Properties In Rats Research Articles

Preparation and evaluation of novel oral tacrolimus nanocochleates for organ transplantation to reduce individual differences and improve drug safety

After organ transplantation, patients require treatment with immunosuppressive drugs to prevent immune rejection and transplantation failure. Tacrolimus (FK506) is a widely used immunosuppressant known for its potent immunosuppressive effect and narrow therapeutic range. Monitoring of FK506 blood concentrations is essential to avoid nephrotoxicity. In this study, a novel FK506 nanomedicine (FK506 cochleates) was developed using a microfluidic method to reduce variability among individuals and improve drug safety. The particle size of FK506 cochleates was (183.3 ± 1.4) nm, the zeta potential was −(39.28 ± 2.12) mV, and the encapsulation efficiency was more than 85 %. Particle size of FK506 cochleates could be maintained for up to 12 weeks in freeze-dried powder form. Small-angle X-ray scattering (SAXS) experiment confirmed the formation of cochleates by adding calcium solution. In vitro release studies demonstrated a sustained-release profile of FK506 from the cochleates carrier. Furthermore, the cochleates carrier could protect FK506 from the influence of stomach acid and slowly release the drug in the intestine. After oral administration, FK506 cochleates exhibited sustained-release properties in rats, accumulating in the spleen and lymph nodes − key anatomical sites for FK506’s pharmacological action. Importantly, FK506 cochleates significantly prolonged the survival time in the rabbit heart transplantation model while maintaining good safety profiles. In conclusion, the FK506 cochleates showed promising potential for enhancing drug safety in therapeutic organ transplantation.

Citrus reticulata Olive Oil: Production and Nutraceutical Effects on the Cardiovascular System in an In Vivo Rat Model of Metabolic Disorder.

Recently, there has been significant exploration into the utilization of food by-products as natural reservoirs of bioactive substances, particularly in the creation of functional foods naturally enriched with antioxidants. Citrus peels represent a viable option for formulating enhanced olive oils that contribute to a healthier diet, due to their bioactive compound content. This study aimed to (i) ascertain the compositional characteristics of Citrus reticulata olive oil (CrOO) and (ii) assess its nutraceutical properties in rats with metabolic disorder induced by 3 weeks of feeding with a high-fat diet (HFD). The results showed a peculiar phytochemical composition, thanks to the contribution of citrus peels, which are excellent bio-products. In addition, it demonstrated HFD-induced weight gain (18 ± 2% for HFD vs. 13 ± 0.9% for CrOO) and showed protective effects on fasting blood glucose levels (90.2 ± 3.8 mg/dL for HFD vs. 72.3 ± 2.6 for CrOO). Furthermore, a reduction in cardiovascular risk (total cholesterol/HDL cholesterol = 5.0 ± 0.3 for HFD vs. 3.8 ± 0.3 for CrOO) and an improvement in myocardial tissue function were observed, as well as a significant reduction in inflammatory mediators such as iNOS, COX-2, and mPGES-1 in aortic vessel tissues, thus preserving endothelial function at the vascular level.

The neuroprotective role of celastrol on hippocampus in diabetic rats by inflammation restraint, insulin signaling adjustment, Aβ reduction and synaptic plasticity alternation

Celastrol, the primary constituent of Tripterygium wilfordii, has demonstrated neuroprotective properties in rats with dementia by reducing inflammation. A high-fat diet and streptozotocin injection were utilized to establish a diabetic rat model, which was then employed to investigate the possible protective effect of celastrol against the development of diabetes-induced learning and memory deficits. Afterwards, the experimental animals received a dose of celastrol by gavage (4 mg/kg/d). An animal study showed that celastrol enhanced insulin sensitivity and glucose tolerance in diabetic rats. In the Morris water maze test, rats with diabetes performed poorly in terms of spatial learning and memory; treatment with celastrol improved these outcomes. Additionally, administration of celastrol downregulated the expression of inflammatory-related proteins (NF-κB, IKKα, TNF-α, IL-1β, and IL-6) and greatly reduced the generation of Aβ in the diabetic hippocampus tissue. Moreover, the insulin signaling pathway-related proteins PI3K, AKT, and GSK-3β were significantly upregulated in diabetic rats after celastrol was administered. Also, celastrol prevented damage to the brain structures and increased the synthesis of synaptic proteins like PSD-95 and SYT1. In conclusion, celastrol exerts a neuroprotective effect by modulating the insulin signaling system and reducing inflammatory responses, which helps to ameliorate the cognitive impairment associated with diabetes.

Levisticum officinale extract protects against CCl4-induced hepatotoxicity through anti-inflammatory, anti-fibrotic, and antioxidant properties in rats

Objective: To investigate the hepatoprotective effects of Levisticum officinale extract on CCl4-induced hepatotoxicity. Methods: Different doses of Levisticum officinale extract were given orally to rats for 10 days, then rats received a single dose of CCl4 (2.5 mL/kg, 50% v/v in liquid paraffin). Biochemical and histopathological assays were performed to assess the effects of the extract on liver function and architecture. Moreover, antioxidant and oxidative markers as well as inflammatory and fibrotic indicators were measured. Results: Pretreatment with Levisticum officinale extract significantly mitigated CCl4-induced damage to liver structure, improved serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, urea, total bilirubin, and total protein, enhanced glutathione content and superoxide dismutase and catalase activities in the liver, as well as decreased plasma and hepatic malondialdehyde levels. Immunohistochemical results demonstrated that the extract reduced Ki-67 and α-SMA expression and Masson’s trichrome staining revealed decreased liver collagen in rats treated with Levisticum officinale extract. Moreover, Levisticum officinale extract markedly decreased the gene expressions of TNF-α, 1L-6, TGF-β1, MCP-1, and COX-2. Conclusions: Levisticum officinale extract exerts hepatoprotective effects on CCl4-induced hepatotoxicity through antioxidant, anti-inflammatory, and anti-fibrotic activities.

Electroacupuncture modulates abnormal brain connectivity after ischemia reperfusion injury in rats: A graph theory-based approach.

Electroacupuncture (EA) has been shown to facilitate brain plasticity-related functional recovery following ischemic stroke. The functional magnetic resonance imaging technique can be used to determine the range and mode of brain activation. After stroke, EA has been shown to alter brain connectivity, whereas EA's effect on brain network topology properties remains unclear. An evaluation of EA's effects on global and nodal topological properties in rats with ischemia reperfusion was conducted in this study. There were three groups of adult male Sprague-Dawley rats: sham-operated group (sham group), middle cerebral artery occlusion/reperfusion (MCAO/R) group, and MCAO/R plus EA (MCAO/R+EA) group. The differences in global and nodal topological properties, including shortest path length, global efficiency, local efficiency, small-worldness index, betweenness centrality (BC), and degree centrality (DC) were estimated. Graphical network analyses revealed that, as compared with the sham group, the MCAO/R group demonstrated a decrease in BC value in the right ventral hippocampus and increased BC in the right substantia nigra, accompanied by increased DC in the left nucleus accumbens shell (AcbSh). The BC was increased in the right hippocampus ventral and decreased in the right substantia nigra after EA intervention, and MCAO/R+EA resulted in a decreased DC in left AcbSh compared to MCAO/R. The results of this study provide a potential basis for EA to promote cognitive and motor function recovery after ischemic stroke.

Ferulic acid nanoemulsion as a promising anti-ulcer tool: in vitro and in vivo assessment

Objective Ferulic acid (FA) is a promising nutraceutical molecule which exhibits antioxidant and anti-inflammatory properties, but it suffers from poor solubility and bioavailability. In the presented study, FA nanoemulsions were prepared to potentiate the therapeutic efficacy of FA in prevention of gastric ulcer. Methods FA nanoemulsions were prepared, pharmaceutically characterized, and the selected nanoemusion was tested for its ulcer-ameliorative properties in rats after induction of gastric ulcer using ethanol, by examination of stomach tissues, assessment of serum IL-1β and TNF-α, assessment of nitric oxide, prostaglandin E2, glutathione, catalase and thiobarbituric acid reactive substance in stomach homogenates, as well as histological and immunohistochemical evaluation. Results Results revealed that the selected FA nanoemulsion showed a particle size of 90.43 nm, sustained release of FA for 8 h, and better in vitro anti-inflammatory properties than FA. Moreover, FA nanoemulsion exhibited significantly better anti-inflammatory and antioxidant properties in vivo, and the gastric tissue treated with FA nanoemulsion was comparable to the normal control upon histological and immunohistochemical evaluation. Conclusion Findings suggest that the prepared ferulic acid nanoemulsion is an ideal anti-ulcer system, which is worthy of further investigations.

Metabolomics combined with network pharmacology reveals anti-asthmatic effects of Nepeta bracteata on allergic asthma rats

ObjectiveTo investigate the mechanisms that underlie the anti-asthmatic effects of Nepeta bracteata (DBJJ, Dabao Jingjie in Chinese) in rats by integrating metabolomics and network pharmacology. MethodsIn this study, the rat model of asthma was induced by using ovalbumin (OVA), and subsequently, the rats were treated with a decoction of N. bracteata. Pathological changes in lung tissue were observed, and the quantification of eosinophils (EOS) and white blood cells (WBC) in bronchoalveolar lavage fluid (BALF) was performed. Furthermore, the serum levels of asthma-related factors induced by OVA were assessed. The proton nuclear magnetic resonance (1H NMR) spectroscopy serum metabolomics method was utilized to identify differential metabolites and their associated metabolic pathways. Moreover, UPLC-QE-MS/MS combined with network pharmacology was employed to predict the core targets and pathways of DBJJ in its action against asthma. Furthermore, the anti-asthmatic properties of DBJJ were investigated using an integrated approach of metabolomics and network pharmacology. Subsequently, the findings were validated through molecular docking and Western blotting analysis of the key targets. ResultsThe findings indicated that the administration of DBJJ effectively alleviated OVA-induced lung histopathological changes and decreased the number of EOS and WBC in BALF. Additionally, DBJJ inhibited the OVA-induced elevation of TNF-α, IL-18, Ig-E, EOS, IL-1β, MDA, VEGF-A, and TGF-β1. A total of 21 biomarkers and 10 pathways were found by metabolomics analysis. The 29 compounds were identified by UPLC-QE-MS/MS and 13 active components were screened by oral availability and Caco-2 cell permeability, the 120 targets and 173 KEGG pathways were predicted. The integration of metabolomics and network pharmacological analysis revealed that DBJJ's primary constituents, including ferulic acid and ursolic acid, exerted their effects on four targets, namely DAO and NOS2, as well as their associated metabolites and pathways. The active constituents of DBJJ demonstrated a high binding affinity towards DAO and NOS2. Furthermore, DBJJ was observed to decrease the protein expression and phosphorylation levels of NOS2, MAPK, and STAT3. ConclusionThe administration of DBJJ demonstrates notable anti-asthma properties in rats with allergic asthma. This effect can be attributed to the modulation of various targets, including NOS2, MAPK, and STAT3, by primary constituents such as ferulic acid and ursolic acid.

Investigation of neuroprotective and therapeutic effects of cannabidiol in an acute coronary syndrome model

PurposeThe ischemia–reperfusion (I/R) injury seen in the heart can cause severe damage to essential organs such as the brain. Cannabidiol (CBD) obtained from Cannabis sativa is used today to treat various diseases. This study aimed to demonstrate CBD's neuroprotective and therapeutic properties in rats with brain damage caused by I/R in the heart. MaterialsRats were divided into four groups; sham, I/R, I/R + Prophylactic CBD, and I/R + Therapeutic CBD. End of the experiment, brain tissues were collected for biochemical, histopathological, and genetic examinations. ResultsI/R damage increased the number of degenerative neurons, caspase-3 and TNF-α immunoexpression, total oxidant status levels, and oxidative stress index. Both prophylactic and therapeutic CBD administration reduced these increased values. In addition, the relative fold changes of AMPK, PGC-1α, SIRT1, and Bcl 2 decreased in the I/R group, and the relative fold change of Bax increased, which are indicators of ER stress and apoptosis. Both administrations of CBD reversed these genes' relative fold changes. ConclusionCBD can be protective against brain injury caused by cardiac I/R damage through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms.

Improving the Edible and Nutritional Quality of Roasted Duck Breasts through Variable Pressure Salting: Implications for Protein Anabolism and Digestion in Rats

Variable pressure salting (VPS) is considered a novel salting approach to improve meat quality. This study aimed to investigate the effects of roasted duck’s edible and nutritional quality after VPS through serum biochemical indicators and in vivo digestion properties in rats. The results show that roasted duck after VPS led to an increase in the total protein content (57.24 g/L) and blood glucose levels (6.87 mmol/L), as well as a decrease in the blood urea nitrogen content (11.81 mmol/L), in rats. Compared to rats fed base diets and roasted duck after static wet salting (SWS), those ingesting roasted duck after VPS exhibited higher values of apparent protein digestibility (51.24%), pepsin activity (2.40 U/mg), and trypsin activity (389.80 U/mg). Furthermore, VPS treatment improved the textural properties and microstructure of duck breasts shown by a higher immobilized water relaxation area and more ordered protein structures (α-helixes and β-sheets). These improvements enhanced the protein anabolism capacity and in vivo digestion properties in rats. Therefore, VPS represents a beneficial salting method for promoting effective digestion and absorption in rats.

BIOANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF 2-(4-ETHOXYPHENYL SULPHONAMIDO) PENTANE-DIAMIDE, A NOVEL ANTITUMOR AND ANTIANGIOGENIC AGENT, IN RAT SERUM AND APPLICATION OF THE METHOD IN DETERMINATION OF PHARMACOKINETIC PARAMETERS

Objective: The present study focuses on the development and validation of a bioanalytical method for the quantification of 2-(4-ethoxyphenyl sulphamido) pentane-diamide, a candidate antitumor and antiangiogenic agent, in rat serum. The developed method was subsequently applied to determine the pharmacokinetic parameters of the compound. Methods: To quantify the compound and determine its pharmacokinetic properties in rats, a liquid chromatography-mass spectrometry (LC-MS) bioanalytical method has been developed and the pharmacokinetic parameters were computed by compartmental model analysis. Results: A linear relationship was detected within the concentration range of 10 to 5000 ng/ml prepared by adding standard solutions of the test compound to the pooled serum of 10 SD rats, which exhibits high levels of precision, accuracy, and reproducibility. An appreciable recovery in the range of 97.20±0.63 to 93.22±1.48 percent was determined, with no noticeable impact from the matrix. The pharmacokinetic parameters, namely oral absorption rate constant (Ka) (5.054±0.238 1/h), elimination rate constant (KE) (2.585±0.357 h), volume of distribution (V) (8.173±0.333 L/kg), and bioavailability of (73.2%), were determined by the utilization of PK-solver software. Conclusion: We developed a simple yet precise and validated LC-MS method to analyze the drug candidate in rat serum. Simple protein precipitation and extraction were cost-effective. This bioanalytical approach was successful due to its good linearity, high recoveries, no matrix influence, and matrix stability. PK solver derived I. V. and oral pharmacokinetics parameters from the best-fit one-compartment model. Because of its high oral absorption, biological half-life, and bioavailability, the compound is suitable for oral administration.

Ficus carica Leaf Ethanolic Extract's Antidiabetic and Antioxidant Properties in Rats with Alloxan-Induced Diabetes

Ficus carica Leaf Ethanolic Extract's Antidiabetic and Antioxidant Properties in Rats with Alloxan-Induced Diabetes

Pyrazole derivatives as selective orexin-2 receptor antagonists (2-SORA): synthesis, structure-activity-relationship, and sleep-promoting properties in rats.

Selective orexin 2 receptor antagonists (2-SORA) such as seltorexant (15) are in clinical development for the treatment of insomnia and other conditions such as depression. Herein, we report our structure-activity-relationship (SAR) optimization efforts starting from an HTS hit (1) (N-(1-((5-acetylfuran-2-yl)methyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide) that was derived from an unrelated in-house GPCR-agonist program. Medicinal chemistry efforts focused on the optimization of orexin 2 receptor (OX2R) antagonistic activity, stability in liver microsomes, time dependent CYP3A4 inhibition, and aqueous solubility. Compounds were assessed for their brain-penetrating potential in in vivo experiments to select the most promising compounds for our in vivo sleep model. Our lead optimization efforts led to the discovery of the potent, brain penetrating and orally active, 2-SORA (N-(1-(2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide) 43 with efficacy in a sleep model in rats comparable to 15.

Discovery of a brain-permeable bromodomain and extra terminal domain (BET) inhibitor with selectivity for BD1 for the treatment of multiple sclerosis

Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease and lacks effective therapeutic agents. Dysregulation of transcription mediated by bromodomain and extra-terminal domain (BET) proteins containing two different bromodomains (BD1 and BD2) is an important factor in multiple diseases, including MS. Herein, we identified a series of BD1-biased inhibitors, in which compound 16 showed nanomolar potency for BD1 (Kd = 230 nM) and a 60-fold selectivity for BRD4 BD1 over BD2. The co-crystal structure of BRD4 BD1 with 16 indicated that the hydrogen bond interaction of 16 with BD1-specific Asp145 is important for BD1 selectivity. 16 showed favorable brain distribution in mice and PK properties in rats. 16 was able to inhibit microglia activation and had significant therapeutic effects on EAE mice including improvement of spinal cord inflammatory conditions and demyelination protection. Overall, these results suggest that brain-permeable BD1 inhibitors have the potential to be further investigated as therapeutic agents for MS.

Protective role of Pleurotus florida against streptozotocin-induced hyperglycemia in rats: A preclinical study

Pleurotus florida (Mont.) Singer is a mushroom species known to be an antioxidant, immunomodulatory, and diuretic agent, reducing blood pressure and cholesterol. The aim of this study was to evaluate the in vivo potency of P. florida's anti-diabetic properties in rats affected by hyperglycemia induced by Streptozotocin (STZ) at 55 mg/kg (i.p.), characterized by oxidative stress impairment, and changes in insulin levels and lipid profile. After inducing hyperglycemia in the rats, they were treated with P. florida acetone and methanol extracts, orally administered for 28 days at doses of 200 mg/kg and 400 mg/kg body weight. The hyperglycemic control (DC) group showed significant increases (P < 0.05) in mean blood sugar, total cholesterol, triglycerides, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, blood urea nitrogen, lipid hydroperoxides, and malondialdehyde, compared to the normal control (NC) group The high-density lipoprotein cholesterol, serum insulin, superoxide dismutase, catalase, glutathione disulfide, glutathione peroxidase, reduced glutathione, guaiacol peroxidase, and vitamin E and C levels showed a significant decrease (P < 0.05) in DC group, compared to the NC group. Blood glucose levels, lipid profiles, and insulin levels improved significantly after 28 days of treatment, in the group treated with glibenclamide (an oral hypoglycemic drug, used as positive control), and in the groups treated with P. florida extracts. In DC group, the treatment with P. florida was found to prevent diabetes, according to histopathological studies of the kidneys, pancreas, and liver of rats. In conclusion, this study has shown that the treatment with P. florida decreased oxidative stress and glucose levels in the blood, as well as restoring changes in lipid profiles.

Dioscorea alata L. Tubers Ethanol Extract Improves Insulin Resistance and Estrogen Defectively in Type 2 Diabetic Ovariectomized Rats

Dioscorea alata L., commonly known as water yam, has attracted the attention of scientific researchers for its potential anti-diabetic and estrogenic properties. However, the existing literature lacks specific studies on the anti-diabetic and estrogenic effects of D. alata in the context of type 2 diabetic ovariectomized rats. Thus, Our research focuses on investigating the influence of D. alata on the antidiabetic and estrogenic properties in rats. These rats have developed diabetes through a high-fat diet and streptozotocin induction and have also undergone ovariectomy, making them type 2 diabetic ovariectomized rats (T2DM OVX). This comprehensive study both in vitro and in vivo methodologies. We conducted a phytochemical analysis, revealing the presence of key bioactive constituents, including flavonoids, alkaloids, terpenoids, tannins, saponins, cardiac glycosides, and steroids. The results of our phytochemical screening confirm the remarkable antidiabetic properties of the D. alata extract, as it effectively inhibits α-glucosidase activity, leading to a significant reduction in fasting blood glucose levels. Additionally, it enhances body weight, serum insulin levels, and pancreatic islet size. The extract also demonstrates notable estrogenic effects by significantly increasing uterine wet weight, endometrial and myometrium thickness, bone calcium, and overall bone density, while reducing bone porosity in the T2DM OVX rats. It is important to note that while the D. alata extract exhibits slightly less potent α-glucosidase inhibition compared to acarbose, it showcases potent antidiabetic activity at a dose of 1,000 mg/kg body weight, comparable to Metformin (250 mg/kg body weight). In terms of estrogenic activity, it is slightly less potent than 17β-estradiol (1 mg/kg body weight). These findings provide robust evidence supporting the traditional use of D. alata and its efficacy in the context of antidiabetic and estrogenic properties within the T2DM OVX model.

Lactococcus lactis CNCM I-5388 versus NCDO2118 by its GABA hyperproduction ability, counteracts faster stress-induced intestinal hypersensitivity in rats.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by its main symptom, visceral hypersensitivity (VH), which is aggravated by stress. Gut-brain interactions and gut bacteria may alleviate IBS symptoms, including VH. γ-amino butyric acid (GABA), produced notably by lactic acid bacteria (LAB), shows promising result in IBS symptoms treatment. In bacteria, GABA is generated through glutamate decarboxylase (GAD) metabolism of L-glutamic acid, maintaining intracellular pH. In mammals, GABA acts as an inhibitory neurotransmitter, modulating pain, stress, and anxiety. Therefore, utilizing GABA-producing LAB as a therapeutic approach might be beneficial. Our previous work showed that a GABA-producing Lactococcus lactis strain, NCDO2118, reduced VH induced by acute stress in rats after a 10-day oral treatment. Here, we identified the strain CNCM I-5388, with a four-fold higher GABA production rate under the same conditions as NCDO2118. Both strains shared 99.1% identical GAD amino acid sequences and invitro analyses revealed the same optimal pH for GAD activity; however, CNCM I-5388 exhibited 17 times higher intracellular GAD activity and increased resistance to acidic pH. Additionally, invivo experiments have demonstrated that CNCM I-5388 has faster anti-VH properties in rats compared with NCDO2118, starting from the fifth day of treatment. Finally, CNCM I-5388 anti-VH effects partially persisted after 5-day treatment interruption and after a single oral treatment. These findings highlight CNCM I-5388 as a potential therapeutic agent for managing VH in IBS patients.

The combined treatment of insulin and naringin improves bone properties in rats with type 1 diabetes mellitus.

We have studied the effects of individual and combined treatment of insulin (I) and naringin (NAR) on the bone structure and biomechanical properties of femurs from streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were divided into five groups: (1) controls, (2) STZ-induced diabetic rats, (3) STZ-induced diabetic rats treated with I, (4) STZ-induced diabetic rats treated with NAR, and (5) STZ-induced diabetic rats treated with I+NAR. Bone mineral density (BMD), bone histomorphometry, biomechanical testing, and bone biomarker expressions were accomplished in femur of all animals, as well as serum biochemical analyses. The combined treatment of I+NAR increased the body weight and the femur BMD from STZ-induced diabetic rats. The bone biomechanical properties and the bone morphology of the femurs from STZ-induced diabetic rats were also improved by the combined treatment. The increased number of osteoclasts in STZ-induced diabetic rats was partially prevented by I, NAR, or I+NAR. NAR or I+NAR completely blocked the decrease in the number of osteocalcin (+) cells in the femur from STZ-induced diabetic rats. RUNX family transcription factor 2 immunostaining was much lower in STZ-induced diabetic rats than in control animals; the combination of I+NAR totally blocked this effect. The combined treatment not only ameliorated bone quality and function, but also normalized the variables related to glucose metabolism. Therefore, the combination of I+NAR might be a better therapeutic strategy than the individual I or NAR administration to reduce bone complications in diabetic patients.

Neuroprotective effects of Coenzyme Q10 in ischemia-reperfusion injury via inflammation and oxidative stress reduction in adult male rats.

This study aimed to investigate the potential neuroprotective effects of coenzyme Q10 in cerebral ischemia-reperfusion injury-induced neuronal damage and explore the underlying mechanisms. Twenty-eight adult male rats, weighing approximately 200-300 grams, were randomly divided into four groups: the sham group (neck dissection without ischemia), the control group (30 minutes of bilateral common carotid artery ligation followed by one hour of reperfusion), the vehicle group (oral carboxymethylcellulose solution for seven days prior to bilateral common carotid artery ligation and reperfusion), and the treatment group (seven days of coenzyme Q10 pretreatment followed by bilateral common carotid artery occlusion and reperfusion). Histopathological analysis and measurement of brain infarct size were performed, and cerebral levels of IL-6, IL-10, TNF-α, ICAM-1, NF-κB p65, and total antioxidant capacity were assessed. These cerebral tissue levels and cerebral infarct size were significantly elevated in the control and vehicle groups compared to the sham group. Conversely, the total antioxidant capacity was significantly reduced in these groups. Coenzyme Q10 treatment resulted in a significant increase in IL-10 and total antioxidant capacity levels, along with a significant decrease in IL-6, ICAM-1, TNF-α, and NF-κB p65 levels. Histopathological analysis revealed a significant reduction in ischemic damage in the coenzyme Q10-treated group. Coenzyme Q10 has neuroprotective properties in rats subjected to cerebral ischemia/reperfusion injury, possibly through its anti-inflammatory and anti-oxidative effects.

Targeting Autophagy, Apoptosis, and SIRT1/Nrf2 Axis with Topiramate Underlies Its Neuroprotective Effect against Cadmium-Evoked Cognitive Deficits in Rats.

Cadmium is an environmental toxicant that instigates cognitive deficits with excessive glutamate excitatory neuroactivity in the brain. Topiramate, a glutamate receptor antagonist, has displayed favorable neuroprotection against epilepsy, cerebral ischemia, and Huntington's disease; however, its effect on cadmium neurotoxicity remains to be investigated. In this study, topiramate was tested for its potential to combat the cognitive deficits induced by cadmium in rats with an emphasis on hippocampal oxidative insult, apoptosis, and autophagy. After topiramate intake (50 mg/kg/day; p.o.) for 8 weeks, behavioral disturbances and molecular changes in the hippocampal area were explored. Herein, Morris water maze, Y-maze, and novel object recognition test revealed that topiramate rescued cadmium-induced memory/learning deficits. Moreover, topiramate significantly lowered hippocampal histopathological damage scores. Mechanistically, topiramate significantly replenished hippocampal GLP-1 and dampened Aβ42 and p-tau neurotoxic cues. Notably, it significantly diminished hippocampal glutamate content and enhanced acetylcholine and GABA neurotransmitters. The behavioral recovery was prompted by hippocampal suppression of the pro-oxidant events with notable activation of SIRT1/Nrf2/HO-1 axis. Moreover, topiramate inactivated GSK-3β and dampened the hippocampal apoptotic changes. In tandem, stimulation of hippocampal pro-autophagy events, including Beclin 1 upregulation, was triggered by topiramate that also activated AMPK/mTOR pathway. Together, the pro-autophagic, antioxidant, and anti-apoptotic features of topiramate contributed to its neuroprotective properties in rats intoxicated with cadmium. Therefore, it may be useful to mitigate cadmium-induced cognitive deficits.

YCH1899, a Highly Effective Phthalazin-1(2H)-one Derivative That Overcomes Resistance to Prior PARP Inhibitors.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have significant efficacy in treating BRCA-deficient cancers, although resistance development remains an unsolved challenge. Herein, a series of phthalazin-1(2H)-one derivatives with excellent enzymatic inhibitory activity were designed and synthesized, and the structure-activity relationship was explored. Compared with olaparib and talazoparib, compound YCH1899 exhibited distinct antiproliferation activity against olaparib- and talazoparib-resistant cells, with IC50 values of 0.89 and 1.13 nM, respectively. Studies of the cellular mechanism revealed that YCH1899 retained sensitivity in drug-resistant cells with BRCA1/2 restoration or 53BP1 loss. Furthermore, YCH1899 had acceptable pharmacokinetic properties in rats and showed prominent dose-dependent antitumor activity in olaparib- and talazoparib-resistant cell-derived xenograft models. Overall, this study suggests that YCH1899 is a new-generation antiresistant PARPi that could provide a valuable direction for addressing drug resistance to existing PARPi drugs.