The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids.

The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain's lipid landscape remain largely unexplored. The levels of saturated FFAs, particularly of myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the PLA1 isoform DDHD2 in mice dramatically reduces saturated FFA responses to memory acquisition across the brain. Furthermore, DDHD2 loss also decreases memory performance in reward-based learning and spatial memory models prior to the development of neuromuscular deficits that mirror human spastic paraplegia. Via pulldown-mass spectrometry analyses, we find that DDHD2 binds to the key synaptic protein STXBP1. Using STXBP1/2 knockout neurosecretory cells and a haploinsufficient STXBP1+/- mouse model of human early infantile encephalopathy associated with intellectual disability and motor dysfunction, we show that STXBP1 controls targeting of DDHD2 to the plasma membrane and generation of saturated FFAs in the brain. These findings suggest key roles for DDHD2 and STXBP1 in lipid metabolism and in the processes of synaptic plasticity, learning, and memory.

Lipids and Secretory Vesicle Exocytosis.

In recent years, the number of studies implicating lipids in the regulation of synaptic vesicle exocytosis has risen considerably. It has become increasingly clear that lipids such as phosphoinositides, lysophospholipids, cholesterol, arachidonic acid and myristic acid play critical regulatory roles in the processes leading up to exocytosis. Lipids may affect membrane fusion reactions by altering the physical properties of the membrane, recruiting key regulatory proteins, concentrating proteins into exocytic "hotspots" or by modulating protein functions allosterically. Discrete changes in phosphoinositides concentration are involved in multiple trafficking events including exocytosis and endocytosis. Lipid-modifying enzymes such as the DDHD2 isoform of phospholipase A1 were recently shown to contribute to memory acquisition via dynamic modifications of the brain lipid landscape. Considering the increasing reports on neurodegenerative disorders associated with aberrant intracellular trafficking, an improved understanding of the control of lipid pathways is physiologically and clinically significant and will afford unique insights into mechanisms and therapeutic methods for neurodegenerative diseases. Consequently, this chapter will discuss the different classes of lipids, phospholipase enzymes, the evidence linking them to synaptic neurotransmitter release and how they act to regulate key steps in the multi-step process leading to neuronal communication and memory acquisition.

Cypermethrin Toxicity-induced Infertility: An Assessment of Longitudinal Transfer of Protective Potentials of Date Fruit Extracts in Wister Rats.

BACKGROUND: There is a potential for longitudinal and horizontal transfer of the cytotoxic effects of cypermethrin, and evidence suggests that date fruit extracts can ameliorate these cytotoxic effects. Thus, the current study evaluated female Wister rats' fertility and pup parameters after mating males treated with cypermethrin and date fruit (Phoenix dactylifera) extract. METHODS: Adult Wistar rats (n = 74; 140 - 207 g) were used to conduct this experiment in two phases: The first phase was a single dose toxicity study (n = 18), while the second phase (n = 56) evaluated female Wister rats' reproductive and pup development parameters after mating with male Wistar rats exposed to date fruit extract and cypermethrin. Male rats were distributed randomly into four groups (n = 7 per group) and administered distilled water (Group I); 60 mg/kg cypermethrin (Group II) to simulate infertility; 250 mg/kg date fruit extract alone (Group III); and date fruit extracts plus 60 mg/kg cypermethrin (Group IV). Treated males were then mated with healthy female rats at a ratio of 1:1. Successfully mated females were appraised for conception and pregnancy rates, gestation length, litter size, and weights at birth, and on days 5, 10, 15, and 21 post-partum, an anogenital distance at day-20, sex ratio, and age of pup when hair growth was evident. RESULTS: Significant differences (p < 0.05) were observed in litter size and male anogenital distance but not in reproductive performance. Also, the study demonstrated that date fruit extract skewed the sex ratio of offspring to more female than male pups when female Wister rats were mated with males that received date fruit extracts alone or cypermethrin and date fruit extracts. The body weight gain did not differ significantly between the control and cypermethrin-treated groups. CONCLUSION: This evidence suggested a longitudinal transfer of the protective effects of date fruit extracts following a weekly exposure of male rats to cypermethrin at 60 mg/kg.

Saudi honey alleviates indomethacin-induced gastric ulcer via improving antioxidant and anti-inflammatory responses in male albino rats.

Recent years have reported a rise in the occurrence of gastric ulceration especially among young children and adults. This study investigated the mechanism by which two types of Saudi honey: Alnahal Aljawal honey (Wadi) or Bin Ghaithan honey (Talh) exerted their antiulcer potential in indomethacin-induced gastric ulceration. Four cohorts of rats were used: Group 1; Healthy controls, Group 2; Ulcerative animals, Group 3; Ulcerative + Wadi honey treatment, Group 4; Ulcerative + Talh honey treatment. We profiled the levels of different indicators of oxidative stress including the activities of gastric mucosal glutathione superoxide dismutase (SOD), catalase (CAT), peroxidase (GPx), reduced glutathione (GSH), and lipid peroxidation (measured as malondialdehyde; MDA). CRP content, IL-10, and plasma tumor necrosis factor-α were also evaluated. The stomach was visually examined for macroscopic lesions and using light microscope for histopathological changes in the glandular mucosa. Wadi or Talh honey significantly reduced the ulcer indices, and essentially protected the glandular mucosa from lesions. Wadi or Talh honey also significantly reduced the gastric mucosal concentrations of GPx, SOD and GSH. In addition, the administration of Wadi or Talh honey decreased gastric mucosal plasma TNF-α and MDA, CRP content, and IL-10 levels. In conclusion, Wadi or Talh honey possibly exerted their antiulcer potential via restoring the homeostasis and stabilizing the enzymatic (SOD and GPx) and non-enzymatic (GSH) antioxidants as well as reducing the levels of inflammatory cytokines (TNF-α, CRP content, IL-10 and, NF-κB activity), and inhibiting the lipid peroxidation in the gastric mucosa. Consequently, Wadi or Talh honey may be of beneficial therapy for patients diagnosed with gastric ulceration. Clinical studies need to be conducted to further support these findings.

Novel Pomegranate-Nanoparticles Ameliorate Cisplatin-Induced Nephrotoxicity and Improves Cisplatin Anti-Cancer Efficacy in Ehrlich Carcinoma Mice Model.

Cisplatin (CISP) is one of the most widely used anti-cancer chemotherapeutic agents with remarkable efficacy against various types of cancers. However, it has been associated with nephrotoxicity amongst other undesirable side effects. Pomegranate (PE) is a potent antioxidant and anti-inflammatory agent effective against cancer, with a superior benefit of not being associated with the common toxicities related to the use of conventional chemotherapeutic agents. However, the application of PE is limited by its reduced solubility and decreased bioavailability. We investigated the potential of a novel nanoparticle (NP) enclosing PE to enhance its solubility and improve its bioavailability, and efficacy to prevent CISP-associated nephrotoxicity in a mice model of Ehrlich solid carcinoma (ESC). All mice were grouped into four cohorts: (I) control, (II) tumor, (III) CISP, and (IV) CISP + PE-NPs. The data obtained demonstrated that PE-NPs was beneficial in potently ameliorating CISP-induced nephrotoxicity in ESC mice. PE-NPs significantly attenuated CISP-induced oxidative stress and lipid peroxidation in the kidney via improving activities of antioxidants (SOD, GSH, and CAT). Additionally, PE-NPs considerably decreased CISP-induced inflammation in the kidney by decreasing the levels of NF-kB, IL-1ß, and TNF-α. Notably, PE-NPs did not assuage the antitumor efficacy of CISP as revealed by histological assessment and tumor weight data. In summary, PE-NPs may be a potent alternative anticancer therapy devoid of nephrotoxicity.

In vitro anthelmintic activity of Dennettia tripetala G. Baker (Annonaceae) Fruits against Haemonchus contortus.

Helminthosis is one of the greatest causes of parasitic disease and loss in animal productivity. As such, the control of helminth parasites is of critical importance. This study was aimed to investigate the in vitro anthelmintic activity of Dennettia tripetala G. Baker (Annonaceae) fruits against Haemonchus contortus. Using in vitro techniques, the anthelmintic activity of extracts and fractions of D. tripetala G. Baker (Annonaceae) was evaluated for ovicidal (Egg hatch inhibition test) and larvicidal (larval mortality test) activity. Besides, the maximum tolerated dose was determined in adult albino rats administered, 300, 400, and 500 mg/kg body weight of the CME fraction, and observed over a period of 48 h for signs of toxicity and mortality. Phytochemical screening uncovered the occurrence of flavonoids, steroids/triterpenes, cardiac glycosides, saponins, tannins, carbohydrates, and alkaloids in the crude methanol extract (CME), the ethyl acetate fraction (EAF), and butanol fraction. The maximum tolerated dose of the CME of D. tripetala did not produce observable signs of toxicity or death in all the rats given up to 500 mg/kg. The CME and EAF of D. tripetala fruits produced a significant ( p < 0.05 ) reduction in the hatchability of H. contortus eggs in a concentration-dependent manner, while the CME at concentrations between 12.5 and 100 mg/ml completely inhibited the hatching of H. contortus eggs. Similarly, EAF at doses of 25, 50, and 100 mg/ml completely inhibited the hatching of H. contortus eggs. The CME and EAF of D. tripetala fruits produced significant ( p < 0.05 ) larvicidal activity against L3 of H. contortus in a concentration-dependent manner while the CME at concentrations between 6.25 and 100 mg/ml caused larval mortality of H. contortus L3 larvae completely. This study suggests that methanol extract and fractions of D. tripetala fruits possess beneficial anthelmintic (ovicidal and larvicidal) activity against H. contortus, and may be a suitable alternative anthelmintic candidate for the control of nematodes.

Anthelmintic activity of methanol extract of Dennettia tripetala G. Baker (Annonaceae) fruits against Haemonchus contortus in red Sokoto goats.

Haemonchosis is a gastrointestinal parasitic disease of economic importance in ruminants especially sheep and goats. In view of the rising costs of conventional veterinary anthelmintics and the development of resistance by Haemonchus contortus, there is a need to develop alternative ethnoveterinary therapies for the treatment and management of Haemonchosis. This study investigated the anthelmintic activity of Dennettia tripetala G. Baker (Annonaceae) fruits against Haemonchus contortus in red Sokoto goats. The maximum tolerated dose was determined in adult albino rats administered, 3000, 4000, and 5000 mg/kg body weight of the crude methanol extract (CME) fraction, and observed over a period of 48 h for signs of toxicity and mortality. The in vivo anthelmintic activity was evaluated using 20 kids infected with H. contortus and randomly allocated into 5 groups (1, 2, 3, 4, and 5). Kids in groups 1, 2, and 3 were treated with CME at doses of 1250, 2500, and 5000 mg/kg respectively for 3 consecutive days per os. Groups 4 and 5 were treated with albendazole (7.5 mg/kg) once and distilled water (5 ml) respectively and served as treated and untreated controls. Blood samples were collected for haematology. The maximum tolerated dose of the CME of D. tripetala did not produce observable signs of toxicity or death in all the rats given up to 5000 mg/kg. There was significant (P < 0.05) reduction in faecal egg count by CME at doses of 1250 mg/kg (91.6%), 2500 mg/kg (98.5%), and 5000 mg/kg (100%) at day 14 post-treatment. The total plasma protein (TPP) and FAMACHA© scoring values were significantly improved (P < 0.05) in the treated groups. These results indicate that methanol extract and fractions of D. tripetala fruits possess beneficial anthelmintic activity against H. contortus and may be a suitable alternative anthelmintic candidate for the control of haemonchosis in goats.

In Vitro Anticoccidial Activities of the Extract and Fractions of Garcinia kola (Heckel h.) Against Eimeria tenella Oocyst.

BACKGROUND: Commercial poultry farming is expanding every day and contributing to the provision of affordable and high-quality protein. However, this sector is confronted with many diseases of which coccidiosis is among the most important. There are many registered patents affirming the health benefits of Garcinia kola in poultry. OBJECTIVE: Evaluation of in vitro anticoccidial activities of the extracts and fractions of Garcinia kola against Eimeria tenella oocyst was carried out. METHODS: Fresh seeds of G. kola were collected, dried under shade at room temperature, and pulverized using a mortar and a pestle. The powder was exhaustively extracted with a soxhlet apparatus using 70% methanol, and the crude methanol extract (CME) was concentrated to dryness using a rotary evaporator. The CME was further partitioned using butanol, ethylacetate, and n-hexane. The CME, butanol fraction (BTF), ethylacetate fraction (EAF), and hexane fraction (HXF) were concentrated in vacuo and tested for the presence of phytochemical constituents using standard procedures. Similarly, the CME, butanol, ethyl acetate, and hexane fractions were evaluated in vitro for oocyst sporulation inhibition. RESULTS: Phytochemical analysis revealed the presence of cardiac glycosides, saponins, carbohydrates, steroids/triterpenes, tannins, flavonoids, and alkaloids in the CME and BTF. The EAF contains all the metabolites mentioned except saponins. Similarly, HXF contains only cardiac glycosides, tannins, and steroids/ triterpenes. The CME and BTF caused a concentration-dependent increase in the inhibition of sporulation of unsporulated oocysts of E. tenella. In the acute toxicity studies, the CME did not produce any toxic effect or mortality at doses between 10 and 5000 mg/kg. The CME was then considered safe, and the LD50 was assumed to be >5000 mg/kg. CONCLUSION: The data obtained in this study suggested that the crude methanol extract (CME) of G. kola could be an appreciable beneficial effect as an anticoccidial agent against Eimeria tenella oocyst.

In Vitro and In Vivo Neutralizing Activity of Uvaria chamae Leaves Fractions on the Venom of Naja nigricollis in Albino Rat and Bovine Blood.

BACKGROUND: Snakebite envenomation is a global priority ranked top among other neglected tropical diseases. There is a folkloric claim that Uvaria chamae is beneficial for the management of snakebite and wounds in African ethnobotanical surveys. Besides, there are many registered patents asserting the health benefits of U. chamae. OBJECTIVE: This study aimed to investigate U. chamae's potentials and identify candidates for the development of tools for the treatment and management of N. nigricollis envenomation. METHODS: Freshly collected U. chamae leaves were air-dried, powdered, and extracted in methanol. The median lethal dose of the extract was determined and further fractionated with n-hexane, n-butanol and ethyl acetate. Each fraction was tested for neutralizing effect against venom-induced haemolytic, fibrinolytic, hemorrhagic, and cytotoxic activities. RESULTS: U. chamae fractions significantly (p<0.05) neutralized the haemolytic activity of N. nigricollis venom in n-butanol; 31.40%, n-hexane; 33%, aqueous residue; 39.60% and ethyl acetate; 40.70% at the concentration of 100mg/ml of each fraction against 10mg/ml of the snake venom when compared to the positive control. The fibrinolytic activity of N. nigricollis venom was significantly (p<0.05) neutralized in n-hexane at 73.88%, n-butanol; 72.22% and aqueous residue; 72.22% by the fractions of U. chamae. In addition, haemorrhagic activity of N. nigricollis venom was significantly (p<0.05) neutralized by U. chamae fractions at the concentrations of 100mg/ml, 200mg/ml and 400mg/ml except for n-butanol and aqueous residues at 400 mg/ml. CONCLUSION: U. chamae leaves fractions possess a high level of protection against N. nigricollis venoms-induced lethality and thus validate the pharmacological rationale for its usage in the management of N. nigricollis envenomation.