Thirty California female rabbits were obtained from the Animal Care Center, College of Agriculture, South Valley University and acclimated to laboratory conditions for one week. The Leiurus quinquestriatus (LQ) venom was collected from mature scorpions by electrical stimulation of the telson. A single dose of crude venom of 0.4 ml/kg (diluted in normal saline with a ratio of 1:1) was injected into a peripheral ear vein. The lungs, brains, hearts, kidneys, were sampled and fixed in 10% formalin from rabbits sacrificed at zero, 30 minutes, 1hr, and 4hrs, post-envenomation (three animals at each sacrifice). Respiratory distress and neurological manifestations were the main clinical signs. Congestion of the lungs was started at one hour postenvenomation. Vascular changes including hyperemia and hemorrhage were also observed till 24 hours post-envenomation. The main histopathological changes of the lungs were edema, hemorrhage, emphysema, and eosinophilic bronchitis. Transmission electron microscopy revealed several eosinophils with abundant granules and breakdown of their membranes suggesting degranulation. The cerebrum showed malacia and edema. Myocardial damage expressed by focal area of myolysis at half-hour post-envenomation and interstitial edema by at 1, and 4 hour post-envenomation was also evident. In conclusion, scorpion venom induced consistent and relevant histopathological changes in all examined organs.

Traditional methods employed to discover new antibiotics are both a time-consuming and financially-taxing venture. This has led researchers to mine existing libraries of clinical molecules in order to repurpose old drugs for new applications (as antimicrobials). Such an effort led to the discovery of auranofin, a drug initially approved as an anti-rheumatic agent, which also possesses potent antibacterial activity in a clinically achievable range. The present study demonstrates auranofin’s antibacterial activity is a complex process that involves inhibition of multiple biosynthetic pathways including cell wall, DNA, and bacterial protein synthesis. We also confirmed that the lack of activity of auranofin observed against Gram-negative bacteria is due to the permeability barrier conferred by the outer membrane. Auranofin’s ability to suppress bacterial protein synthesis leads to significant reduction in the production of key methicillin-resistant Staphylococcus aureus (MRSA) toxins. Additionally, auranofin is capable of eradicating intracellular MRSA present inside infected macrophage cells. Furthermore, auranofin is efficacious in a mouse model of MRSA systemic infection and significantly reduces the bacterial load in murine organs including the spleen and liver. Collectively, this study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antibacterial for treatment of invasive bacterial infections.

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Parkinson’s disease (PD) is a neurodegenerative disease characterised by histopathological and biochemical manifestations such as loss of midbrain dopaminergic (DA) neurons and decrease in dopamine levels accompanied by a concomitant neuroinflammatory response in the affected brain regions. Over the past decades, the use of toxin-based animal models has been crucial to elucidate disease pathophysiology, and to develop therapeutic approaches aimed to alleviate its motor symptoms. Analyses of transgenic mice deficient for cytokines, chemokine as well as neurotrophic factors and their respective receptors in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have broadened the current knowledge of neuroinflammation and neurotrophic support. Here, we provide a comprehensive review that summarises the contribution of microglia-mediated neuroinflammation in MPTP-induced neurodegeneration. Moreover, we highlight the contribution of neurotrophic factors as endogenous and/or exogenous molecules to slow the progression of midbrain dopaminergic (mDA) neurons and further discuss the potential of combined therapeutic approaches employing neuroinflammation modifying agents and neurotrophic factors.

The objectives of the present study were to investigate the effects of dietary urea supplementation (1.0% and 3.0%) on oocytes quality, timing expected of embryo cleavages, offspring numbers and weights, blood components and rectal temperature in mice. Sixty of growing albino mice were classified into three groups; the control group was given basal control diet and the other two groups were fed on basal control diet supplemented with 1.0% and 3.0% urea. Body weights were recorded at the beginning and after 5 weeks. Thereafter, five female mice of each group were injected with 7.5 IU of pregnant mare serum gonadotropin (PMSG) for determination of oocyte quality after 48h of injection. The fifteen female mice of each group were injected with 7.5 IU of PMSG followed by 7.5 IU of human chorionic gonadotropin (hCG) after 48h and mated with males of proven fertility. Five mated females of each group were used for determination of embryo cleavages to four cell stage and the other five mated females were used for determination of embryo cleavages to eight cell stage upon 59-60 and 70 h of hCG injection, respectively. Rectal temperatures were recorded and blood samples were collected. The remaining five mated females of each group were left for parturition. The offspring number, litter size and male:female ratio were recorded. Hematocrit and hemoglobin concentrations were determined in blood whereas urea, total protein, albumin, glucose calcium and phosphorus concentrations were determined in plasma. The results indicated that offspring number and weight of litter size at birth were significantly (P0.05) increased in the urea groups compared to control group. Percentage of good quality oocytes was high (70%) in control group compared to 3% urea group (60%). Dietary 3% urea was delayed cleavages to four-cell stage embryos at the expected time. Dietary urea was significantly (P0.05) increased concentrations of hematocrit and hemoglobin in blood and urea, total protein, globulin, glucose, potassium and phosphorus in plasma. In conclusions, although 3% dietary urea decreased oocytes quality and timing expected of embryo cleavages to four cell stages, it increased significantly (P0.05) offspring number and weight of litter size.

The objectives of the present study were to investigate the effects of dietary urea supplementation (1.0% and 3.0%) on oocytes quality, timing expected of embryo cleavages, offspring numbers and weights, blood components and rectal temperature in mice. Sixty of growing albino mice were classified into three groups; the control group was given basal control diet and the other two groups were fed on basal control diet supplemented with 1.0% and 3.0% urea. Body weights were recorded at the beginning and after 5 weeks. Thereafter, five female mice of each group were injected with 7.5 IU of pregnant mare serum gonadotropin (PMSG) for determination of oocyte quality after 48h of injection. The fifteen female mice of each group were injected with 7.5 IU of PMSG followed by 7.5 IU of human chorionic gonadotropin (hCG) after 48h and mated with males of proven fertility. Five mated females of each group were used for determination of embryo cleavages to four cell stage and the other five mated females were used for determination of embryo cleavages to eight cell stage upon 59-60 and 70 h of hCG injection, respectively. Rectal temperatures were recorded and blood samples were collected. The remaining five mated females of each group were left for parturition. The offspring number, litter size and male:female ratio were recorded. Hematocrit and hemoglobin concentrations were determined in blood whereas urea, total protein, albumin, glucose calcium and phosphorus concentrations were determined in plasma. The results indicated that offspring number and weight of litter size at birth were significantly (P0.05) increased in the urea groups compared to control group. Percentage of good quality oocytes was high (70%) in control group compared to 3% urea group (60%). Dietary 3% urea was delayed cleavages to four-cell stage embryos at the expected time. Dietary urea was significantly (P0.05) increased concentrations of hematocrit and hemoglobin in blood and urea, total protein, globulin, glucose, potassium and phosphorus in plasma. In conclusions, although 3% dietary urea decreased oocytes quality and timing expected of embryo cleavages to four cell stages, it increased significantly (P0.05) offspring number and weight of litter size.

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There is a pressing need for novel and innovative therapeutic strategies to address infections caused by intracellular pathogens. Peptide nucleic acids (PNAs) present a novel method to target intracellular pathogens due to their unique mechanism of action and their ability to be conjugated to cell penetrating peptides (CPP) to overcome challenging delivery barriers. In this study, we targeted the RNA polymerase α subunit (rpoA) using a PNA that was covalently conjugated to five different CPPs. Changing the conjugated CPP resulted in a pronounced improvement in the antibacterial activity observed against Listeria monocytogenes in vitro, in cell culture, and in a Caenorhabditis elegans (C. elegans) infection model. Additionally, a time-kill assay revealed three conjugated CPPs rapidly kill Listeria within 20 minutes without disrupting the bacterial cell membrane. Moreover, rpoA gene silencing resulted in suppression of its message as well as reduced expression of other critical virulence genes (Listeriolysin O, and two phospholipases plcA and plcB) in a concentration-dependent manner. Furthermore, PNA-inhibition of bacterial protein synthesis was selective and did not adversely affect mitochondrial protein synthesis. This study provides a foundation for improving and developing PNAs conjugated to CPPs to better target intracellular pathogens.

There is a pressing need for novel and innovative therapeutic strategies to address infections caused by intracellular pathogens. Peptide nucleic acids (PNAs) present a novel method to target intracellular pathogens due to their unique mechanism of action and their ability to be conjugated to cell penetrating peptides (CPP) to overcome challenging delivery barriers. In this study, we targeted the RNA polymerase α subunit (rpoA) using a PNA that was covalently conjugated to five different CPPs. Changing the conjugated CPP resulted in a pronounced improvement in the antibacterial activity observed against Listeria monocytogenes in vitro, in cell culture, and in a Caenorhabditis elegans (C. elegans) infection model. Additionally, a time-kill assay revealed three conjugated CPPs rapidly kill Listeria within 20 minutes without disrupting the bacterial cell membrane. Moreover, rpoA gene silencing resulted in suppression of its message as well as reduced expression of other critical virulence genes (Listeriolysin O, and two phospholipases plcA and plcB) in a concentration-dependent manner. Furthermore, PNA-inhibition of bacterial protein synthesis was selective and did not adversely affect mitochondrial protein synthesis. This study provides a foundation for improving and developing PNAs conjugated to CPPs to better target intracellular pathogens.

The scourge of multidrug-resistant bacterial infections necessitates the urgent development of novel antimicrobials to address this public health challenge. Drug repurposing is a proven strategy to discover new antimicrobial agents; given that these agents have undergone extensive toxicological and pharmacological analysis, repurposing is an effective method to reduce the time, cost and risk associated with traditional antibiotic innovation. In this study, the in vitro and in vivo antibacterial activities of an antirheumatic drug, auranofin, was investigated against multidrug-resistant Staphylococcus aureus. The results indicated that auranofin possesses potent antibacterial activity against all tested strains of S. aureus, including meticillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA), with minimum inhibitory concentrations (MICs) ranging from 0.0625 μg/mL to 0.125 μg/mL. In vivo, topical auranofin proved superior to conventional antimicrobials, including fusidic acid and mupirocin, in reducing the mean bacterial load in infected wounds in a murine model of MRSA skin infection. In addition to reducing the bacterial load, topical treatment of auranofin greatly reduced the production of inflammatory cytokines, including tumour necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and monocyte chemoattractant protein-1 (MCP-1), in infected skin lesions. Moreover, auranofin significantly disrupted established in vitro biofilms of S. aureus and Staphylococcus epidermidis, more so than the traditional antimicrobials linezolid and vancomycin. Taken together, these results support that auranofin has potential to be repurposed as a topical antimicrobial agent for the treatment of staphylococcal skin and wound infections.