnification. However, our data indicate that bioaccumulation is an active process in the dolphins of the Madeira River Basin.

Carnosine improves aging-induced cognitive impairment and brain regional neurodegeneration in relation to the neuropathological alterations in the secondary structure of amyloid beta (Aβ).

Aging-induced proteinopathies, including deterioration of amyloid beta (Aβ) conformation, are associated with reductions in endogenous levels of carnosine and cognitive impairments. Carnosine is a well-known endogenous antioxidant, which counteracts aging-induced Aβ plaque formation. The aim of this study was to investigate the effects of exogenous carnosine treatments on aging-induced changes (a) in the steady-state level of endogenous carnosine and conformation of Aβ secondary structure in the different brain regions (cerebral cortex, hippocampus, hypothalamus, pons-medulla, and cerebellum) and (b) cognitive function. Young (4months) and aged (18 and 24months) male albino Wistar rats were treated with carnosine (2.0μgkg-1 day-1 ; i.t.) or equivalent volumes of vehicle (saline) for 21 consecutive days and were tested for cognition using 8-arm radial maze test. Brains were processed to assess the conformational integrity of Aβ plaques using Raman spectroscopy and endogenous levels of carnosine were measured in the brain regions using HPLC. Results indicated that carnosine treatments improved the aging-induced deficits in cognitive function and reduced the β-sheets in the secondary structure of Aβ protein, as well as mitigating the reduction in the steady-state levels of carnosine and spine density in the brain regions examined. These results thus, suggest that carnosine can attenuate the aging-induced: (a) conformational changes in Aβ secondary structure by reducing the abundance of β-sheets and reductions in carnosine content in the brain regions and (b) cognitive impairment.

Thyroid hormones, Sertoli cell proliferation and differentiation in progenies from carbamazepine-treated rat dams during pregnancy and lactation.

Carbamazepine (CBZ) is used in the control of seizure and affective disorders, causing hypothyroidism. Thyroid hormones regulate the Sertoli cell proliferation and differentiation. Clinical aspects must be considered since epileptic fertile women need to continuously use CBZ during pregnancy and lactation. This study aimed to evaluate the effects of CBZ on testis development of rat offspring from dams treated during pregnancy/lactation. Rat dams received CBZ (20mgkg-1 day-1 ) or vehicle by intra-peritoneal route during gestation and lactation. Progenies were euthanised at 4, 14, 41, 63 and 93-days post-partum (dpp) for the evaluation of T3, T4 and TSH plasma total levels. Testicular cross sections were submitted to anti-Ki67, anti-PCNA, anti-p27kip1 and anti-transferrin immunolabelling for the evaluation of Sertoli cells. There was a significant reduction in p27kip1 -positive Sertoli cell numerical densities and an increase in TSH level at 14 dpp. CBZ exposure affected the volume density of transferrin-positive immunolabelling at 63 dpp. These results suggest that CBZ may cause a dysregulation of the controller system of thyroid hormones homeostasis leading to an increase in the proliferation rate at the neonatal phase and a differentiation delay of the Sertoli cell, culminating in an altered function at late puberty. The occurrence of hypothyroidism cannot be completely discarded.

Myricetin improves metabolic outcomes but not cognitive deficit associated to metabolic syndrome in male mice

Myricetin is a flavonol highly prevalent in edible vegetables and fruits, with recognized hypoglycemic and anti-obesity effects, besides great antioxidant capacity. Thus, this study sought to investigate whether myricetin is able to improve metabolic and behavioral outcomes found in monosodium l-glutamate (MSG) obese mice, a model of metabolic syndrome characterized by early hyperinsulinemia associated to obesity, dyslipidemia, hepatic steatosis, anxiety and cognitive deficit. Newborn male mice received MSG (4 mg kg-1 day-1, s.c.) on alternate days during the first 10 days of life for obesity induction, while control pups received equimolar saline solution. From postnatal day 90 to 135, MSG mice were orally treated with myricetin (50 mg kg-1 day-1) or distilled water, while control animals received vehicle. During the last week of treatment, all groups were submitted to behavioral tests: open field maze, elevated plus maze and Morris water maze. At the end of treatment, animals were euthanized for collection of liver, serum and adipose tissue fat pads. Myricetin treatment reduced the elevated serum levels of glucose and triglycerides, typically found in MSG mice, as well as restored peripheral insulin sensitivity and liver steatosis. Moreover, myricetin ameliorated the lack of thigmotaxis and exploratory behavior, but did not improve the cognitive deficit presented by MSG mice. Therefore, this study contributes to the pharmacological validation of myricetin as an affordable and healthy therapeutic adjuvant for the treatment of metabolic syndrome and most of its comorbidities.

Nox2 signaling and muscle fiber remodeling are attenuated by losartan administration during skeletal muscle unloading.

Reduced mechanical loading results in atrophy of skeletal muscle fibers. Increased reactive oxygen species (ROS) are causal in sarcolemmal dislocation of nNOS and FoxO3a activation. The Nox2 isoform of NADPH oxidase and mitochondria release ROS during disuse in skeletal muscle. Activation of the angiotensin II type 1 receptor (AT1R) can elicit Nox2 complex formation. The AT1R blocker losartan was used to test the hypothesis that AT1R activation drives Nox2 assembly, nNOS dislocation, FoxO3a activation, and thus alterations in morphology in the unloaded rat soleus. Male Fischer 344 rats were divided into four groups: ambulatory control (CON), ambulatory + losartan (40 mg kg−1 day−1) (CONL), 7 days of tail‐traction hindlimb unloading (HU), and HU + losartan (HUL). Losartan attenuated unloading‐induced loss of muscle fiber cross‐sectional area (CSA) and fiber‐type shift. Losartan mitigated unloading‐induced elevation of ROS levels and upregulation of Nox2. Furthermore, AT1R blockade abrogated nNOS dislocation away from the sarcolemma and elevation of nuclear FoxO3a. We conclude that AT1R blockade attenuates disuse remodeling by inhibiting Nox2, thereby lessening nNOS dislocation and activation of FoxO3a.

The Oral Delivery of Water-Soluble Phenol TS-13 Ameliorates Granuloma Formation in an In Vivo Model of Tuberculous Granulomatous Inflammation.

The redox-sensitive signaling system Keap1/Nrf2/ARE is a premier protective mechanism against oxidative stress that plays a key role in the pathogenesis and development of various diseases, including tuberculous granulomatous inflammation. We have previously reported that novel water-soluble phenolic antioxidant TS-13 (sodium 3-(4′-methoxyphenyl)propyl thiosulfonate) induces Keap1/Nrf2/ARE and attenuates inflammation. The aim of this study is the examination of the effect of TS-13 on tuberculous granulomatous inflammation. BALB/c mice were administered TS-13 (100 mg kg−1 day−1) through their drinking water starting immediately after Bacillus Calmette-Guérin (BCG) intravenous injection. Histological changes, production of reactive oxygen species (ROS) (activity of free-radical oxidation processes), and mRNA expression of Nrf2-driven, NF-κB-, AP-1-, and autophagy-dependent signal pathway genes in the liver and peritoneal exudate were evaluated 30 days later. After the 30th day of infection, the activity of the Keap1/Nrf2/ARE system was decreased and its effector genes entailed increasing ROS production in the liver. Therapeutic intervention with TS-13 is aimed at activating the Keap1/Nrf2/ARE system that leads to an increase in Nrf2 and Nrf2-mediated gene expression and a decrease in NF-κB expression. Changes in these pathways resulted in a decline of ROS production and a decrease in the number and the size of granulomas. In total, the results indicate that the Keap1/Nrf2/ARE system can be an effective pharmacological target in host-adjunctive treatment of tuberculosis.

Modulation of Liver P-Glycoprotien Expression May Contribute to Gossypin Protection against Methotrexate-Induced Hepatotoxicity.

OBJECTIVES:Methotrexate (MTX) is a broadly used anticancer. Its major side effect is hepatotoxicity. Gossypin is a flavonoid has a hepatoprotective effect as well as antitumor property. The study aimed at inspecting the protective effect of gossypin against MTX hepatotoxicity.MATERIALS AND METHODS:Twenty-four adult male rats arranged into four groups (six rats each): control, gossypin control, MTX, and MTX+ gossypin. Animals were orally administered gossypin at 10 mg kg-1 day-1 for 7 days. MTX was injected i.p. (20 mg/kg-1 once) on 5th day. Liver enzyme and oxidative stress markers were assessed. BAX, transforming growth factor-beta (TGF-β) gene expressions, and P-glycoprotein (P-gp) were assessed. The histopathological study as well as the immunohistochemical study for hepatic caspase 3 and nuclear factor kappa-B (NFκ-B) was done.RESULTS:MTX produced a significant increase of liver enzymes and distortion of hepatic architecture alongside with increased the hepatic collagen content. MTX administration significantly increased the oxidative stress markers and upregulated the pro-apoptotic BAX and the pro-fibrogenic TGF-β. MTX increased caspase 3 and NFκ-B expression, while diminished the expression of P-gp. Gossypin pretreatment improved the previous parameters, restored the normal hepatic architecture, reduced the hepatic fibrosis, and regained nearly normal expressions for BAX, TGF-β, caspase 3, and NFκ-B. Gossypin caused more reduction in P-gp hepatic expression.CONCLUSIONS:Gossypin may be a valuable adjuvant therapy that protects the liver against MTX toxicity through antioxidant, anti-inflammatory, antiapoptotic mechanisms, and mediated P-gp expression reduction.

Efficacy of halofuginone products to prevent or treat cryptosporidiosis in bovine calves: a systematic review and meta-analyses.

A prior systematic review on the efficacy of halofuginone (HFG) treatment to prevent or treat cryptosporidiosis in bovine calves was inconclusive. We undertook an updated synthesis and meta-analyses on key outcomes for the treatment of calves with HFG. Evaluated outcomes were oocyst shedding, diarrhoea, mortality and weight gain. Experiments had to describe results for same age animals in contemporary arms. Most doses were 100-150 mcg kg-1 day-1. Results were subgrouped by study design, experiments with the lowest risk of bias and lack of industry funding. Eighteen articles were found that described 25 experiments. Most evidence came from randomized controlled trials in Europe. Significantly lower incidence of oocyst shedding, diarrhoea burden and mortality was reported when treatment started before calves were 5 days old. Most studies reported on outcomes for animals up to at least 28 days old. Publication bias was possible in all outcomes and seemed especially likely for diarrhoea outcomes. Beneficial results when HFG treatment was initiated in calves older than 5 days were also found. Prophylactic treatment to prevent cryptosporidiosis is effective in preventing multiple negative outcomes and is beneficial to calf health and will result in a reduction of environmental contamination by Cryptosporidium oocysts.

Cratoxylum formosum dyer extract alleviates testicular damage in hypertensive rats.

The effects of a Cratoxylum formosum (Jack) Dyer ssp. (CF) extract on testicular damage were assessed in hypertensive rats. Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME; 40mgkg-1 day-1 ) was administered for 5weeks to induce hypertension in male Sprague-Dawley rats, and treated with CF extract (100, 300 or 500mgkg-1 day-1 ) or sildenafil (5mgkg-1 day-1 ) during the final 2weeks (n=8/group). Biochemical components of the CF extract were identified and mainly contained phenolic compounds. The CF extract significantly reduced systolic blood pressure and alleviated impaired sperm quality and seminiferous tubular morphology in hypertensive rats. CF extract restored reduced serum testosterone and protein expression of steroidogenic acute regulatory protein (StAR), nuclear factor erythroid-related factor 2 (Nrf2), and haem oxygenase 1 (HO-1) in L-NAME rats. Hypertensive rats presented decreased antioxidant enzyme activities, and increased testicular and plasma malondialdehyde (MDA) levels and superoxide production, all of which were normalised by CF extract. Furthermore, endothelial nitric oxide synthase (eNOS) expression in testicular tissue and plasma nitrate/nitrite levels were restored in hypertensive rats administered CF extract. Conclusion: CF extract alleviated testicular damage in hypertensive rats. Potential molecular mechanisms may involve suppression of oxidative stress and restoration of StAR, Nrf2, HO-1 and eNOS expression in hypertensive rats.