Novel insights on the probable mechanism associated with histamine oral model-inducing neuropathological and behavioral toxicity in rats.

Histamine (HIS) is an important chemical mediator that causes vasodilation and contributes to anaphylactic reactions. Recently, HIS is an understudied neurotransmitter in the central nervous system, and its potential role in neuroinflammation and neurodegeneration is a critical area of research. So, the study's goal is to investigate the consequences of repeated oral intake of HIS on the rat's brain and explore the mechanistic way of its neurotoxicity. Thirty male rats were divided into three groups (n = 10). The following treatments were administered orally to all rats every day for 14 days. Group (1) was given distilled water, whereas groups (2 & 3) were given HIS at dosage levels 250 and 500 mg/kg body weight (BWT), respectively. Brain tissue samples were collected at 7- and 14-days from the beginning of the experiment. Our results revealed that continuous oral administration of HIS at both doses for 14 days significantly reduced the BWT and induced severe neurobehavioral changes, including depression, dullness, lethargy, tremors, abnormal walking, and loss of spatial learning and memory in rats. In all HIS receiving groups, HPLC data showed a considerable raise in the HIS contents of the brain. Additionally, the daily consumption of HIS causes oxidative stress that is dose- and time-dependent which is characterized by elevation of malondialdehyde levels along with reduction of catalase activity and reduced glutathione levels. The neuropathological lesions were commonly observed in the cerebrum, striatum, and cerebellum and confirmed by the immunohistochemistry staining that demonstrating moderate to strong caspase-3 and inducible nitric oxide synthase expressions in all HIS receiving groups, mainly those receiving 500 mg/kg HIS. NF-κB, TNF-α, and IL-1ß gene levels were also upregulated at 7- and 14-days in all HIS groups, particularly in those getting 500 mg/kg. We concluded that ROS-induced apoptosis and inflammation was the essential mechanism involved in HIS-mediated neurobehavioral toxicity and histopathology.

The potential mechanism underlying the hepatorenal toxicity induced by hymexazol in rats and the role of NF-κB signaling pathway.

Hymexazol (HML) is widely used in agriculture as a systemic fungicide and plant growth promoter. Humans are continuously exposed to HML via various routes. The liver and kidneys are essential organs for the detoxification, metabolism, and excretion of HML. However, data concerning the impact of HML on nontarget organisms are scarce. The present study aimed to determine the mechanism of dose-dependent hepatorenal toxicity of HML in rats. Twenty-one rats were divided into three equal groups that received the following treatments via oral intake daily for 14 days: group 1, normal saline; group 2, low dose of HML (1/80 LD50 ); group 3, high dose of HML (1/40 LD50 ). We weighed the rats at the beginning and the end of the experiment to record the weight gain in each group. The results showed that HML induced dose-dependent hepatorenal toxicity manifested by a significant increase in malondialdehyde levels, a decrease in total antioxidant capacity and reduced glutathione contents, and upregulation of the transcriptase levels of the nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1ß) genes. The HML-exposed groups displayed various histopathological changes in both organs, with significant elevation of all serum liver and kidney biomarkers. In conclusion, HML produced hepatorenal toxicity in rats through oxidative stress that mediates the NF-κB signaling pathway in response to pro-inflammatory cytokines such as TNF-α and IL-1ß. We advise limiting the use of HML in agricultural and veterinary practices and finding an alternative agent to avoid the human and animal health risks induced by HML exposure.

Chitosan coating silver nanoparticles as a promising feed additive in broilers chicken.

The present study aimed to evaluate the potential of chitosan coating silver nanoparticles to enhance the growth performance and immune status of broilers without inducing oxidative stress-related pathological lesions in any organs or leaving residues of silver in the edible parts. Five clusters of Cobb one-day-old chicks (n = 10/group in each replication) were given oral therapy, once a week for 36 days as follows: (1) distilled water, (2, 3) 0.5- and 5 ppm silver nanoparticles (AgNPs), respectively, (4, 5) 0.5- and 5 ppm chitosan/silver nanoconjugates (CS/Ag-NCs), respectively. The results demonstrated a marked elevation in the body weight gain with a decline in the food conversion ratio and marked improvement in feeding and drinking behavior of all nanoparticles treated groups, but higher in CS/Ag-NCs groups than AgNPs groups and control group. In contrast to the 0.5 ppm AgNPs receiving group, the group receiving 5 ppm AgNPs noticed remarkable histological changes in some organs, including the liver, kidneys, spleen, and heart. Moreover, the administration of CS/Ag-NCs at two dosage levels didn't influence any histological changes. The AgNPs groups' antibody titers against the ND and AI viruses were almost identical to those of the control group. Otherwise, CS/Ag-NCs groups recorded the highest antibody titers. Additionally, there was a significant increase in silver content in most edible organs of AgNPs groups at a dosage level of 5 ppm. Otherwise, the coating of AgNPs by CSNPs could decrease the aggregation of silver in the biological organs. Thus, we recommend utilizing 0.5 ppm CS/Ag-NCs in broiler farms to promote their growth performance and strengthen their immune defense.

A Comprehensive Study on the Mechanistic Way of Hexaflumuron and Hymexazol Induced Neurobehavioral Toxicity in Rats.

Pesticides are widely used in agriculture to kill pests, but their action is non-selective and results in several hazardous effects on humans and animals. Pesticide toxicity has been demonstrated to alter a variety of neurological functions and predisposes to various neurodegenerative diseases. Although, there is no data available for hexaflumuron (HFM) and hymexazol (HML) neurotoxicity. Hence, the present study aims to investigate the possible mechanisms of HFM and HML neurotoxicity. 21 male Wistar rats were divided into three groups and daily received the treatment via oral gavage for 14 days as follows: group (1) normal saline, group (2) HFM (1/100LD50), and group (3) HML (1/100 LD50). Our results revealed that both HFM and HML produced a significant increase in MDA levels and a decrease in GSH and CAT activity in some brain areas. There were severe histopathological alterations mainly neuronal necrosis and gliosis in different examined areas. Upregulation of mRNA levels of JNK and Bax with downregulation of Bcl-2 was also recorded in both pesticides exposed groups. In all studied toxicological parameters, HML produced neurotoxicity more than HFM. HFM targets the cerebral cortex and striatum, while HML targets the cerebral cortex, striatum, hippocampus, and cerebellum. We can conclude that both HFM and HML provoke neurobehavioral toxicity through oxidative stress that impairs the mitochondrial function and activates the JNK-dependent apoptosis pathway.

Neurobehavioral Toxicity Induced by Carbendazim in Rats and the Role of iNOS, Cox-2, and NF-κB Signalling Pathway.

Carbendazim (CBZ) is one of the most common fungicides used to fight plant fungal diseases, otherwise, it leaves residue on fruits, vegetables, and soil that contaminate the environment, water, animal, and human causing serious health problems. Several studies have reported the reproductive and endocrine pathological disorders induced by CBZ in several animal models, but little is known about its neurotoxicity. So that, the present study aimed to explain the possible mechanisms of CBZ induced neurotoxicity in rats. Sixty male Wistar rats were divided into 4 groups (n = 15). Group (1) received normal saline and was kept as the negative control group, whereas groups (2, 3, 4) received CBZ at 100, 300, 600 mg/kg b.wt respectively. All rats received the aforementioned materials daily via oral gavage. Brain tissue samples were collected at 7, 14, 28 days from the beginning of the experiment. CBZ induced oxidative stress damage manifested by increasing MDA levels and reducing the levels of TAC, GSH, CAT in some brain areas at 14 and 28 days. There were extensive neuropathological alterations in the cerebrum, hippocampus, and cerebellum with strong caspase-3, iNOS, Cox-2 protein expressions mainly in rats receiving 600 mg/kg CBZ at each time point. Moreover, upregulation of mRNA levels of NF-κB, TNF-α, IL-1B genes and downregulation of the transcript levels of both AchE and MAO genes were recorded in all CBZ receiving groups at 14 and 28 days especially those receiving 600 mg/kg CBZ. Our results concluded that CBZ induced dose- and time-dependent neurotoxicity via disturbance of oxidant/antioxidant balance and activation of NF-κB signaling pathway. We recommend reducing the uses of CBZ in agricultural and veterinary fields or finding other novel formulations to reduce its toxicity on non-target organisms and enhance its efficacy on the target organisms.

Novel insights into the potential mechanisms underlying carbendazim-induced hepatorenal toxicity in rats.

Carbendazim (CBZ) is a common environmental pollutant that can contaminate food and water and severely damage human health. Some studies revealed the adverse effect of CBZ on different organs, but its detailed toxicity mechanism has not been elucidated yet. Thus, the present study aims to clarify the mechanisms of CBZ-induced hepatorenal toxicity in rats. Therefore, we partitioned 40 male Wistar rats into four groups (n = 10): a negative control group and three treatment groups, which received 100, 300, and 600 mg/kg of CBZ. All rats received the treatment daily by oral gavage. We collected blood and organ samples (liver and kidney) at 14 and 28 days postdosing. CBZ caused extensive pathological alterations in both the liver and kidneys, such as cellular degeneration and necrosis accompanied by severe inflammatory reactions in a dose- and time-dependent manner. All the CBZ-treated groups displayed strong tumor necrosis factor-α and nuclear factor-κB (NF-κB) immunopositivity. Additionally, CBZ dose-dependently elevated the alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, urea, and creatinine serum levels and reduced the serum albumin levels. Furthermore, CBZ-induced apoptosis, as indicated by the observed Bax gene upregulation and Bcl-2 gene downregulation in both organs. All these changes may be related to oxidative stress, as indicated by the increase in malondialdehyde levels and the decrease in total antioxidant capacity. Our results demonstrate that CBZ-induced dose- and time-dependent hepatorenal damage through oxidative stress, which activated both the NF-κB signaling pathway and Bcl-based programmed cell death.

Origanum majorana essential oil improves the rat's sexual behavior and testicular oxidative damage induced by imidacloprid via modulating the steroidogenesis pathways.

The neonicotinoid insecticide imidacloprid has been linked to significant reproductive damage in mammals. Origanum majorana essential oil (OME) is a natural herbal product used in the management of many diseases due to its strong antioxidant effects. The oil was hydrodistilled from O. Majorana and analyzed using GC/MS then its possible protective mechanisms against IMI-induced reprotoxicity in male rats were investigated. 28-adult male Wistar rats were divided into 4 groups as follows: group (1) control group, group (2) OME, group (3) IMI, and group (4) IMI + OME. The treatments were applied daily via oral gavage for 60 days. Remarkable abnormalities in both territorial aggressive and sexual behaviors were observed in IMI-treated rats with a significant elevation of serum FSH and LH as well as altered testicular redox status. Along with inhibition of the testicular expression of StAR and aromatase genes and serum total testosterone in addition to abnormal sperm count, viability, motility, and morphology. Histopathological examination showed severe degeneration and necrosis in both germ cells and Leydig cells with atrophy in most of the seminiferous tubules. Co-administration of OME with IMI notably improved all the above-mentioned studied parameters, and restored rats' spermatogenesis, sexual behavior, and favorably modulates the levels of both testosterone and gonadotropic hormones via its potent antioxidant effect. These findings support the use of OME as a fertility enhancer and suggest that it could be used to manage pesticide-induced male infertility.

Neuropathological and Cognitive Effects Induced by CuO-NPs in Rats and Trials for Prevention Using Pomegranate Juice.

Copper oxide nanoparticles (CuO-NPs) are extensively utilized in several industries and in pharmaceutical production. This excess exposure elevates the concern about its expected poisonous impacts on humans and animals. Pomegranate juice (PJ) is a natural source of polyphenols and exhibits potent antioxidant activities. Our experiment intended to explore the neurobehavioral and toxicopathological impacts of CuO-NPs and to explain the mechanistic role of PJ to reduce their toxicity. Thirty Wistar albino rats received the subsequent materials through oral gavage, every day for 28d: (1) normal saline, (2) 3 mL/kg bwt PJ, (3) 6 mL/kg bwt PJ, (4) 300 mg/kg bwt CuO-NPs, (5) CuO-NPs + 3 mL/kg bwt PJ, (6) CuO-NPs + 6 mL/kg bwt PJ. Continuous exposure to CuO-NPs caused a significant elevation of MDA levels and reduction of total antioxidant capacity associated with remarkable pathological alterations in all brain regions including cerebrum, hippocampus and cerebellum. Progressive decline of memory along with cognitive and psychiatric disturbances were observed in rats exposed to CuO-NPs not in PJ co-treated rats. Continuous exposure to CuO-NPs caused over expression of the immunohistochemical markers of caspase-3, iNOS and GFAP altogether with DAN fragmentation and down-regulation of HO-1 and Nrf2 gene in the whole brain tissues. Conversely, rats co-treated with PJ showed dose dependent improvements in the entire toxicological, behavioral, and pathological parameters. We showed that PJ had the ability to reduce the oxidative stress damage via up-regulation of HO-1 and Nrf2 genes in the brain. So that PJ had the ability to protect the brain and DNA from further damage.

Cisplatin-conjugated gold nanoparticles-based drug delivery system for targeting hepatic tumors.

Cisplatin is a highly cytotoxic anticarcinogenic drug used to treat several kinds of solid tumors such as liver tumors. With the increase in the incidences associated with hepatic tumors and a lack of selectivity of cisplatin to cancer cells, it is important to explore new therapeutic strategies against them. The present study was designed to verify the ability of gold nanoparticles (GNPs) to improve the hepatotherapeutic effect of cisplatin against DENA-induced hepatic tumors and to declare its ability to reduce the renal toxicity induced by cisplatin. Forty male Wistar rats were divided into two groups (n = 20): Group (A)-negative control and group (B)-model of hepatocellular tumor induction. After 4 months, each group was subdivided into four subgroups as the following: Group (1) received normal saline, Group (2) was treated by cisplatin, Group (3) was treated by GNPs, Group (4) was treated by GNPs-cisplatin conjugates. Our results revealed a marked elevation in liver and kidney function tests and oxidant levels with a reduction in antioxidant levels in the DENA-administrated group. Remarkable histopathological alterations in the liver and kidney tissue sections were observed and confirmed by the overexpression of the immunohistochemical staining of placental glutathione S-transferase, Hep Par 1, and proliferating cell nuclear antigen. Noticeable improvements in all the measurable toxicological parameters were recorded in the group treated with either GNPs or GNPs-cisplatin conjugate not observed in the group treated with cisplatin. We can conclude that GNPs not only improve the distribution of cisplatin, targeting it to the site of tumors, but it also reduces the renal toxicity induced by cisplatin, which are the primary concerns in cancer therapy.

The ameliorative effect of N-acetylcysteine against penconazole induced neurodegenerative and neuroinflammatory disorders in rats.

Penconazole (PEN) is a widely used systemic fungicide to treat various fungal diseases in plants but it leaves residues in crops and food products causing serious environmental and health problems. N-acetylcysteine (NAC) is a precursor of the antioxidant glutathione in the body and exerts prominent antioxidant and anti-inflammatory effects. The present study aimed to explore the mechanistic way of NAC to ameliorate the PEN neurotoxicity in male rats. Twenty-eight male rats were randomly divided into four groups (n = 7) and given the treated material via oral gavage for 10 days as the following: Group I (distilled water), Group II (50 mg/kg body weight [bwt] PEN), Group III (200 mg/kg bwt NAC), and Group IV (NAC + PEN). After 10 days all rats were subjected to behavioral assessment and then euthanized to collect brain tissues to perform oxidative stress, molecular studies, and pathological examination. Our results revealed that PEN exhibits neurobehavioral toxicity manifested by alteration in the forced swim test, elevated plus maze test, and Y-maze test. There were marked elevations in malondialdehyde levels with reduction in total antioxidant capacity levels, upregulation of messenger RNA levels of bax, caspase 3, and caspase 9 genes with downregulation of bcl2 genes. In addition, brain sections showed marked histopathological alteration in the cerebrum and cerebellum with strong bax and inducible nitric oxide synthetase protein expression. On the contrary, cotreatment of rats with NAC had the ability to improve all the abovementioned neurotoxic parameters. The present study can conclude that NAC has a neuroprotective effect against PEN-induced neurotoxicity via its antioxidant, anti-inflammatory, and antiapoptotic effect. We recommend using NAC as a preventive and therapeutic agent for a wide variety of neurodegenerative and neuroinflammatory disorders.

Rosmarinic acid attenuates chromium-induced hepatic and renal oxidative damage and DNA damage in rats.

Hexavelant chromium (Cr (V1)) is a widely distributed environmental pollutant inducing damage in different organs of human and animals. The current study was designed to investigate the mechanistic role of rosmarinic acid (RA) to diminish chromium-induced hepatorenal oxidative damage and preneoplastic lesions in rats. Plant material was collected, identified, and extracted. The isolated RA was elucidated relying on the nuclear magnetic resonance spectroscopic data. Twenty-eight male Wistar rats received the following materials daily via oral gavage for 60 days; (Gp1): normal saline, (Gp2) 25 mg/kg.bwt RA, (Gp3) 10 mg/kg.bwt potassium dichromate (K2 Cr2 O7 ), (Gp4) K2 Cr2 O7 + RA. All rats were euthanized at the end of the experiment by cervical dislocation and the liver and kidney were collected. Prolonged continuous exposure of rats to chromium-induced oxidant/antioxidant imbalance manifested by significant elevation of malondialdehyde with reduction in reduced glutathione levels. Remarkable histopathological alterations in the liver and kidney tissue sections were recorded and confirmed by overexpression of the immunohistochemical staining of caspase-3, placental glutathione-S transferase, proliferating cell nuclear antigen together with a significant downregulation of nuclear factor erythroid-2 related factor 2 (Nrf2) gene and upregulation of nibrin gene. Observable improvements in the entire toxicopathological parameters were recorded in group cotreated with RA. Our findings revealed that Cr-induced preneoplastic lesions on the liver and kidney tissues of rats when exposed daily for long period of time, as well as confirmed the ability of RA to alleviate this toxicity through upregulation of Nrf2 pathway and its powerful antioxidant effects.

Histopathological, immunohistochemical, and molecular studies for determination of wound age and vitality in rats.

In forensic medicine, it is vital to verify with the best attainable accuracy once injuries occurred during vital or post-mortem conditions. An immunohistochemical study was carried out to examine the time-dependent expression of macrophage-specific gene CD68 (cluster of differentiation 68), alpha-smooth muscle actin (α-SMA), and vascular endothelial growth factor (VEGF) in different skin wound timings (0, 1, 3, 5, 7, and 14 days) in rats. Histopathological studies were performed to assess the wound age and vitality. Eighteen male albino Wister rats (weighing 170-200 g) were used for wound induction. Rats (n = 3) were euthanised at 0, 1, 3, 5, 7, and 14 days from the starting point of wound induction. Histopathological examination showed that the epidermal re-epithelialisation was completed 14 days after skin incision. The inflammatory phase was recorded during the first 3 days of healing and reached the maximum levels at 5 days, then declined after 7 days, and completely removed at 14 days. The beginning of the proliferative phase was dated to day 3 and the peak at days 5 and 7. The initiation of the granulation tissue formation and remodelling phase of the healing process was observed 5 days after wounding. By immunohistochemical staining, negative VEGF gene expressions at early stages (0-3 days) were observed, as well as neither CD68+ macrophages nor α-SMA+ myofibroblast cells were detected. By increasing the wound ages (5-7 days), granulation tissue and angiogenesis were observed, with the migration of macrophages and fibroblast, which expressed VEGF, CD68, and α-SMA positive reaction. Time-dependent expression of the above markers suggested that they would be useful indicators for the determination of wound age. Both VEGF and transforming growth factor-beta 1 (TGFb1) mRNA levels were determined in different skin wound ages. The transcription of TGFb1 and VEGF increased shortly after wounding, until post-wounding day 7. It then declined constantly, reaching minimal values on day 14.

Mechanistic Approach on the Pulmonary Oxido-Inflammatory Stress Induced by Cobalt Ferrite Nanoparticles in Rats.

Cobalt ferrite nanoparticles (CFN) are employed in data storage, imaging, medication administration, and catalysis due to their superparamagnetic characteristics. The widespread use of CFN led to significantly increased exposure to people and the environment to these nanoparticles. Until now, there is not any published paper describing the adverse effect of repeated oral intake of this nanoformulation on rats' lungs. So, the current research aims to elucidate the pulmonary toxicity prompted by different concentrations of CFN in rats as well as to explore the mechanistic way of such toxicity. We used 28 rats that were divided equally into 4 groups. The control group received normal saline, and the experimental groups received CFN at dosage levels 0.05, 0.5, and 5 mg/kg bwt. Our findings revealed that CFN enhanced dose-dependent oxidative stress manifested by raising in the MDA levels and declining in the GSH content. The histopathological examination revealed interstitial pulmonary inflammation along with bronchial and alveolar damage in both 0.5 and 5 mg CFN given groups. All these lesions were confirmed by the immunohistochemical staining that demonstrated strong iNOS and Cox-2 protein expression. There was also a significant upregulation of TNFα, Cox-2, and IL-1ß genes with downregulation of IL-10 and TGF-ß genes. Additionally, the group receiving 0.05 mg CFN did not exhibit any considerable toxicity in all measurable parameters. We concluded that the daily oral intake of either 0.5 or 5 mg CFN, but not 0.05 mg, could induce pulmonary toxicity via NPs and/or its leached components (cobalt and iron)-mediated oxido-inflammatory stress. Our findings may help to clarify the mechanisms of pulmonary toxicity generated by these nanoparticles through outlining the standards for risk assessment in rats as a human model.

Acetamiprid Induces Cardiotoxicity in Rats by Dysregulating α7 nAChR and its Downstream Targets: the Ameliorative Role of Resveratrol.

Acetamiprid (ACP) is a novel neonicotinoid insecticide used for controlling insect pests. Resveratrol (RSV) is a natural polyphenol that possesses anti-oxidant, anti-inflammatory and anti-apoptotic actions. The current research explores the mechanism of ACP-induced cardiotoxicity and the alleviative effects of RSV. Male rats were allocated to four groups of ten each. Rats were treated daily for 90 days via oral route. Control rats received distilled water, ACP rats received 25 mg acetamiprid/kg, RSV rats received 20 mg resveratrol/kg and ACP + RSV rats received both ACP and RSV. ACP exposure increased serum creatine phosphokinase activity and cardiac troponin level. It also induced oxidative stress, as evidenced by the glutathione reduction, and malondialdehyde elevation, as well as the detrimental histopathological and immunohistochemical changes in the myocardium. Gene expression analysis revealed down-regulation in the mRNA expression of the survival-related genes α7 nAChR, Erk and Bcl-2, and up-regulation in the apoptosis-related genes Jnk, Bax and Caspase-3. Conversely, the concomitant administration of ACP with RSV alleviated most of the aforementioned toxic impacts. It can be concluded that ACP induces cardiotoxicity by dysregulating the mRNA expression of α7 nAChR and its downstream targets. Additionally, RSV is proved to be a promising ameliorative agent against ACP-induced cardiotoxicity.

Silver and gold nanoparticles as a novel approach to fight Sarcoptic mange in rabbits.

Various kinds of pets have been known to contract the ectoparasite Sarcoptes scabiei. Current acaricides are becoming less effective because of the resistance developed by the mite besides their adverse effects on the general activity and reproductive performance of domestic pets. For this reason, the present study aims to discover a novel and safe approach using silver and gold nanoparticles to fight Sarcoptic mange in rabbits as well as to explain their mechanism of action. 15 pet rabbits with clinical signs of Sarcoptic mange that were confirmed by the microscopic examination were used in our study. All rabbits used in this study were assessed positive for the presence of different developing stages of S. scabiei. Three groups of rabbits (n = 5) were used as follows: group (1) didn't receive any treatment, and group (2 and 3) was treated with either AgNPs or GNPs, respectively. Both nanoparticles were applied daily on the affected skin areas via a dressing and injected subcutaneously once a week for 2 weeks at a dose of 0.5 mg/kg bwt. Our results revealed that all rabbits were severely infested and took a mean score = 3. The skin lesions in rabbits that didn't receive any treatments progressed extensively and took a mean score = of 4. On the other hand, all nanoparticle-treated groups displayed marked improvement in the skin lesion and took an average score of 0-1. All NPs treated groups showed remarkable improvement in the microscopic pictures along with mild iNOS, TNF-α, and Cox-2 expression. Both nanoparticles could downregulate the m-RNA levels of IL-6 and IFγ and upregulate IL-10 and TGF-1ß genes to promote skin healing. Dressing rabbits with both NPs didn't affect either liver and kidney biomarkers or serum Ig levels indicating their safety. Our residual analysis detected AgNPs in the liver of rabbits but did not detect any residues of GNPs in such organs. We recommend using GNPs as an alternative acaricide to fight rabbit mange.

Ameliorative effects of rutin and rutin-loaded chitosan nanoparticles on testicular oxidative stress and histological damage induced by cyclophosphamide in male rats.

Cyclophosphamide (CP) is broadly used to kill various tumor cells; however, its repeated uses have been reported to cause reproductive dysfunction and infertility. Natural flavonoid, rutin (RUT), possesses strong antioxidant and antiapoptotic activity that is attributed to ameliorate the reproductive dysfunction induced by CP. Many previous studies proved that the formulation of flavonoids in nanoemulsion has a promising perspective in mitigating the side effects of chemotherapy. Therefore, the main objective of this study was to investigate the ameliorative effects of RUT and RUT-loaded chitosan nanoparticles (RUT-CH NPs) against CP-induced reproductive dysfunction in male rats. For this aim, thirty-six male albino rats were randomly allocated into six groups as follows: control, RUT, RUT-CH NPs, CP, CP + RUT, and CP + RUT-CH NPs. In the CP groups, a single intraperitoneal injection of CP (150 mg/kg bwt) was administered on the first day of the experiment. RUT and RUT-CH NPs were orally administered either alone or with CP injection at a dose of 10 mg/kg bwt per day for 60 days. The results revealed that CP administration caused significant testicular oxidative stress damage through increasing the nitric oxide and malondialdehyde levels as well as decreasing the total antioxidant capacity and reduced glutathione contents. It also impaired spermatogenesis and steroidogenesis via altering the transcription levels of CYP11A1, HSD-3b, StAR, Bax, bcl-2, and Nrf-2 genes. Otherwise, the oral intake of either RUT or RUT-CH NPs with CP injection effectively attenuated these alterations and significantly improved the microscopic appearance of testicular tissue. In conclusion, this study highlights the potential of RUT either free or NPs in mitigating CP-induced testicular dysfunction via its antioxidant and anti-apoptotic properties.

Plumieride as a novel anti-fungal and anti-inflammatory iridoid against superficial candidiasis in mice.

In the past few decades, there has been a notable rise in the occurrence of several types of candidiasis. Candida albicans is the most common cause of superficial fungal infections in humans. In this study, plumieride, one of the major iridoids from Plumeria obtusa L. leaves, was isolated and investigated for its potential against Candida albicans (CA)-induced dermatitis in mice. qRT-PCR was done to assess the impact of plumieride on the expression of the major virulence genes of CA. Five groups (n = 7) of adult male BALB/c mice were categorized into: group I: non-infected mice; group II: mice infected intradermally with 107-108 CFU/mL of CA; group III: CA-infected mice treated with standard fluconazole (50 mg/kg bwt.); group IV and V: CA-infected mice treated with plumieride (25- and 50 mg/kg. bwt., respectively). All the treatments were subcutaneously injected once a day for 3 days. Skin samples were collected on the 4th day post-inoculation to perform pathological, microbial, and molecular studies. The results of the in vitro study proved that plumieride has better antifungal activity than fluconazole, manifested by a wider zone of inhibition and a lower MIC. Plumieride also downregulated the expression of CA virulence genes (ALS1, Plb1, and Hyr1). CA-infected mice showed extensive dermatitis, confirmed by strong iNOS, TNF-α, IL-1ß, and NF-κB genes or immune expressions. Whereas the treatment of CA-infected mice with plumieride significantly reduced the microscopic skin lesions and modulated the expression of all measured proinflammatory cytokines and inflammatory markers in a dose-dependent manner. Plumieride interfered with the expression of C. albicans virulence factors and modulated the inflammatory response in the skin of mice infected with CA.

The mollifying effect of Sambucus nigra extract on StAR gene expression, oxidative stress, and apoptosis induced by fenpropathrin in male rats.

Fenpropathrin (FNP) is a man-made insecticide of to the pyrethroid class, commonly employed in agricultural and horticultural practices. However, it has a prolonged persistence in the environment. Sambucus nigra, also referred to as SN, is a botanical species recognized for its notable antioxidant characteristics. The objective of this study was to examine if SN extract could mitigate the reproductive toxicity induced by FNP in rats. A total of thirty rats were categorized into six distinct groups: a control group with no treatment, two groups getting SN extract at varying doses, a group receiving FNP, and two groups receiving both FNP and SN extract. The exposure to FNP led to a decline in the number and movement of sperm, lowered levels of testosterone, and reduced the activity of the StAR gene in the FNP group compared to the control group (p < 0.05). In addition, FNP resulted in a significant increase in malondialdehyde levels with a significant drop in GSH content compared to the control group (p < 0.05). Also, a significant increase in the expression of caspase 3. Nevertheless, the administration of SN extract alleviated these effects and reinstated spermatogenesis, thereby bringing the parameters closer to those observed in the control group. The data indicate that FNP can induce testicular harm and infertility, but SN extract can mitigate these detrimental consequences.

The potential mechanism of histamine-inducing cardiopulmonary inflammation and apoptosis in a novel oral model of rat intoxication.

Histamine (HIS) is a potent vasodilator that contributes to anaphylactic reactions. Our investigation aims to study the possible toxic impact of repeated oral administration of histamine on the target organs of HIS poisoning (lung & heart) in rats as a model of scombroid poisoning. We used 15 rats that were separated into three groups with 5 rats in each. All rats received the treatments orally for 14 days as follows; (1): distilled water, (2) HIS at a dosage level of 250 mg/kg BWT daily and (3) HIS at a dosage level of 1750 mg/kg BWT weekly. Our results revealed that the consumption of HIS either daily or weekly could cause marked cardiopulmonary toxicity in rats. HIS can trigger inflammatory reactions in the cardiopulmonary tissues and induce oxidative stress damage along with apoptosis of such organs. HIS was markedly increase the MDA levels and decrease the CAT and GSH activity in both lung and heart tissues. The main pathological lesion observed is inflammation which was confirmed by immunohistochemistry and demonstrated strong iNOS and TNF-α protein expressions. Cardiac muscles showed extensive degeneration and necrosis and displayed strong casp-3 protein expression. Additionally, all HIS receiving groups noticed marked elevation of the pulmonary transcription levels of Cox2, TNF-α, and IL1ß along with substantial elevation of casp-3 and bax genes and downregulation of Bcl2 gene in the cardiac tissue. We concluded that the oral administration of HIS either daily or weekly can induce cardiopulmonary toxicity via the upregulation of proinflammatory cytokines resulting in ROS overgeneration and inducing both oxidative stress and apoptosis.

Chitosan nanoparticle encapsulation increased the prophylactic efficacy of Lactobacillus plantarum RM1 against AFM1-induced hepatorenal toxicity in rats.

Aflatoxin M1 (AFM1) is a significant contaminant of food, particularly dairy products and can resist various industrial processes. Several probiotic strains like Lactobacillus plantarum are known to reduce aflatoxin availability in synthetic media and some food products. The current work investigated the possible chitosan coating prophylactic efficacy of Lactobacillus plantarum RM1 nanoemulsion (CS-RM1) against AFM1-induced hepatorenal toxicity in rats. Twenty-eight male Wistar rats were divided into four groups (n = 7) as follows: group 1 received normal saline, group 2 received CS-RM1 (1mL contains 6.7 × 1010 CFU), group 3 received AFM1 (60 µg/kg bwt), and group 4 received both CS-RM1(1 mL contains 6.7 × 1010 CFU) and AFM1 (60 µg/kg bwt). All receiving materials were given to rats daily via oral gavage for 28 days. AFM1 caused a significant elevation in serum levels of ALT, AST, ALP, uric acid, urea, and creatinine with marked alterations in protein and lipid profiles. Additionally, AFM1 caused marked pathological changes in the liver and kidneys, such as cellular necrosis, vascular congestion, and interstitial inflammation. AFM1 also increased the MDA levels and decreased several enzymatic and non-enzymatic antioxidants. Liver and kidney sections of the AFM1 group displayed strong caspase-3, TNF-α, and iNOS immunopositivity. Co-treatment of CS-RM1 with AFM1 significantly lowered the investigated toxicological parameter changes and markedly improved the microscopic appearance of liver and kidneys. In conclusion, AFM1 induces hepatorenal oxidative stress damage via ROS overgeneration, which induces mitochondrial caspase-3-dependent apoptosis and inflammation. Furthermore, CS-RM1 can reduce AFM1 toxicity in both the liver and kidneys. The study recommends adding CS-RM1 to milk and milk products for AFM1-elimination.