An Anti-inflammatory Fe3 O4 -Porphyrin Nanohybrid Capable of Apoptosis through Upregulation of p21 Kinase Inhibitor Having Immunoprotective Properties under Anticancer PDT Conditions.

We report the influence of Fe3 O4 nanoparticles (NPs) on porphyrins in the development of photosensitizers (PSs) for efficient photodynamic therapy (PDT) and possible post-PDT responses for inflicting cancer cell death. Except for Au, most metal-based nanomaterials are unsuitable for clinical applications. The US Food and Drug Administration and other agencies have approved Feraheme and a few other iron oxide NPs for clinical use, paving the way for novel biocompatible immunoprotective superparamagnetic iron oxide nanohybrids to be developed as nanotherapeutics. A water-soluble nanohybrid, referred to here as E-NP, comprising superparamagnetic Fe3 O4 NPs functionalised with tripyridyl porphyrin PS was introduced through a rigid 4-carboxyphenyl linker. As a PDT agent, the efficacy of E-NP toward the AGS cancer cell line showed enhanced photosensitising ability as determined through in vitro photobiological assays. The cellular uptake of E-NPs by AGS cells led to apoptosis by upregulating ROS through cell-cycle arrest and loss of mitochondrial membrane potential. The subcellular localisation of the PSs in mitochondria stimulated apoptosis through upregulation of p21, a proliferation inhibitor capable of preventing tumour development. Under both PDT and non-PDT conditions, this nanohybrid can act as an anti-inflammatory agent by decreasing the production of NO and superoxide ions in murine macrophages, thus minimising collateral damage to healthy cells.

Synthesis and biological evaluation of novel schisanhenol derivatives as potential hepatoprotective agents.

Twenty-one new schisanhenol derivatives were synthesized, and their hepatoprotective effects against liver injury induced by concanavalin A (Con A) were evaluated in vitro using an MTT assay. The data indicated that most derivatives exhibited equivalent or better protective activity than the positive control (dimethyl dicarboxylate biphenyl, DDB) under the same conditions. Among them, compound 1b showed the most potent hepatoprotective activity against Con A-induced immunological injury. Mechanistic studies in vitro revealed that 1b inhibited cell apoptosis and inflammatory responses caused by Con A treatment via IL-6/JAK2/STAT3 signaling pathway. Consistently, it also exhibited significant hepatoprotective activity in mice with Con A-induced immunological liver injury. These results clearly indicated that 1b might be a highly potent hepatoprotective agent targeting IL-6/STAT3 signaling pathway.

Discovery of a novel and orally active Farnesoid X receptor agonist for the protection of acetaminophen-induced hepatotoxicity.

Acetaminophen (APAP) overdose is a leading cause of acute hepatic failure and liver transplantation, while the existing treatments are poorly effective. Therefore, it is necessary to develop effective therapeutic drugs for APAP-induced hepatotoxicity. Farnesoid X receptor (FXR) is a potential target for the treatment of liver disease, and the activation of FXR protects mice against APAP-induced hepatotoxicity. Compound 5, a glycine-conjugated derivative of FXR agonist 4, was designed to extend the chemical space of existing FXR agonists. Molecular modeling study indicated that compound 5 formed hydrogen bond network with key residues of FXR. Moreover, compound 5 (10 mg/kg) revealed better protective effects against APAP-induced hepatotoxicity than parent compound 4 (30 mg/kg). Further mechanical research indicated that compound 5 regulated the expressions of genes related to FXR and oxidative stress. These findings suggest that compound 5 is a promising FXR agonist suitable for further research, and it is the first time to verify that the glycine-conjugated derivative five exerted better protective effects than its parent compound.

Targeting Ferroptosis by Polydopamine Nanoparticles Protects Heart against Ischemia/Reperfusion Injury.

Ferroptosis is a new form of regulated cell death depending on elevated iron (Fe2+) and lipid peroxidation levels. Myocardial ischemia/reperfusion (I/R) injury has been shown to be closely associated with ferroptosis. Therefore, antiferroptosis agents are considered to be a new strategy for managing myocardial I/R injury. Here, we developed polydopamine nanoparticles (PDA NPs) as a new type of ferroptosis inhibitor for cardioprotection. The PDA NPs features intriguing properties in inhibiting Fe2+ accumulation and restoring mitochondrial functions in H9c2 cells. Subsequently, we demonstrated that administration of PDA NPs effectively reduced Fe2+ deposition and lipid peroxidation in a myocardial I/R injury mouse model. In addition, the myocardial I/R injury in mice was alleviated by PDA NPs treatment, as demonstrated by reduced infarct size and improved cardiac functions. The present work indicates the therapeutic effects of PDA NPs against myocardial I/R injury via preventing ferroptosis.

Panduratin A Derivative Protects against Cisplatin-Induced Apoptosis of Renal Proximal Tubular Cells and Kidney Injury in Mice.

BACKGROUND: Panduratin A is a bioactive cyclohexanyl chalcone exhibiting several pharmacological activities, such as anti-inflammatory, anti-oxidative, and anti-cancer activities. Recently, the nephroprotective effect of panduratin A in cisplatin (CDDP) treatment was revealed. The present study examined the potential of certain compounds derived from panduratin A to protect against CDDP-induced nephrotoxicity. METHODS: Three derivatives of panduratin A (DD-217, DD-218, and DD-219) were semi-synthesized from panduratin A. We investigated the effects and corresponding mechanisms of the derivatives of panduratin A for preventing nephrotoxicity of CDDP in both immortalized human renal proximal tubular cells (RPTEC/TERT1 cells) and mice. RESULTS: Treating the cell with 10 µM panduratin A significantly reduced the viability of RPTEC/TERT1 cells compared to control (panduratin A: 72% ± 4.85%). Interestingly, DD-217, DD-218, and DD-219 at the same concentration did not significantly affect cell viability (92% ± 8.44%, 90% ± 7.50%, and 87 ± 5.2%, respectively). Among those derivatives, DD-218 exhibited the most protective effect against CDDP-induced renal proximal tubular cell apoptosis (control: 57% ± 1.23%; DD-218: 19% ± 10.14%; DD-219: 33% ± 14.06%). The cytoprotective effect of DD-218 was mediated via decreases in CDDP-induced mitochondria dysfunction, intracellular reactive oxygen species (ROS) generation, activation of ERK1/2, and cleaved-caspase 3 and 7. In addition, DD-218 attenuated CDDP-induced nephrotoxicity by a decrease in renal injury and improved in renal dysfunction in C57BL/6 mice. Importantly, DD-218 did not attenuate the anti-cancer efficacy of CDDP in non-small-cell lung cancer cells or colon cancer cells. CONCLUSIONS: This finding suggests that DD-218, a derivative of panduratin A, holds promise as an adjuvant therapy in patients receiving CDDP.

Two New Zn(II)/Cu(II) Compounds: Photoluminescent and Photocatalytic Properties, and Protective Activity on Parkinson Disease.

Two coordination polymers, that is [Zn(pdc)(im)(H2O)]n (1) and [Cu(pdc)(im)2]n·n(H2pdc) (2) (H2pdc = terephthalic acid, im = imidazole), were hydrothermally synthesized via the reactions of H2pdc and im in combination with Zn(II) or Cu(II) ions. Compound 1 shows intense blue luminescence and compound 2 shows good photocatalytic activity for the methyl violet degradation under the irradiation of ultraviolet light. In addition, the assessment of the two compounds' application values against Parkinson's disease were carried out and their specific mechanism was tested simultaneously. First of all, the real time RT-PCR was implemented and the relative expression levels of N-methyl-D-aspartic acid receptor receptor on neurons were measured. Besides, the Annexin V-FITC/PI apoptosis assay was utilized for the assessment of the influence of the compounds on the dopaminergic neuron death rate. The hemolysis toxicity detection was conducted to detect the biocompatible of the compounds.

AZD5438-PROTAC: A selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss.

Cyclin-dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of hearing loss and cancer. Previously, we identified AZD5438 and AT7519-7 as potent inhibitors of CDK2, however, they also targeted additional kinases, leading to unwanted toxicities. Proteolysis Targeting Chimeras (PROTACs) are a new promising class of small molecules that can effectively direct specific proteins to proteasomal degradation. Herein we report the design, synthesis, and characterization of PROTACs of AT7519-7 and AZD5438 and the identification of PROTAC-8, an AZD5438-PROTAC, that exhibits selective, partial CDK2 degradation. Furthermore, PROTAC-8 protects against cisplatin ototoxicity and kainic acid excitotoxicity in zebrafish. Molecular dynamics simulations reveal the structural requirements for CDK2 degradation. Together, PROTAC-8 is among the first-in-class PROTACs with in vivo therapeutic activities and represents a new lead compound that can be further developed for better efficacy and selectivity for CDK2 degradation against hearing loss and cancer.

iKeap1 activates Nrf2 signaling to protect myocardial cells from oxygen glucose deprivation/re-oxygenation-induced oxidative injury.

Nuclear factor E2-related factor 2 (Nrf2) activation could efficiently protect myocardial cells from oxygen glucose deprivation/re-oxygenation (OGDR). An ultra-large structure-based virtual screening has discovered iKeap1 as a novel, direct and potent Keap1 inhibitor. Here we found that iKeap1 efficiently activated Nrf2 signaling in H9c2 myocardial cells and primary murine myocardiocytes. iKeap1 induced Keap1-Nrf2 disassociation, cytosol Nrf2 protein stabilization and nuclear translocation. The antioxidant response element (ARE) activity and expression of Nrf2 cascade genes (HO1, NQO1 and GCLC) were increased in iKeap1-treated myocardial cells. In H9c2 cells and murine myocardiocytes, iKeap1 potently inhibited OGDR-induced oxidative injury by inhibiting reactive oxygen species (ROS) production, mitochondrial depolarization, lipid peroxidation and DNA damage. In addition, OGDR-induced myocardial cell death and apoptosis were largely ameliorated after pretreatment with the novel Keap1 inhibitor. Significantly, in H9c2 cells iKeap1-induced myocardial cytoprotection against OGDR was abolished with Nrf2 silencing or knockout (using CRISPR/Cas9 method). Moreover, CRISPR/Cas9-induced Keap1 knockout led to constitutive activation of Nrf2 cascade and inhibited OGDR-induced oxidative injury. Importantly, iKeap1 was unable to further protect Keap1-knockout H9c2 cells from OGDR. Together, iKeap1 activated Nrf2 signaling to protect myocardial cells from OGDR-induced oxidative injury and cell death.

Dibenzocyclooctadiene lignans from Kadsura coccinea alleviate APAP-induced hepatotoxicity via oxidative stress inhibition and activating the Nrf2 pathway in vitro.

Phytochemical investigation on the roots of Kadsura coccinea led to the isolation five previously unknown dibenzocyclooctadiene lignans, named heilaohusuins A-E (1-5). Their structures determined by NMR spectroscopy, HR-ESI-MS, and ECD spectra. Hepatoprotection effects of a series of dibenzocyclooctadiene derivatives (1-68) were investigated against acetaminophen (APAP) induced HepG2 cells. Compounds 2, 10, 13, 21, 32, 41, 46, and 49 showed remarkable protective effects, increasing the viabilities to > 52.2% (bicyclol, 52.1 ± 1.3%) at 10 µM. The structure-activity relationships (SAR) for hepatoprotective activity were summarized, according to the activity results of dibenzocyclooctadiene derivatives. Furthermore, we found that one new dibenzocyclooctadiene lignan heilaohusuin B attenuates hepatotoxicity, the mechanism might be closely correlated with oxidative stress inhibition via activating the Nrf2 pathway.

Design, synthesis and pharmacological screening of novel renoprotective methionine-based peptidomimetics: Amelioration of cisplatin-induced nephrotoxicity.

Cisplatin (CP) is an effective chemotherapeutic agent for treatment of various types of cancer, however efforts are needed to reduce its toxic side effect. Previous studies revealed promising effect of peptides in decreasing CP induced nephrotoxicity. Herein, novel Met-based peptidomimetics were synthesized using N-acylbenzotriazole as acylating agent in high yield. Evaluation of renoprotective effect of the synthesized targets on CP treated kidney cell line (LLC-PK1) revealed that pretreatment with 1/3 IC50 of targets II, IIIa-g attenuated CP induced cell death where the IC50 of CP was raised from 3.28 µM to 9.25-41.1 µM. The most potent compounds IIIg, II and IIIb exhibited antioxidative stress in CP-treated LLC-PK1 cells as confirmed by raising GSH/GSSG ratio and SOD concentration as well as decreasing ROS and MDA. Additionally, in vivo experiments using Sprague Dawley rats showed renoprotective effect of IIIg against CP-induced nephrotoxicity as evidenced by improved results of renal function tests and attenuated CP-induced renal structural injury. Moreover, antioxidant activity of IIIg was demonstrated via its ability to reduce renal MDA level and up-regulate renal antioxidant element GSH level. Further, immunohistochemistry of renal specimens showed the ability of IIIg to restore CP-induced suppression of Nrf2. Interestingly, in vivo and in vitro studies demonstrated that IIIg had no effect on CP antiproliferative activity. An assessment of the ADMET properties revealed that targets IIIg, II and IIIb showed good drug-likeness in terms of their physicochemical, pharmacokinetic properties. The findings presented here showcase that IIIg is a promising renoprotective candidate with antioxidative stress potential.

Design, green synthesis, antioxidant activity screening, and evaluation of protective effect on cerebral ischemia reperfusion injury of novel monoenone monocarbonyl curcumin analogs.

Antioxidants with high efficacy and low toxicity have the potential to treat cerebral ischemia reperfusion injury (CIRI). Dienone monocarbonyl curcumin analogs (DMCA) capable of overcoming the instability and pharmacokinetic defects of curcumin possess notable antioxidant activity but are found to be significantly toxic. In this study, a novel skeleton of the monoenone monocarbonyl curcumin analogue sAc possessing reduced toxicity and improved stability was designed on the basis of the DMCA skeleton. Moreover, 32 sAc analogs were obtained by applying a green, simple, and economical synthetic method. Multiple sAc analogs with an antioxidant protective effect in PC12 cells were screened using an H2O2-induced oxidative stress damage model, and quantitative evaluation of structure-activity relationship (QSAR) model with regression coefficient of R2 = 0.918921 was built through random forest algorithm (RF). Among these compounds, the optimally active compound sAc15 elicited a potent protective effect on cell growth of PC12 cells by effectively eliminating ROS generation in response to oxidative stress injury by activating the Nrf2/HO-1 antioxidant signaling pathway. In addition, sAc15 exhibited good protection against CIRI in the mice middle cerebral artery occlusion (MCAO) model. In this paper, we provide a novel class of antioxidants and a potential compound for stroke treatment.

Structure-based molecular hybridization design of Keap1-Nrf2 inhibitors as novel protective agents of acute lung injury.

Blocking the Kelch-like epichlorohydrin-related protein 1 (Keap1)-nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway represents as a promising strategy to reduce oxidative stress and related-inflammation, including acute lung injury (ALI). NXPZ-2, a naphthalensulfonamide derivative, was previously reported to effectively inhibit the Keap1-Nrf2 protein-protein interaction (PPI) by our group. In the present work, a series of novel isothiocyanate-containing naphthalensulfonamides with the thioether, sulfoxide and sulfone moieties were designed by a structure-based molecular hybridization strategy using NXPZ-2 and the Nrf2 activator sulforaphane. They possessed good Keap1-Nrf2 PPI inhibitory activity and low cytotoxicity. The molecular docking study was performed to further explain the different activity of the thioether-, sulfoxide- and sulfone-containing naphthalensulfonamides. Among these new derivatives, 2-((N-(4-((N-(2-amino-2-oxoethyl)-4-((3-isothiocyanatopropyl)sulfinyl)phenyl)sulfonamido) naphthalen-1-yl)-4-methoxyphenyl)sulfonamido)acetamide (SCN-16) showed a good KD2 value of 0.455 µM to disrupt the PPI. In an LPS-induced peritoneal macrophage cell model, this compound could cause a significant increase in the nuclear Nrf2 protein, decrease in the cytosolic Nrf2 protein, and further elevate the downstream protective enzymes HO-1 and NQO-1, which were better than the lead compound NXPZ-2 and sulforaphane. What's more, the production of ROS and NO and the expression of pro-inflammatory cytokine TNF-α were also suppressed. In the LPS-induced ALI model, SCN-16 could significantly reduce LPS-induced inflammations and alleviate lung injuries by triggering Nrf2 nuclear translocation. Collectively, our results suggested that SCN-16 could be a novel lead compound targeting Keap1-Nrf2 protective pathway for clinical treatment of ALI.

The combination of sesamol and clofibric acid moieties leads to a novel potent hypolipidemic agent with antioxidant, anti-inflammatory and hepatoprotective activity.

Oxidative stress and inflammation have been considered the main factors in the liver injury of clofibrate (CF). To obtain a novel antihyperlipidemic agent with antioxidant, anti-inflammation and hepatoprotection, the combination of sesamol and clofibric acid moieties was performed and achieved sesamol-clofibrate (CF-Sesamol). CF-Sesamol showed significant hypolipidemia effects in hyperlipidemia mice induced by Triton WR 1339, reducing TG by 38.8% (P < 0.01) and TC by 35.1% (P < 0.01). CF-Sesamol also displayed an alleviating effect on hepatotoxicity. The hepatic weight and hepatic coefficient were decreased. The amelioration of liver function was observed, such as aspartate and lactate transaminases (AST and ALT), alkaline phosphatase (ALP) and total proteins (TP) levels. Liver histopathological examination showed that hepatocyte necrosis, cytoplasmic loosening, nuclear degeneration and inflammatory cell infiltration reduced obviously by treatment with CF-Sesamol. Related molecular mechanisms on hepatoprotection showed that CF-Sesamol up-regulated Nrf2 and HO-1 expression and down-regulated p-NF-κB p65 expression in hepatic tissues. CF-Sesamol has significant antioxidant and anti-inflammatory effects. Plasma antioxidant enzymes such as SOD and CAT increased, anti-lipid peroxidation product MDA decreased. The expression of TNF-α and IL-6 inflammatory cytokines in liver was significantly lower than that in the CF group. The results indicated that CF-Sesamol exerted more potent antihyperlipidemic effects and definite hepatoprotective activity partly through the Nrf2/NF-κB-mediated signaling pathway.

Twin drug design, synthesis and evaluation of diosgenin derivatives as multitargeted agents for the treatment of vascular dementia.

A novel series of multitargeted molecules were designed and synthesized by combining the pharmacological role of cholinesterase inhibitor and antioxidant of steroid as potential ligands for the treatment of Vascular Dementia (VD). The oxygen-glucose deprivation (OGD) model was used to evaluate these molecules, among which the most potent compound ML5 showed the highest activity. Firstly, ML5 showed appropriate inhibition of cholinesterases (ChEs) at orally 15 mg/kg in vivo. The further test revealed that ML5 promoted the nuclear translocation of Nrf2. Furthermore, ML5 has significant neuroprotective effect in vivo model of bilateral common carotid artery occlusion (BCCAO), significantly increasing the expression of Nrf2 protein in the cerebral cortex. In the molecular docking research, we predicted the ML5 combined with hAChE and Keap1. Finally, compound ML5 displayed normal oral absorption and it was nontoxic at 500 mg/kg, po, dose. We can draw the conclusion that ML5 could be considered as a new potential compound for VD treatment.

Design, Synthesis, and Biological Evaluation of Dexamethasone-Salvianolic Acid B Conjugates and Nanodrug Delivery against Cisplatin-Induced Hearing Loss.

Cisplatin (CDDP) is an extensively used chemotherapeutic agent but has a high incidence of severe ototoxicity. Although a few molecules have entered clinical trials, none have been approved to prevent or treat CDDP-induced hearing loss by the Food and Drug Administration. In this study, an amphiphilic drug-drug conjugate was synthesized by covalently linking dexamethasone (DEX) and salvianolic acid B (SAL) through an ester or amide bond. The conjugates could self-assemble into nanoparticles (NPs) with ultrahigh drug loading capacity and favorable stability. Compared with DEX, SAL, or their physical mixture at the same concentrations, both conjugates and NPs showed enhanced otoprotection in vitro and in vivo. More importantly, the conjugates and NPs almost completely restored hearing in a guinea pig model with good biocompatibility. Immunohistochemical analyses suggested that conjugates and NPs activated the glucocorticoid receptor, which may work as one of the major mechanisms for their protective effects.

1,3-Benzodioxole-based fibrate derivatives as potential hypolipidemic and hepatoprotective agents.

A series of target compounds 1,3-benzodioxole-based fibrate derivatives were designed and synthesized. All the target compounds were preliminarily evaluated by hyperlipidemia mice induced by Triton WR-1339, in which compound 12 displayed a greater anti-hyperlipidemia activity than other compounds as well as positive drug fenofibrate (FF). 12 showed a significant reduction of plasma lipids, such as triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterin (LDL-C), in high fat diet (HFD) induced hyperlipidemic mice. In addition, hepatic transaminases (AST and ALT) were ameliorated after administration of 12, in particular the AST, and the histopathological examination showed that 12 improved the hepatic lipid accumulation. The expression of PPAR-α involved in lipids metabolism was up-regulated in the liver tissues of 12-treated group. Other significant activity such as antioxidant, and anti-inflammation was confirmed and reinforced the effects of 12 as a potential hypolipidemia and hepatoprotective agent.

Myricetin protects pancreatic ß-cells from human islet amyloid polypeptide (hIAPP) induced cytotoxicity and restores islet function.

The aberrant misfolding and self-assembly of human islet amyloid polypeptide (hIAPP)-a hormone that is co-secreted with insulin from pancreatic ß-cells-into toxic oligomers, protofibrils and fibrils has been observed in type 2 diabetes mellitus (T2DM). The formation of these insoluble aggregates has been linked with the death and dysfunction of ß-cells. Therefore, hIAPP aggregation has been identified as a therapeutic target for T2DM management. Several natural products are now being investigated for their potential to inhibit hIAPP aggregation and/or disaggregate preformed aggregates. In this study, we attempt to identify the anti-amyloidogenic potential of Myricetin (MYR)- a polyphenolic flavanoid, commonly found in fruits (like Syzygium cumini). Our results from biophysical studies indicated that MYR supplementation inhibits hIAPP aggregation and disaggregates preformed fibrils into non-toxic species. This protection was accompanied by inhibition of oxidative stress, reduction in lipid peroxidation and the associated membrane damage and restoration of mitochondrial membrane potential in INS-1E cells. MYR supplementation also reversed the loss of functionality in hIAPP exposed pancreatic islets via restoration of glucose-stimulated insulin secretion. Molecular dynamics simulation studies suggested that MYR molecules interact with the hIAPP pentameric fibril model at the amyloidogenic core region and thus prevents aggregation and distort the fibrils.

ß-Selective Glycosylation Using Axial-Rich and 2-O-Rhamnosylated Glucosyl Donors Controlled by the Protecting Pattern of the Second Sugar.

Herein, we describe two counterexamples of the previously reported ß/α-selectivity of 96/4 for glycosylation using ethyl 2-O-[2,3,4-tris-O-tert-butyldimethylsilyl (TBS)-α-L-rhamnopyranosyl]-3,4,6-tris-O-TBS-thio-ß-D-glucopyranoside as the glycosyl donor. Furthermore, we investigated the effects of protecting group on the rhamnose moieties in the glycosylation with cholestanol and revealed that ß-selectivity originated from the two TBS groups at the 3-O and 4-O positions of rhamnose. In contrast, the TBS group at the 2-O position of rhamnose hampered the ß-selectivity. Finally, the ß/α-selectivity during the glycosylation was enhanced to ≥99/1. The results obtained herein suggest that the protecting groups on the sugar connected to the 2-O of a glycosyl donor with axial-rich conformation can control the stereoselectivity of glycosylation.

Novel phenylpyrimidine derivatives containing a hydrazone moiety protect rice seedlings from injury by metolachlor.

One strategy for solving the phytotoxicity of herbicides is to apply herbicide safeners that can efficiently alleviate the injuries of agricultural crops caused by herbicides. When metolachlor, a chloroacetamide herbicide, is applied with paddy rice, for example, the mechanisms associated with metolachlor and its residue negatively impact on the growth and yields of rice. To identify novel high-activity herbicide safener candidates for metolachlor, a series of (E)-4-(2-substituted hydrazinyl)-6-chloro-2-phenyl pyrimidines were synthesized and their structures were confirmed using IR (infrared radiation), 1H NMR, 13C NMR, and HRMS (high resolution mass spectrometry). The herbicide safener activities were then evaluated via primary tests. Compounds 3i and 3t were found to have the best herbicide activity on plant height. These compounds were then further screened for their activities at lower concentrations and showed better or similar activities compared to the positive control fenclorim, a commercial herbicide safener. The compounds 3i and 3t significantly enhanced glutathione S-transferase (GST) activity related with the herbicide safener activity in both shoots and roots tissues. Moreover, a qPCR (Real-time quantitative polymerase chain reaction) analysis found that the 3i and 3t treatments enhanced the expressions of OsGSTU3, OsGsTU39, and OsGSTF5. Finally, the results of an acute toxicity assessment with zebrafish (Danio rerio) embryos using treatments 3i and 3t indicated they are relatively safe to aquatic organisms.

Optimized piperine-phospholipid complex with enhanced bioavailability and hepatoprotective activity.

Piper species is one of the most widely consumed spices for culinary purposes. Piperine (PIP) present in Piper species has a wide range of therapeutic activity including hepatoprotection. However, the major biological limitation of PIP is its low bioavailability after oral administration. Purpose of the study was to prepare an optimized and adequately characterized PIP-phospholipid complex (PPC) as a delivery system to overcome these limitations and to investigate the pharmacokinetics and hepato-protectivity of the formulation in the animal model. Response surface methodology was adopted to optimize the process parameters for PPC preparation. FT-IR, DTA, PXRD, SEM, molecular docking etc. were used for characterization. Solubility, log P, dissolution efficiency and in vivo pharmacokinetics were also investigated. PPC showed enhanced hepatoprotective potential as compared to pure PIP at the same dose level (25 and 50 mg/kg). PPC restored the levels of serum marker and antioxidant enzymes. PPC also increased the bioavailability of PIP in rat serum by 10.40-fold in comparison with pure PIP at the same dose level and enhanced the elimination half-life (t1/2 el) from 0.477 ± 1.76 to 9.80 ± 1.98 h. Results concluded that PPC enhanced the hepatoprotection of PIP which may be due to the improved bioavailability and pharmacokinetics of PIP in rats.