Neuroinflammation in the Central Nervous System: Exploring the Evolving Influence of Endocannabinoid System.

Neuroinflammation is a complex biological process that typically originates as a protective response in the brain. This inflammatory process is triggered by the release of pro-inflammatory substances like cytokines, prostaglandins, and reactive oxygen and nitrogen species from stimulated endothelial and glial cells, including those with pro-inflammatory functions, in the outer regions. While neuronal inflammation is common in various central nervous system disorders, the specific inflammatory pathways linked with different immune-mediated cell types and the various factors influencing the blood-brain barrier significantly contribute to disease-specific characteristics. The endocannabinoid system consists of cannabinoid receptors, endogenous cannabinoids, and enzymes responsible for synthesizing and metabolizing endocannabinoids. The primary cannabinoid receptor is CB1, predominantly found in specific brain regions such as the brainstem, cerebellum, hippocampus, and cortex. The presence of CB2 receptors in certain brain components, like cultured cerebellar granular cells, Purkinje fibers, and microglia, as well as in the areas like the cerebral cortex, hippocampus, and cerebellum is also evidenced by immunoblotting assays, radioligand binding, and autoradiography studies. Both CB1 and CB2 cannabinoid receptors exhibit noteworthy physiological responses and possess diverse neuromodulatory capabilities. This review primarily aims to outline the distribution of CB1 and CB2 receptors across different brain regions and explore their potential roles in regulating neuroinflammatory processes.

Carboxymethylated Gums and Derivatization: Strategies and Significance in Drug Delivery and Tissue Engineering.

Natural polysaccharides have been widely exploited in drug delivery and tissue engineering research. They exhibit excellent biocompatibility and fewer adverse effects; however, it is challenging to assess their bioactivities to that of manufactured synthetics because of their intrinsic physicochemical characteristics. Studies showed that the carboxymethylation of polysaccharides considerably increases the aqueous solubility and bioactivities of inherent polysaccharides and offers structural diversity, but it also has some limitations that can be resolved by derivatization or the grafting of carboxymethylated gums. The swelling ratio, flocculation capacity, viscosity, partition coefficient, metal absorption properties, and thermosensitivity of natural polysaccharides have been improved as a result of these changes. In order to create better and functionally enhanced polysaccharides, researchers have modified the structures and properties of carboxymethylated gums. This review summarizes the various ways of modifying carboxymethylated gums, explores the impact that molecular modifications have on their physicochemical characteristics and bioactivities, and sheds light on various applications for the derivatives of carboxymethylated polysaccharides.

Phytocannabinoids as Potential Multitargeting Neuroprotectants in Alzheimer's Disease.

The Endocannabinoid System (ECS) is a well-studied system that influences a variety of physiological activities. It is evident that the ECS plays a significant role in metabolic activities and also has some neuroprotective properties. In this review, we emphasize several plant-derived cannabinoids such as ß-caryophyllene (BCP), Cannabichromene (CBC), Cannabigerol (CBG), Cannabidiol (CBD), and Cannabinol (CBN), which are known to have distinctive modulation abilities of ECS. In Alzheimer's disease (AD), the activation of ECS may provide neuroprotection by modulating certain neuronal circuitry pathways through complex molecular cascades. The present article also discusses the implications of cannabinoid receptors (CB1 and CB2) as well as cannabinoid enzymes (FAAH and MAGL) modulators in AD. Specifically, CBR1 or CB2R modulations result in reduced inflammatory cytokines such as IL-2 and IL-6, as well as a reduction in microglial activation, which contribute to an inflammatory response in neurons. Furthermore, naturally occurring cannabinoid metabolic enzymes (FAAH and MAGL) inhibit the NLRP3 inflammasome complex, which may offer significant neuroprotection. In this review, we explored the multi-targeted neuroprotective properties of phytocannabinoids and their possible modulations, which could offer significant benefits in limiting AD.

Recent Advancements in Topical Anti-Psoriatic Nanostructured Lipid Carrier-Based Drug Delivery.

Psoriasis is linked with unusual differentiation and hyperproliferation of epidermal keratinocytes that significantly impair the quality of life (QoL) of patients. The present treatment options only provide symptomatic relief and are surrounded by various adverse effects. Recently, nanostructured lipid carriers (NLCs) have emerged as next-generation nanocarriers with better physicochemical characteristics. The current manuscript provides background information on psoriasis, its pathophysiology, existing treatment options, and its limitations. It highlights the advantages, rationale, and mechanism of the permeation of NLCs for the treatment of psoriasis. It further gives a detailed account of various NLC nanoformulations for the treatment of psoriasis. In addition, tabular information is provided on the most relevant patents on NLCs for treating psoriasis. Lastly, light is shed on regulatory considerations related to NLC-like nanoformulations. In the treatment of psoriasis, NLCs display a sustained release drug profile, an ability to incorporate both hydrophobic and hydrophilic drugs, an enhancement in skin hydration, penetrability, retention, and bioavailability of the drug, along with reduced staining potential as compared to conventional ointments, and decreased side effects of drug molecules. This affirms the bright future of NLC nanoformulations in the treatment of psoriasis. However, academic industry collaboration and more sound regulatory controls are required to commercialize the NLC nanoformulations for psoriasis treatment.

Antimicrobial Remedies and Emerging Strategies for the Treatment of Diabetic Foot Ulcers.

BACKGROUND: Diabetic foot ulcers (DFU) are one of the most serious complications in diabetic health treatment. The treatment for DFUs is more challenging, especially in individuals with a weakened immune system. Furthermore, due to developing antibiotic resistance characteristics among harmful bacteria and fungi, existing antibiotics may not be helpful in combating microbial infections in the wound site. OBJECTIVE: This review will focus on the newest advances in antimicrobial treatments, such as dressings and topical therapies, as well as drugs and debridement methods. METHODS: The English-language publications published on DFU were collected from a variety of sources, including Scopus, Web of Science, Bentham Science, Science Direct, and Google Scholar. RESULTS: DFU therapy necessitates a multidisciplinary strategy including the use of appropriate diagnostic instruments, expertise, and experience. This begins with patient education and the use of new classifications to direct care in order to avoid amputations. To gain a deeper understanding of the microbiota in DFUs, new diagnostic approaches, such as the 16S ribosomal DNA sequence in bacteria, should become usable. CONCLUSION: DFU is said to have a polymicrobial nature and, depending on its geographical area, some distinct characteristics, such as wound characteristics, antibiograms based on local epidemiology, individualized antimicrobial driven treatment, routine debridement, regular wound examination, and dressing changes. New biological and molecular therapies that have been shown to enhance infection prevention, the management of the local inflammatory profile, and the efficiency of the cicatrizing mechanism often help with the above characteristics.

Ghrelin alleviates depression-like behaviour in rats subjected to high-fat diet and diurnal rhythm disturbance.

OBJECTIVES: In the era of globalization, a sedentary lifestyle is highly linked with obesity and neurobehavioral complications such as depression. While depression is associated with dopamine dysfunction in the ventral tegmental area (VTA), ghrelin enhances the dopaminergic activity in the VTA. Therefore, the present study aimed to assess the effect of ghrelin on depression-like behaviour in rats subjected to a high-fat diet (HFD) and disturbed diurnal rhythm (DDR) for 45 days. METHODS: The neurobehavioral deficits resulting from HFD and DDR in rats, and the behaviour modulation by intra-VTA administration of ghrelin, alone or in combination with ghrelin receptor antagonist were confirmed by evaluation of behavioural parameters in the elevated plus-maze, forced swim test, open field test, and rotarod assessment. Further, the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6, oxidative stress marker malondialdehyde (MDA), and antioxidants enzymes like superoxide dismutase (SOD), reduced glutathione (GSH), and catalase (CAT) were measured. RESULTS: The levels of TNF-α, IL-1ß, IL-6, and MDA were increased in the brain of HFD and DDR exposed rats, while that of SOD, GSH, and CAT were reduced. Intra-VTA ghrelin administration from day 41-45 to the HFD and DDR exposed rats improved cognitive behaviour and physical activity confirming the antidepressant effect. Moreover, ghrelin restored the levels of SOD, GSH and CAT efficiently, and reduced that of MDA, TNF-α, IL-1ß and IL-6, which signifies its protective effect. CONCLUSION: Overall, this study confirmed the ameliorative effect of ghrelin in HFD- and DDR-induced depression-like behaviour.

Therapeutic Potential and Pharmaceutical Development of a Multitargeted Flavonoid Phloretin.

Phloretin is a flavonoid of the dihydrogen chalcone class, present abundantly in apples and strawberries. The beneficial effects of phloretin are mainly associated with its potent antioxidant properties. Phloretin modulates several signaling pathways and molecular mechanisms to exhibit therapeutic benefits against various diseases including cancers, diabetes, liver injury, kidney injury, encephalomyelitis, ulcerative colitis, asthma, arthritis, and cognitive impairment. It ameliorates the complications associated with diabetes such as cardiomyopathy, hypertension, depression, memory impairment, delayed wound healing, and peripheral neuropathy. It is effective against various microbial infections including Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Escherichia coli, Candida albicans and methicillin-resistant Staphylococcus aureus. Considering the therapeutic benefits, it generated interest for the pharmaceutical development. However, poor oral bioavailability is the major drawback. Therefore, efforts have been undertaken to enhance its bioavailability by modifying physicochemical properties and molecular structure, and developing nanoformulations. In the present review, we discussed the pharmacological actions, underlying mechanisms and molecular targets of phloretin. Moreover, the review provides insights into physicochemical and pharmacokinetic characteristics, and approaches to promote the pharmaceutical development of phloretin for its therapeutic applications in the future. Although convincing experimental data are reported, human studies are not available. In order to ascertain its safety, further preclinical studies are needed to encourage its pharmaceutical and clinical development.

Verapamil hydrochloride loaded solid lipid nanoparticles: Preparation, optimization, characterisation, and assessment of cardioprotective effect in experimental model of myocardial infarcted rats.

Verapamil, a calcium channel blocker has poor bioavailability (20-30%) owing to extensive hepatic first-pass metabolism. Hence, the major objective of this research was to improve the oral bioavailability of Verapamil by Solid Lipid Nanoparticles (V-SLNs) using high shear homogenization and ultrasonication technology. A 32 factorial design was employed to statistically optimize the formulation to get minimum particle size with maximum entrapment efficiency. The average particle size was 218 nm and the entrapment efficiency was 80.32%. The V-SLN formulation exhibited biphasic behavior with a rapid release at first, then a steady release (75-80%) up to 24 h following the Korsmeyer Peppas release model. In the Isoproterenol induced myocardial necrosis model, oral administration of V-SLNs positively modulated almost all the studied hemodynamic parameters such as left ventricular end-diastolic pressure, cardiac injury markers, and tissue architecture. The cardioprotective effect was also confirmed with histopathological studies. When compared with free drugs, in-vivo pharmacokinetic studies demonstrated a rise in t1/2, AUC0-∞, and Cmax, indicating that bioavailability has improved. These encouraging results demonstrate the promising potential of developed V-SLNs for oral delivery and thereby improve the therapeutic outcome.

Ghrelin mediated regulation of neurosynaptic transmitters in depressive disorders.

Ghrelin is a peptide released by the endocrine cells of the stomach and the neurons in the arcuate nucleus of the hypothalamus. It modulates both peripheral and central functions. Although ghrelin has emerged as a potent stimulator of growth hormone release and as an orexigenic neuropeptide, the wealth of literature suggests its involvement in the pathophysiology of affective disorders including depression. Ghrelin exhibits a dual role through the advancement and reduction of depressive behavior with nervousness in the experimental animals. It modulates depression-related signals by forming neuronal networks with various neuropeptides and classical neurotransmitter systems. The present review emphasizes the integration and signaling of ghrelin with other neuromodulatory systems concerning depressive disorders. The role of ghrelin in the regulation of neurosynaptic transmission and depressive illnesses implies that the ghrelin system modulation can yield promising antidepressive therapies.

Thymoquinone Produces Cardioprotective Effect in ß-Receptor Stimulated Myocardial Infarcted Rats via Subsiding Oxidative Stress and Inflammation.

Earlier studies reported that long-term treatment with thymoquinone (TQ) at a high dose (20 mg/kg) exerts a cardioprotective effect against isoproterenol (ISO)-triggered myocardial infarction (MI) in rats. In the present study, we tested the hypothesis that TQ, as a potent molecule, can exhibit cardioprotective effects at the lower dose for a short-term regimen. The rats were administered with TQ (5 mg/kg, intraperitoneal) at the 4 h interval for 2 days. ISO (100 mg/kg/day, subcutaneous) was given for 2 days to produce MI. ISO challenge results in deformation in ECG wave front, elevated left ventricular (LV) end-diastolic pressure, and reduced LVdP/dtmax and LVdP/dtmin. The levels of the cardiac biomarker in serum, such as creatine kinase MB, alanine aminotransferase, and aspartate aminotransferase, were increased. In the myocardium, a rise in malonaldehyde and decreased superoxide dismutase, glutathione, and catalase contents were observed. Furthermore, increased levels of tumor necrotic factor-α, interleukin-6, and interleukin-1ß were observed in the myocardium. TQ pretreatment significantly normalized alterations in hemodynamic parameters, strengthened the antioxidant defense system, and decreased the contents of pro-inflammatory cytokines and hepatic enzymes as compared to the ISO group. Based on the results, TQ appears to be cardioprotective at low doses, and effective even administered for a shorter duration.

An Update on Advancements and Challenges in Inhalational Drug Delivery for Pulmonary Arterial Hypertension.

A lethal condition at the arterial-alveolar juncture caused the exhaustive remodeling of pulmonary arterioles and persistent vasoconstriction, followed by a cumulative augmentation of resistance at the pulmonary vascular and, consequently, right-heart collapse. The selective dilation of the pulmonary endothelium and remodeled vasculature can be achieved by using targeted drug delivery in PAH. Although 12 therapeutics were approved by the FDA for PAH, because of traditional non-specific targeting, they suffered from inconsistent drug release. Despite available inhalation delivery platforms, drug particle deposition into the microenvironment of the pulmonary vasculature and the consequent efficacy of molecules are influenced by pathophysiological conditions, the characteristics of aerosolized mist, and formulations. Uncertainty exists in peripheral hemodynamics outside the pulmonary vasculature and extra-pulmonary side effects, which may be further exacerbated by underlying disease states. The speedy improvement of arterial pressure is possible via the inhalation route because it has direct access to pulmonary arterioles. Additionally, closed particle deposition and accumulation in diseased tissues benefit the restoration of remolded arterioles by reducing fallacious drug deposition in other organs. This review is designed to decipher the pathological changes that should be taken into account when targeting the underlying pulmonary endothelial vasculature, especially with regard to inhaled particle deposition in the alveolar vasculature and characteristic formulations.

Development and biological evaluation of protective effect of kidney targeted N-acetylated chitosan nanoparticles containing thymoquinone for the treatment of DNA damage in cyclophosphamide-induced haemorrhagic cystitis.

Thymoquinone (TQ), the most prominent constituent of Nigella sativa seeds, essential oil, is reported to possess an organ protective effect via Nrf2 expression and activation of Phase-II antioxidant enzymes. Haemorrhagic cystitis is the sudden onset of haematuria combined with bladder pain and irritable bladder symptoms are the known toxic effects of cyclophosphamide (CYP) chemotherapy. The objective of the present study was to investigate and compare the protective effect of thymoquinone (TQ) and thymoquinone nanoparticles (TQ-NP) in the kidney against CYP-induced haemorrhagic cystitis. Primarily, TQ-NP was fabricated by synthesis of N-acetylated chitosan and nanoparticle preparation by the ionic gelation technique. They were characterized by particle size, polydispersive index (PDI), zeta potential, entrapment efficiency (EE), SEM, and dynamic scattering calorimetry (DSC). Moreover, fluorescein isothiocyanate (FITC) labeled NPs were prepared for biodistribution studies. The protective mechanisms of TQ-NP included its anti-inflammatory activity, inhibitory effects on cytokine levels, and protection against the DNA damage in the bladder epithelium. The cystitis was induced in rats by orally administering 200 mg/kg of CYP. The dose-dependent protective effect of the TQ-NP was determined by intravenously administering 1, 2, and 5 mg/kg of the TQ-NP to CYP-treated rats. The present study revealed that the TQ-NP prepared by ionic gelation method provides kidney targeted delivery of TQ as compared to TQ solution. The mean particle size, PDI, and %EE of TQ-NP were 272.6 nm, 0.216, 70.81 ± 0.12% respectively. The zeta potential of thymoquinone-loaded nanoparticles was found to be -20.7 mV and - 22.6 mV respectively before and after lyophilization. SEM study also confirmed the small size and spherical shape. Pharmacokinetic studies revealed the improvement in half-life and prolonged action of the TQ-NP as compared to the TQ solution. Also, TQ-NP administration showed more protection against the characteristic histological alterations in the bladder in comparison to TQ solution. The present study indicates that TQ-NP exerts potent anti-oxidant, DNA protective and cytokine inhibitory activity at considerably lower concentrations as compared to plain TQ solution. The nano formulation of TQ using N-acetylated chitosan provides effective kidney targeted delivery of TQ, which in turn improves its retention and protective efficacy against CYP-induced haemorrhagic cystitis.

Intranasal Nanoemulsions A Potential Strategy for Targeting The Neurodegenerative Disorder: Parkinson's.

Intranasal delivery has great potential to cross the blood-brain barrier and deliver the drug molecule into the central nervous system faster than traditional methods. The olfactory neuronal and trigeminal pathways both are involved in intranasal delivery. The nano-technology is an innovative strategy for the nose to brain delivery. The mucoadhesive nanoemulsion formulation is a modified technology that increases the duration of drug accumulation and provides prolonged delivery at a targeted site. The nanoemulsion formulation oil, surfactant, and co-surfactant components maintain lower surface tension and particle coalescence. The globule dimension and zeta potential are affected in brain targeting. The globule size of the innovative formulation should be < 200 nm for drug permeation because, in humans, the average axon magnitude ranges from around 100 to 700. Furthermore, modified technology of nanoemulsion like nanogel and nanoemulsion in-situ gel provide a great advantage to cure neurodegenerative disorders. Therefore, focusing on the innovative pharmaceutical approaches of nanoemulsion in intranasal drug delivery, the current review provides insight into the applications of nanoemulsion in neurodegenerative disorders like Parkinson's disease, which are due to the depletion of dopamine in substania nigra resulting in cardinal motor activity bradykinesia and tremors. The review also touches upon the pathways for intranasal delivery of nanoemulsion, the pathogenesis of Parkinson's disease, and the future direction of the research on intranasal nanoemulsion.

Curcumin Protects Diabetic Mice against Isoproterenol-Induced Myocardial Infarction by Modulating CB2 Cannabinoid Receptors.

Molecular docking revealed curcumin as a potent CB2 cannabinoid receptor (CB2R) agonist. Since CB2R is involved in cardioprotective functions, we explored its role in ameliorative actions of curcumin against myocardial damage triggered by isoproterenol in diabetic animals. Mice were kept on a high-fat diet (HFD) throughout the experiment (30 days). Following 7 days of HFD feeding, streptozotocin was administered (150 mg/kg, intraperitoneal) to induce diabetes. From day 11 to 30, diabetic mice received either curcumin (100 or 200 mg/kg/day, oral), CB2R antagonist AM630 (1 mg/kg/day, intraperitoneal) or both, with concurrent isoproterenol (150 mg/kg, subcutaneous) administration on day 28 and 29. Diabetic mice with myocardial infarction showed an altered hemodynamic pattern and lipid profile, reduced injury markers, antioxidants with increased lipid peroxidation in the myocardium, and elevated glucose and liver enzymes in the blood. Moreover, an increased pro-inflammatory markers, histological severity, myonecrosis, and edema were observed. Curcumin compensated for hemodynamic fluctuations, restored biochemical markers, preserved antioxidant capacity, decreased cytokines levels, and restored cardiac functionality. However, the AM630 pre-treatment attenuated the effects of curcumin. The data suggest the involvement of CB2R in the actions of curcumin such as in the prevention of myocardial stress and in the improvement of the normal status of the myocardial membrane associated with diabetes.

Health Benefits, Pharmacological Effects, Molecular Mechanisms, and Therapeutic Potential of α-Bisabolol.

α-Bisabolol is one of the important monocyclic sesquiterpenes, derived naturally from essential oils of many edible and ornamental plants. It was first obtained from Matricaria chamomilla, commonly known as chamomile or German chamomile. The available literature indicates that this plant along with other α-Bisabolol containing plants is popularly used in traditional medicine for potential health benefits and general wellbeing. Nutritional studies are indicative of the health benefits of α-Bisabolol. Numerous experimental studies demonstrated pharmacological properties of α-Bisabolol including anticancer, antinociceptive, neuroprotective, cardioprotective, and antimicrobial. This review aims to collectively present different pharmacological activities based on both in vitro and in vivo studies. In the present review using synoptic tables and figures, we comprehensively present that α-Bisabolol possesses therapeutic and protective activities, therefore, it can be used for potential health benefits based on pharmacological effects, underlying molecular mechanism, and favorable pharmaceutical properties. Based on the studies mostly performed on cell lines or animal models, it is evident that α-Bisabolol may be a promising nutraceutical and phytomedicine to target aberrant biological mechanisms which result in altered physiological processes and various ailments. Given the polypharmacological effects and pleiotropic properties, along with favorable pharmacokinetics, and dietary availability and safety, α-Bisabolol can be used as a dietary agent, nutraceutical or phytopharmaceutical agent or as an adjuvant with currently available modern medicines. The regulatory approval of this molecule for use as food additives, and in cosmetics and fragrance industry is also supportive of its human usage. Moreover, further studies are necessary to address pharmaceutical, pharmacological, and toxicological aspects before clinical or nutritional usage in humans. The biological actions and health benefits open opportunities for pharmaceutical development with pharmacological basis of its use in future therapeutics.

In vitro and in vivo characterization of Entacapone-loaded nanostructured lipid carriers developed by quality-by-design approach.

Entacapone, a reversible catechol-o-methyl transferase inhibitor, is used to enhance the action of dopamine agonists by reducing their metabolism and the 'Wearing-off' effects associated with long-term use in the treatment of Parkinson's disease. It is used as an adjunct to levodopa/Carbidopa therapy. Due to limited dissolution and first-pass clearance, it suffers low and variable bioavailability issues. To overcome this problem, the present study aims to explore the potential of nanostructured lipid carriers (NLCs) for the delivery of Entacapone. The Quality by Design (QbD) approach was used for the systematic development of NLCs. The 23 full factorial designs were investigated using Design-Expert®11 software. The three independent variables namely content of total lipid (X1), surfactant (X2), and sonication time (X3) were optimized against two responses namely particle size and entrapment efficiency. The optimized NLCs were characterized for their size, surface morphology, entrapment efficiency, drug release, thermal and crystallographic studies. In-vivo pharmacokinetic studies in Entacapone-loaded NLCs showed an increase in t1/2, AUC0-∞, MRT compared to free drug. The reduction in elimination (Kel) depicts the prolonged action of Entacapone by loading in NLCs. The results displayed Entacapone-loaded NLCs have promising potential for oral delivery and enhanced therapeutic effect which otherwise was a major issue.

Ezetimibe-Loaded Nanostructured Lipid Carrier Based Formulation Ameliorates Hyperlipidaemia in an Experimental Model of High Fat Diet.

Ezetimibe (EZE) possesses low aqueous solubility and poor bioavailability and in addition, its extensive hepatic metabolism supports the notion of developing a novel carrier system for EZE. Ezetimibe was encapsulated into nanostructured lipid carriers (EZE-NLCs) via a high pressure homogenization technique (HPH). A three factor, two level (23) full factorial design was employed to study the effect of amount of poloxamer 188 (X1), pressure of HPH (X2) and number of HPH cycle (X3) on dependent variables. Particle size, polydispersity index (PDI), % entrapment efficiency (%EE), zeta potential, drug content and in-vitro drug release were evaluated. The optimized formulation displays pragmatic inferences associated with particle size of 134.5 nm; polydispersity index (PDI) of 0.244 ± 0.03; zeta potential of -28.1 ± 0.3 mV; % EE of 91.32 ± 1.8% and % CDR at 24-h of 97.11%. No interaction was observed after X-ray diffraction (XRD) and differential scanning calorimetry (DSC) studies. EZE-NLCs (6 mg/kg/day p.o.) were evaluated in the high fat diet fed rats induced hyperlipidemia in comparison with EZE (10 mg/kg/day p.o.). Triglyceride, HDL-c, LDL-c and cholesterol were significantly normalized and histopathological evaluation showed normal structure and architecture of the hepatocytes. The results demonstrated the superiority of EZE-NLCs in regard to bioavailability enhancement, dose reduction and dose-dependent side effects.

Plant-derived natural therapeutics targeting cannabinoid receptors in metabolic syndrome and its complications: A review.

The endocannabinoid system (ECS) is natural physiological system in the humans. The presence of the ECS system involves different roles in body. The endocannabinoid system involves regulation of most of the centers, which regulates the hunger and leads to changes in the weight. In the present article, we reviewed the role of natural cannabinoid compounds in metabolic disorders and related complications. We studied variety of a plant-derived cannabinoids in treating the metabolic syndrome including stoutness, fatty acid liver diseases, insulin obstruction, dementia, hypertension, lipid abnormalities, non-alcoholic steatohepatitis, endothelial damage, and polycystic ovarian syndrome and so on. The activation of cannabinoid receptors demonstrates a significant number of beneficial approaches concerning metabolic syndrome and reduces the pro-inflammatory cytokines on account of aggravation, decreased oxidative stress and uneasiness, diminishes liver fibrosis, with reduces adiponectin. Pre-clinical investigations of plant-derived cannabinoids resulted in promising outcomes. The different distinctive plant-derived cannabinoids were discovered like cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), and cannabidiol (CBG). It has been observed that endogenous cannabinoids and plant-derived cannabinoids have an advantageous impact on limiting the metabolic disorder arising due to lifestyle changes.

Methotrexate-Loaded Nanostructured Lipid Carrier Gel Alleviates Imiquimod-Induced Psoriasis by Moderating Inflammation: Formulation, Optimization, Characterization, In-Vitro and In-Vivo Studies.

INTRODUCTION: Methotrexate exhibits poor cutaneous bioavailability and systemic side effects on topical administration, so there is an unmet need for a novel carrier and its optimized therapy. Methotrexate-loaded nanostructured lipid carriers (MTXNLCs) were formulated and characterized to determine in vitro drug release and evaluate the role of MTXNLC gel in the topical treatment of psoriasis. METHODS: A solvent diffusion technique was employed to prepare MTXNLCs, which was optimized using 32 full factorial designs. The mean diameter and surface morphology of MTXNLCs was evaluated. The crystallinity of lyophilized MTXNLCs was characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). MTXNLCs were integrated in 1% w/w Carbopol 934 P gel base, and in vitro skin deposition studies in human cadaver skin (HCS) were carried out. RESULTS: The optimized MTXNLCs were rod-shaped, with an average particle size of 253 ± 8.65 nm, a zeta potential of -26.4±0.86 mV, and EE of 54.00±1.49%. DSC and XRD data confirmed the formation of NLCs. Significantly higher deposition of MTX was found in HCS from MTXNLC gel (71.52 ±1.13%) as compared to MTX plain gel (38.48±0.96%). In vivo studies demonstrated significant improvement in therapeutic response and reduction in local side effects with MTXNLCs-loaded gel in the topical treatment of psoriasis. Anti-psoriatic efficacy of MTXNLCs 100 ug/cm2 compared with plain MTX gel was evaluated using imiquimod (IMQ)-induced psoriasis in BALB/c mice. The topical application of MTXNLCs to the mouse ear resulted in a significant reduction of psoriatic area and severity index, oxidative stress, inflammatory cytokines like TNF-α, IL-1ß, and IL-6 and IMQ-induced histopathological alterations in mouse ear samples. CONCLUSION: Developed formulation of MTXNLC gel demonstrated better anti-psoriatic activity and also displayed prolonged and sustained release effect, which shows that it can be a promising alternative to existing MTX formulation for the treatment of psoriasis.

Eplerenone attenuates myocardial infarction in diabetic rats via modulation of the PI3K-Akt pathway and phosphorylation of GSK-3ß.

We investigated the effect of eplerenone on myocardial infarcted diabetic rats via modulation of the PI3K/Akt pathway and its downstream target GSK-3ß. Diabetes was induced by administration of a single dose of streptozotocin (55 mg/kg IP). Diabetic rats received either eplerenone or PI3k/Akt antagonist (wortmannin) or in combination for 14 days with concurrent administration of isoproterenol (100 mg/kg s.c) on 13th and 14th day. Isoproterenol prompted cardiotoxicity and was demonstrated by a decrease in the maximal positive rate of developed left ventricular pressure, the maximal negative rate of developed left ventricular pressure and an increase in left ventricular end-diastolic pressure along with oxidative stress. Myocardial infarcted diabetic rats exhibited increased myonecrosis, edema, and apoptotic cell death. Treatment with eplerenone significantly improved the redox status of the myocardium. Eplerenone markedly inhibited Bax expression, TUNEL-positive cells, and myonecrosis. On the other hand, the administration of eplerenone and wortmanin did not draw out the same effects, when administered concomitantly or individually. Moreover, the rats treated with eplerenone showed increased expression of PI3K/Akt and decreased its downstream target GSK-3ß. The present study confirms the protective effects of eplerenone on myocardial infarction in diabetic rats via modulation of PI3K/Akt pathway and its downstream regulator GSK-3ß.