Biochemical evaluation and medicinal ability of Jatropha mollissima in hepatic disorders.

OBJECTIVE: Jatropha mollissima is one of the most valuable medicinal plants used for the treatment of hepatic disorders. It is evident that 500 mg/kg of sodium valproate causes the hepatotoxicity, ototoxicity, gastrotoxicity, bone marrow suppression, and inflammation. This study was designed to explore the medicinal uses of Jatropha mollissima in hepatic disorders. METHODS: Hepatotoxicity was induced in Wister albino rats by injecting sodium valproate at the rate of 500 mg/kg once daily for fourteen days. Six male rats, each weighing 220-270 g, were placed into four separate groups for the study. The first group was treated with normal saline. Treatment of the second group was carried out by SVP for four days consecutively together with saline for three weeks. Group three and four were treated with sodium valproate and Jm hydroalcoholic extract applied in the concentrations of the 200 mg/kg and 400 mg/kg for the period of the three weeks. Phytochemical screening and HPLC analysis were conducted to identify the phytochemical nature and polyphenols in extract, respectively. DPPH, SOD, and NO tests were performed to measure the antioxidant activity. RESULTS: With the initial dose of treatments to rats, anatomic, physiological, or histopathologic abnormalities were detected. After three weeks, extract of Jatropha mollissima was used to treat the valproic acid-induced hepatotoxicity (P < 0.05). CONCLUSION: It was concluded that sodium valproate (SVP) and Jm extract were administered together. The hepatoprotective effects were extraordinarily high, with high concentrations of 400 mg/kg.

In vivo antioxidants, chemical characterization and biochemical and medicinal potential of Murraya koenigii in cisplatin-induced nephrotoxicity.

Murraya koenigii (Mk) is an old plant with a significant therapeutic value throughout Africa, Asia, and Latin America. The excessive use of cisplatin (Cis> 50 mg/m2) is associated with nephrotoxicity, ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions. Remedial measures are needed for the protection of nephrotoxicity against cisplatin. Thus, we have investigated Mk leaf extract's nephroprotective effects to prevent cisplatin-induced nephrotoxicity in Wistar albino rats. The presence of polyphenols, phenolic compounds, tannins, and saponins was revealed during phytochemical investigation, and antioxidant activity was recorded. There were no toxicological symptoms in the treated rats, and no anatomical, physiological, or histological abnormalities were found compared to the control rats. The results of correcting cisplatin-induced nephrotoxicity revealed that the extract has a significant ability to treat kidney damage, with most parameters returning to normal after only three weeks of therapy. It was concluded that co-administered cisplatin with Mk leaves extract showed exceptional nephroprotective effects at a 400 mg/kg dose ratein Cis-induced nephrotoxicity.

A Review of Twenty Years of Research on the Regulation of Signaling Pathways by Natural Products in Breast Cancer.

Breast cancer (BC) is the second leading cause of death among women, and it has become a global health issue due to the increasing number of cases. Different treatment options, including radiotherapy, surgery, chemotherapy and anti-estrogen therapy, aromatase inhibitors, anti-angiogenesis drugs, and anthracyclines, are available for BC treatment. However, due to its high occurrence and disease progression, effective therapeutic options for metastatic BC are still lacking. Considering this scenario, there is an urgent need for an effective therapeutic strategy to meet the current challenges of BC. Natural products have been screened as anticancer agents as they are cost-effective, possess low toxicity and fewer side effects, and are considered alternative therapeutic options for BC therapy. Natural products showed anticancer activities against BC through the inhibition of angiogenesis, cell migrations, proliferations, and tumor growth; cell cycle arrest by inducing apoptosis and cell death, the downstream regulation of signaling pathways (such as Notch, NF-κB, PI3K/Akt/mTOR, MAPK/ERK, and NFAT-MDM2), and the regulation of EMT processes. Natural products also acted synergistically to overcome the drug resistance issue, thus improving their efficacy as an emerging therapeutic option for BC therapy. This review focused on the emerging roles of novel natural products and derived bioactive compounds as therapeutic agents against BC. The present review also discussed the mechanism of action through signaling pathways and the synergistic approach of natural compounds to improve their efficacy. We discussed the recent in vivo and in vitro studies for exploring the overexpression of oncogenes in the case of BC and the current status of newly discovered natural products in clinical investigations.

Novasomes as Nano-Vesicular Carriers to Enhance Topical Delivery of Fluconazole: A New Approach to Treat Fungal Infections.

The occurrence of fungal infections has increased over the past two decades. It is observed that superficial fungal infections are treated by conventional dosage forms, which are incapable of treating deep infections due to the barrier activity possessed by the stratum corneum of the skin. This is why the need for a topical preparation with advanced penetration techniques has arisen. This research aimed to encapsulate fluconazole (FLZ) in a novasome in order to improve the topical delivery. The novasomes were prepared using the ethanol injection technique and characterized for percent entrapment efficiency (EE), particle size (PS), zeta potential (ZP), drug release, Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM) and antifungal activity. The FN7 formulation with 94.45% EE, 110 nm PS and -24 ZP proved to be the best formulation. The FN7 formulation showed a 96% release of FLZ in 8 h. FTIR showed the compatibility of FLZ with excipients and DSC studies confirmed the thermal stability of FLZ in the developed formulation. The FN7 formulation showed superior inhibition of the growth of Candida albicans compared to the FLZ suspension using a resazurin reduction assay, suggesting high efficacy in inhibiting fungal growth.

Synthesis of Chemically Cross-Linked pH-Sensitive Hydrogels for the Sustained Delivery of Ezetimibe.

In recent years, pH-sensitive hydrogels have been developed for the delivery of therapeutic agents to specific target sites that have a defined pH range. The use of pH-responsive polymers in hydrogels allows drug delivery to the desired pH range of the target organ. The primary aim is to increase the retention time of the drug in the small intestine by utilizing the swelling mechanism of the hydrogel at intestinal pH. In this study, polyethylene glycol (PEG) was used as a polymer to formulate a pH-sensitive hydrogel of Ezetimibe to deliver the drug to the small intestine where it inhibits the absorption of cholesterol. Design Expert software was applied to design and optimize the trial formulations in order to obtain an optimized formulation that has all the desired characteristics of the hydrogels. The PEG/Acrylic Acid hydrogels showed the maximum swelling at pH 6.8, which is consistent with the pH of the small intestine (pH 6-7.4). The maximum entrapment efficiency of the hydrogels was 99%. The hydrogel released 80-90% of the drug within 24 h and followed first-order release kinetics, which showed that the release from the drug was sustained. Hence, the results showed that the choice of a suitable polymer can lead to the development of an efficient drug-loaded hydrogel that can deliver the drug at the specific pH of the target organ.

Evaluation of the hepatoprotective activity of hydroalcoholic extract of Alhagi camelorum against valproic acid-induced hepatotoxicity in rats.

BACKGROUND AND PURPOSE: Despite many liver disorders, clinically useful drugs are scarce. Moreover, the available therapies are facing the challenges of efficacy and safety. Alhagi camelorum has been used in folk medicine globally for millennia to treat several ailments. Alhagi camelorum (Ac) is an old plant with a significant therapeutic value throughout Africa, Asia, and Latin America. Our goal was to determine the hepatoprotective activity of Alhagi camelorum against valproic acid induced hepatotoxicity using an animal model. EXPERIMENTAL APPROACH: The animals were segregated in 4-groups (6 male rats each) weighing 250-290 g. Group-1 animals were treated with normal saline, Group-2 animals were treated with VPA at the dose of 500 mg/kg i.p for 14 days consecutively, while Group-3 and 4 were treated with valproic acid (VPA) at the dose of 500 mg/kg i.p for 14 days along with 400 mg/kg and 600 mg/kg of Ac hydroalcoholic extract respectively. Subsequently, blood serum samples and liver tissues were collected for biochemical and histopathological analysis. Phytochemical screening was carried out to screen for phytochemical classes and HPLC analysis was conducted to screen polyphenols. The antioxidant activity was carried by different assays such as DPPH, SOD, NO etc. KEY RESULTS: The administration of Ac showed hepatoprotection at the doses of 400 and 600 mg/kg. Ac significantly reduces the elevated serum levels of liver biomarkers compared to the valproic acid-induced hepatotoxic group. These findings were confirmed with histopathological changes where Ac was capable of reversing the toxic effects of valproic acid on liver cells CONCLUSION: It is concluded that Ac showed significant hepatoprotective effects at different doses in the animal model used in this study.

Nephroprotective Effects of Alhagi camelorum against Cisplatin-Induced Nephrotoxicity in Albino Wistar Rats.

Alhagi camelorum (AC) is an old plant with a significant therapeutic value throughout Africa, Asia, and Latin America. The overuse of cisplatin (Cis > 50 mg/m2) is associated with observed nephrotoxicity, ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions. Remedial measures are needed for the protection of nephrotoxicity against cisplatin. Thus, we investigated the nephroprotective effects of AC plant extract to prevent cisplatin-induced nephrotoxicity in albino Wistar rats. The presence of polyphenols, phenolic compounds, tannins, and saponins was revealed during phytochemical investigation, and a significantly intense antioxidant activity was recorded. There were no toxicological symptoms in the treated rats, and no anatomical, physiological, or histological abnormalities were found compared to the control rats. The results of correcting cisplatin-induced nephrotoxicity revealed that the extract has a significant ability to treat kidney damage, with most parameters returning to normal after only three weeks of therapy. It is concluded that co-administration of cisplatin with AC extract showed exceptional nephroprotective effects at a dose of 600 mg/kg for Cis-induced nephrotoxicity.

Post interferon therapy decreases male fertility through gonadotoxic effect.

Prevalence of hepatitis C virus (HCV) has been seen in more than 15% of Pakistani population. For the treatment of this infection, only two medicines, interferon, and ribavirin were approved in 1998. The concerned physicians evaluate side effects of these two antiviral drugs only during the treatment period. The long-term extra hepatic side effects are being neglected. This retrospective study was conducted with reference to induced infertility in HCV treated 40 male patients from the period 2008-2015. Possible effects of interferon therapy on fertility hormones and seminal parameters were assessed. Level of fertility hormones like serum Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), and testosterone was measured. For seminal parameters, guidelines from World Health Organization (WHO) were followed. Among forty cases of HCV patients who received interferon, only 14 (35%) have children and 26 (65%) could not conceive (p = 0.0372). After HCV treatment, HCV positive patients showed a significant change in the level of FSH, LH (p<0.05). Especially, it decreased testosterone level (p=0.0096). Similarly, HCV treatment significantly decreased sperm count (p=0.001) and motility (p=0.0005).

3D Printing Technology in Design of Pharmaceutical Products.

BACKGROUND: Three-dimensional printing (3DP) is a novel technology for fabrication of personalized medicine. As of late, FDA affirmed 3D printed tranquilize item in August 2015, which is characteristic of another section of Pharmaceutical assembling. 3DP incorporates a wide range of assembling procedures, which are altogether founded on computer-aided design (CAD), and controlled deposition of materials (layer-by-layer) to make freestyle geometries. Conventionally, many pharmaceutical processes like compressed tablet have been used from many years for the development of tablet with established regulatory pathways. But this simple process is outdated in terms of process competence and manufacturing flexibility (design space). 3DP is a new technology for the creation of plan, proving to be superior for complex products, customized items and items made on-request. It creates new opportunities for improving efficacy, safety, and convenience of medicines. METHOD: There are many of the 3D printing technology used for the development of personalized medicine on demand for better treatment like 3D powder direct printing technology, fused-filament 3D printing, 3D extrusion printer, piezoelectric inkjet printer, fused deposition 3D printing, 3D printer, ink-jet printer, micro-drop inkjet 3DP, thermal inkjet printer, multi-nozzle 3D printer, stereolithographic 3D printer. RESULT: This review highlights features how item and process comprehension can encourage the improvement of a control technique for various 3D printing strategies. CONCLUSION: It is concluded that the 3D printing technology is a novel potential for manufacturing of personalized dose medicines, due to better patient compliance which can be prepared when needed.

Melatonin ameliorates hypoglycemic stress-induced brain endothelial tight junction injury by inhibiting protein nitration of TP53-induced glycolysis and apoptosis regulator.

Severe hypoglycemia has a detrimental impact on the cerebrovasculature, but the molecular events that lead to the disruption of the integrity of the tight junctions remain unclear. Here, we report that the microvessel integrity was dramatically compromised (59.41% of wild-type mice) in TP53-induced glycolysis and apoptosis regulator (TIGAR) transgenic mice stressed by hypoglycemia. Melatonin, a potent antioxidant, protects against hypoglycemic stress-induced brain endothelial tight junction injury in the dosage of 400 nmol/L in vitro. FRET (fluorescence resonance energy transfer) imaging data of endothelial cells stressed by low glucose revealed that TIGAR couples with calmodulin to promote TIGAR tyrosine nitration. A tyrosine 92 mutation interferes with the TIGAR-dependent NADPH generation (55.60% decreased) and abolishes its protective effect on tight junctions in human brain microvascular endothelial cells. We further demonstrate that the low-glucose-induced disruption of occludin and Caludin5 as well as activation of autophagy was abrogated by melatonin-mediated blockade of nitrosative stress in vitro. Collectively, we provide information on the detailed molecular mechanisms for the protective actions of melatonin on brain endothelial tight junctions and suggest that this indole has translational potential for severe hypoglycemia-induced neurovascular damage.

Calmodulin inhibitor ameliorates cognitive dysfunction via inhibiting nitrosative stress and NLRP3 signaling in mice with bilateral carotid artery stenosis.

AIMS: Vascular dementia (VaD) is a heterogeneous brain disorder for which there are no effective approved pharmacological treatments available. We aimed to evaluate the effect of calmodulin inhibitor, DY-9836, and its loaded nanodrug carrier system on cognitive impairment and gain a better understanding of the protective mechanisms in mice with bilateral carotid artery stenosis (BCAS). RESULTS: DY-9836 (0.5 or 1 mg/kg) or DY-9836 (0.25 mg/kg)-encapsulated polysialic acid-octadecylamine (PSA-ODA) micelles (PSA-ODA/DY) were given to BCAS mice for 4 weeks. Administration of DY-9836 or PSA-ODA/DY reduced escape latency in space exploration and working memory test compared with vehicle group. Vehicle-treated mice showed reduced phospho-CaMKII (Thr286/287) levels in the hippocampus, whereas partially restored by DY-9836 (1 mg/kg) or PSA-ODA/DY (0.25 mg/kg) treatment. In accordance with the pharmacological profile of DY-9836 observed during behavioral studies, experimental molecular and biochemical markers induced by BCAS, such as protein tyrosine nitration, Nod-like receptor protein 3 (NLRP3), caspase-1, and interleukin-1ß, were reduced by DY-9836 and PSA-ODA/DY treatment. CONCLUSIONS: These data disclose novel findings about the therapeutic potential of DY-9836, and its encapsulated nanodrug delivery system significantly enhanced the cognitive function via inhibitory effect on nitrosative stress and NLRP3 signaling in VaD mice.

Anti-cholinergic and Ca2+-antagonist mechanisms explain the pharmacological basis for folkloric use of Sisymbrium irio Linn. in gastrointestinal, airways and vascular system ailments.

ETHNOPHARMACOLOGICAL RELEVANCE: Seeds of Sisymbrium irio Linn has been used traditionally in different regions of Pakistan for the treatment of gastrointestinal, airways and vascular system ailments. To insight the pharmacological basis, in vitro study was conducted in order to validate its folkloric uses. MATERIAL AND METHODS: 70% aqueous-methanolic extract of seeds from S. irio (Si.MEs) was tested on isolated rabbit aorta, jejunum and trachea strip hanged in tissue bath having physiological solutions aerated with carbogen and their responses were measured and recorded via Power Lab. RESULTS: The Si.MEs exhibited the transient spasmogenic effect (0.01-1.0mg/mL) on spontaneous jejunum contractions, followed by the spasmolytic effect. The addition of atropine resulted in blocking in spasmogenic effect while the spasmolytic effect was originated, suggesting the presence of an antimuscarinic effect. Likewise verapamil, Si.MEs (0.03-5mg/mL) repressed the high concentration K+(80mM)-induced contraction and also drifted the Ca2+ concentration-response curves toward right (0.3-3.0mg/mL), possibly signifying the Ca2+ channel blockade. Furthermore, Si.MEs exhibited nonspecific relaxant effect on carbachol (1µM)- and high concentration K+(80mM)-induced tracheal contractions in a way comparable to dicyclomine, suggesting the coexistence of Ca2+-antagonistic and/or antimuscarinic properties. Additionally, Si.MEs also relaxed the phenylephrine(1µM)- and high concentration K+(80mM)-induced aortic contraction (0.01-3mg/mL), suggesting blockade of Ca2+ channel. Moreover, oral administration of Si.MEs, as high as 6g per kg, did not produce lethality among the treated groups of mice. CONCLUSIONS: Aqueous-methanolic extract of seeds from S. irio (Si.MEs) exhibited the bronchodilator and gut modulator (spasmogenic and spasmolytic) activities, probably through dual blockade of muscarinic receptors and Ca2+ channels, whereas, vasodilator effect may be due to Ca2+ channels blockade.

Diuretic and serum electrolyte regulation potential of aqueous methanolic extract of Solanum surattense fruit validates its folkloric use in dysuria.

BACKGROUND: Solanum surattense Burm. (Solanaceae) is traditionally used for management of various ailments. The study was conducted for provision of pharmacological justification for folkloric uses of Solanum surattense in the treatment of dysuria. METHODS: Rats were randomly divided into 5 groups, each of (n = 6). Aqueous methanolic fruit extract of S. surattense were also administered intraperitoneally to the rats at doses of 50, 70 and 100 mg/kg. Furosemide (10 mg/kg i.p) was used as standard drug whereas controls were given saline solution (40 mL/kg i.p). The electrolytes in urine were measured using a flame photometer whereas serum sodium, potassium, calcium, bicarbonate and blood urea nitrogen (BUN) were determined by using an automatic analyzer. Urine osmolality was assayed by the micro-osmometer. RESULTS: The extract S. surattense induced diuretic effects in a dose-dependent manner as compared with control. Upon administration of extract (70 and 100 mg/kg), we observed the prominent (p < 0.01) increase in the urine volume and osmolality in comparison to control group. However, plant extract (100 mg/kg) significantly increase the urinary electrolyte excretion especially calcium (p < 0.05) to that of the furosemide whereas level of magnesium remains constant. Moreover, our results showed a decrease in serum levels of sodium, potassium, calcium and blood urea nitrogen (BUN), but concentration dependent increase in bicarbonate was found in the test groups. There was no substantial change in the pH of urine samples of the extract-treated groups. CONCLUSION: These results indicate that S. surattense investigated exert its action by causing diuresis in the treatment of dysuria.

Melatonin reverses the decreases in hippocampal protein serine/threonine kinases observed in an animal model of autism.

Lower global cognitive function scores are a common symptom of autism spectrum disorders (ASDs). This study investigates the effects of melatonin on hippocampal serine/threonine kinase signaling in an experimental ASD model. We found that chronic melatonin (1.0 or 5.0 mg/kg/day, 28 days) treatment significantly rescued valproic acid (VPA, 600 mg/kg)-induced decreases in CaMKII (Thr286), NMDAR1 (Ser896), and PKA (Thr197) phosphorylation in the hippocampus without affecting total protein levels. Compared with control rats, the immunostaining of pyramidal neurons in the hippocampus revealed a decrease in immunolabeling intensity for phospho-CaMKII (Thr286) in the hippocampus of VPA-treated rats, which was ameliorated by chronic melatonin treatment. Consistent with the elevation of CaMKII/PKA/PKC phosphorylation observed in melatonin-treated rat, long-term potentiation (LTP) was enhanced after chronic melatonin (5.0 mg/kg) treatment, as reflected by extracellular field potential slopes that increased from 56 to 60 min (133.4 ± 3.9% of the baseline, P < 0.01 versus VPA-treated rats) following high-frequency stimulation (HFS) in hippocampal slices. Accordingly, melatonin treatment also significantly improved social behavioral deficits at postnatal day 50 in VPA-treated rats. Taken together, the increased phosphorylation of CaMKII/PKA/PKC signaling might contribute to the beneficial effects of melatonin on autism symptoms.

The effect of lipid nanoparticle PEGylation on neuroinflammatory response in mouse brain.

Nanocarrier-based drug delivery systems have attracted wide interest for the treatment of brain disease. However, neurotoxicity of nanoparticle has limited their therapeutic application. Here we demonstrated that lipid nanoparticles (LNs) accumulated in the brain parenchyma within 3 h of intravenous injection to mice and persisted for more than 24 weeks, coinciding with a dramatic activation of brain microglia. Morphological characteristic of microglial activation also observed in LNs-treated Cx3cr1GFP/+ mice. In vivo study with two-photon confocal microscopy revealed abnormal Ca²âº waves in microglia following LNs injection. The correlated activation of caspase-1, IL-1ß and neurovascular damage following LNs injection was attenuated in P2X7-/- mice. PEGylation of LNs reduced correlated nanoparticles aggregation. Moreover, PEGylation of LNs ameliorated the P2X7/caspase-1/IL-1ß signalling-dependent microglia activation and neurovascular damage. In conclusion, PEGylation of LNs is a promising biomaterial for brain-targeted therapy that inhibits P2X77-dependent neuroinflammatory response.