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Multitude of diseases and side effects from conventional drugs have surged the use of herbal remedies. Thus, the current study aimed to appraise various pharmacological attributes of Artemisia brevifolia Wall. ex DC. Extracts prepared by successive solvent extraction were subjected to phytochemical and multimode antioxidant assays. Various polyphenolics and artemisinin derivatives were detected and quantified using RP-HPLC analysis. Compounds present in methanol (M) and distilled water (DW) extracts were identified using high resolution mass spectrometry (HRMS). Extracts were pharmacologically evaluated for their antibacterial, antifungal, antimalarial, antileishmanial and antidiabetic potentials. Moreover, cytotoxicity against Artemiasalina, human cancer cell lines and isolated lymphocytes was assessed. Genotoxicity was evaluated using comet, micronucleus and chromosomal aberration assays. Lastly, anti-inflammatory potential was determined through a series of in vitro and in vivo assays using BALB/c mice. Maximum extract recovery (5.95% w/w) was obtained by DW extract. Highest phenolics and flavonoids content, total antioxidant capacity, total reduction potential, percentfree radical scavenging, β-carotene scavenging and iron chelating activities were exhibited by M extract. RP-HPLC analysis revealed significant amounts of various polyphenolic compounds (vanillic acid, syringic acid, emodin and luteolin), artemisinin, dihydro artemisinin, artesunate and artemether in ethyl acetate (EA) extract. Total 40 compounds were detected through HRMS. A noteworthy antimicrobial activity (MIC 22.22 µg/ml) was exhibited by EA extract against A. fumigatus and several bacterial strains. Maximum antimalarial, antileishmanial, brine shrimp lethality and cytotoxic potential against cancer cells was manifested by EA extract. None of the extracts exhibited genotoxicity and toxicity against isolated lymphocytes. Highest α-amylase and α-glucosidase inhibition capacities were demonstrated by DW extract. Various in-vivo anti-inflammatory models revealed significant (p < 0.05) anti-inflammatory potential of M and DW extracts. In conclusion, present findings divulged theremarkable pharmacological potential of A. brevifolia and endorse its richness in artemisinin. [ABSTRACT FROM AUTHOR]

Withanolides are natural medicinal agents whose safety and therapeutic profiles make them valuable to mankind. Among multiple withanolides, withametelin is underexplored. The present study was aimed to create a general biological profile of isolated withametelin from Datura innoxia Mill. targeting different biological models. In-silico studies include drug-likeliness, pharmacokinetics, toxicity, molecular targets and cytotoxicity to cancer cell lines predictions. In silico directed preliminary in-vitro evaluation comprised of cancer/normal cell cytotoxicity, DPPH and protein kinase inhibition assays while in-vivo bioactivities include antiinflammatory, analgesic, antidepressant and anticoagulant assays. Pharmacological findings were strengthened by molecular docking studies to check interactions with various proteins and to propose the future path of studies. Results indicated compliance with Lipinski drug-likeliness rule (score −0.55). ADMET prediction showed strong plasma protein binding, GI absorption (Caco-2 cells permeability = 46.74 nm/s), blood brain barrier penetration (Cbrain/Cblood = 0.31), efflux by P-glycoprotein, metabolism by CYP1A2, CYP2C19 and CYP3A4, medium hERG inhibition and non-carcinogenicity in rodents. Predicted molecular targets included mainly receptors (glucocorticoid, kappa opioid, delta opioid, adrenergic and dopamine), oxidoreductase (arachidonate 5-lipoxygenase and cyclooxygenase-2), enzymes (HMG-CoA reductase) and kinase (NFκb). Withametelin was more cytotoxic to cancer cells (DU145 IC 50 7.67 ± 0.54 µM) than normal lymphocytes (IC 50 33.55 ± 1.31 µM). It also showed good antioxidant and protein kinase inhibition potentials. Furthermore, withametelin (20 mg/kg) significantly reduced inflammatory paw edema (68.94 ± 5.55%), heat-induced pain (78.94 ± 6.87%) and immobility time (50%) in animals. Molecular docking showed hydrogen bonding interactions (binding energies: −11.3 to −7.8 kcal/mol) with arachidonate 5 lipoxygenase, NFκb and glucocorticoid receptor. Withametelin has potential for advance investigations for its cytotoxic, anti-inflammatory, analgesic and antidepressant activities. [ABSTRACT FROM AUTHOR]

CoFe 2 O 4 are important magnetic NPs with high coercivity and moderate magnetization. These properties of CoFe 2 O 4 NPs show variation when doped with various metals. Recent studies explained that Cobalt ferrites doped with metal ion like Mn+2, have attracted increasing attention in many applications, particularly in biomedical applications. A relatively simple way is employing plants and their extracts as precursors instead of toxic chemicals to produce NPs with desirable characteristic. In current study we report green synthesis and characterization of magnetic (CoFe 2 O 4 , MnCoFe 2 O 4 , CoFe 2 O 4 @S.C, MnCoFe 2 O 4 @S.C) nanoparticles using ethanolic extract of Swertia Chirata. To enhance application as biocompatible magnetic nano drug delivery vector and cell targeting efficacy of drugs, Glimepiride (GLM), Dexamethasone (DXM), Fexofenadine (FEX) and Levofloxacin (LVX) 1were loaded on synthesized NPs. Synthesized CFNPs has been broadly characterized and applied for in vitro anticancer, antidiabetic and antibacterial potential. For synthesis of CoFe 2 O 4 (CF), CoMnFe 2 O 4 (CFM), CoFe 2 O 4 @S.C (SCF) & CoMnFe 2 O 4 @S.C (SCFM), stochiometric amounts 5 mmol of CoCl 2 ·6 H 2 O (0.284 g) and 10 mmol FeCl 3 ·6 H 2 O (0.378 g) were dissolved in 13 mL of deionized water. To this sodium acetate (3.05 g) and urea (0.6 g) were added until complete dissolution. Afterward n-heptane was added, and contents were then transferred to Teflon lining autoclave at 180 °C for 4 h. Black powder CoFe 2 O 4 NPs after washing, were dried and calcined at 450 oC for 2 h. XRD diffractogram of CF have proved the single-phase cubic spinel structure formation for all samples. Swertia Chirata formulations were shown to have effective in vitro antidiabetic activity. CF, CFM & SCFM showed good inhibition of α -glucosidase with very low concentration 6 µg/mL, 5 µg/mL and 4 µg/mL as compare to 12.41 µg/mL of acarbose. SCF showed that the value slightly higher than 16 µg/mL compared to standard. Drug loaded CFNPs (L -CFNPs, F-CFNPs, D -CFNPs & G-CFNPs) also effectively inhibited α -glucosidase. IC50 value for CFNPs inhibition of α -glucosidase was 12.4 µg/mL. All synthesized CF NPs showed cytotoxic potential against breast cancer cells MCF-7. About 50–60% cell viability and cytotoxicity 40% were observed for bare CFNPs as compare to Doxorubicin with related toxicity 80% and 20% cell viability. Among synthesized samples almost all samples without conjugation of any drug showed activities against at least one bacterial strain. CFM, SCF, SCFM were active against S. aureus at concentration 100 µg/mL, 100 µg/mL, and 50 µg/mL respectively. The synthesized CF NPs showed significant cytotoxic potential against MCF-7 breast cancer cell line. Further, drug loaded samples displayed lesser cell viability and slightly increased cytotoxicity in range of 40–50% in comparison with bare CFNPs. However, higher toxicity was observed for CFMGS towards MCF-7 cells with results nearly equal to Doxorubicin with significant decrease in viability. CF, CFM & SCFM showed good inhibition of α -glucosidase with very low concentration 6 µg/mL, 5 µg/mL and 4 µg/mL as compare to 12.41 µg/mL of acarbose. Among synthesized samples almost all samples without conjugation of any drug showed activities against at least one bacterial strain. [ABSTRACT FROM AUTHOR]

Living donor liver transplant in addition to its lifesaving therapy is a cost-effective alternate to long-term disease management in patients with chronic liver disease. Financial constraint is the biggest hurdle faced by patients in developing countries in availing the liver transplantation. So, we conducted this study to report a government-funded financial support system for liver transplant services. A total of 198 patients who underwent living donor liver transplant with at least 90 days follow-up were included in the study. According to proxy means test score, 52.2% patients were from low and middle socioeconomic groups and 64.6% of patients underwent liver transplantation through government support. Out of 198 patients who underwent liver transplantation 29.6% had monthly income below 25,000 Pakistani rupees ($114). In recipients, 90-day mortality was 7.1% and morbidity was 67.1%. Donor morbidity was 23.2% without any mortality. This financial model can serve as a valuable source for middle and low income group countries to overcome the financial challenge and make liver transplant an accessible, affordable, and economically viable option. [ABSTRACT FROM AUTHOR]

Abstract: The application of methoprene, and providing access to diet including hydrolyzed yeast, are treatments known to enhance mating success in the male melon fly Bactrocera cucurbitae Coquillett (Diptera: Tephritidae), supporting their use in mass rearing protocols for sterile males in the context of sterile insect technique (SIT) programmes. The objective of the present laboratory study was to investigate the effect of methoprene application and diet supplementation with hydrolyzed yeast (protein) on the turnover of body lipids and protein to confirm the feasibility of their application in melon fly SIT mass-rearing programmes. While females had access to a diet that included hydrolyzed yeast (protein), males were exposed to one of the following treatments: (1) topical application of methoprene and access to diet including protein (M+P+); (2) only diet including protein (M−P+); (3) only methoprene (M+P−) and (4) untreated, only sugar-fed, control males (M−P−). Total body carbon (TBC) and total body nitrogen (TBN) of flies were measured at regular intervals from emergence to 35 days of age for each of the different treatments. Nitrogen assimilation and turnover in the flies were measured using stable isotope (15N) dilution techniques. Hydrolyzed yeast incorporation into the diet significantly increased male body weight, TBC and TBN as compared to sugar-fed males. Females had significantly higher body weight, TBC and TBN as compared to all males. TBC and TBN showed age-dependent changes, increasing until the age of sexual maturity and decreasing afterwards in both sexes. Methoprene treatment did not significantly affect TBC or TBN. The progressive increase with age of TBC suggests that lipogenesis occurs in adult male B. cucurbitae, as is the case in other tephritids. Stable isotope dilution was shown to be an effective method for determining N uptake in B. cucurbitae. This technique was used to show that sugar-fed males rely solely on larval N reserves and that the N uptake rate in males with access to diet including hydrolyzed yeast was higher shortly after emergence and then stabilized. The implications of the results for SIT applications are discussed. [Copyright &y& Elsevier]

Abstract: The effect of access to dietary protein (P) and the topical application of a juvenile hormone analogue (methoprene (M)) on mating behaviour of male melon fly Bactrocera cucurbitae was assessed in the laboratory and in field cages. Age, dietary protein and methoprene application increased the mating success and influenced the mating behaviour. Treatment with methoprene (M+) to protein-deprived (P−) males had only a modest effect on the acceleration of sexual maturity, but application of methoprene (M+) to protein-fed (P+) males greatly accelerated sexual maturity. Protein diet (P+) increased mating success of males in comparison to protein-deprived (P−) males. Protein and methoprene have a synergistic effect on mating behaviour, since M+P+ treated males exhibit reduced mating latency and achieved higher mating in younger ages than methoprene and/or protein-deprived males. Copulation duration was correlated with nutritional status and M+P+ males copulated longer at the age of advanced sexual maturity than M−P+ males. Our results suggest that in this species with a lek mating system, females discriminate between the males based on their sexual signals, which were influenced by protein in the adult diet, methoprene application and age. The results are discussed in the light of mating competitiveness of precocious treated young males and their relevance to Sterile Insect Technique application against this pest species. [ABSTRACT FROM AUTHOR]

There are numerous extra- and intra-cellular processes involved in the production of reactive oxygen species (ROS). Augmented ROS generation can cause the damage of biomolecules such as proteins, nucleic acid and lipids. ROS act as an intracellular signaling component and is associated with various inflammatory responses, chronic arthropathies, including rheumatoid arthritis (RA). It is well documented that ROS can activate different signaling pathways having a vital importance in the patho-physiology of RA. Hence, understanding of the molecular pathways and their interaction might be advantageous in the development of novel therapeutic approaches for RA. [ABSTRACT FROM AUTHOR]

Seaweed and their constituents have been traditionally employed for the management of various human pathologic conditions such as edema, urinary disorders and inflammatory anomalies. The current study was performed to investigate the antioxidant and anti-arthritic effects of fucoidan from Undaria pinnatifida . A noteworthy in vitro antioxidant potential at 500 μg/ml in 2, 2-diphenyl-1-picrylhydrazyl scavenging assay (80% inhibition), nitrogen oxide inhibition assay (71.83%), hydroxyl scavenging assay (71.92%), iron chelating assay (73.55%) and a substantial ascorbic acid equivalent reducing power (399.35 μg/mg ascorbic acid equivalent) and total antioxidant capacity (402.29 μg/mg AAE) suggested fucoidan a good antioxidant agent. Down regulation of COX-2 expression in rabbit articular chondrocytes in a dose (0–100 μg) and time (0–48 h) dependent manner, unveiled its in vitro anti-inflammatory significance. In vivo carrageenan induced inflammatory rat model demonstrated a 68.19% inhibition of inflammation whereas an inflammation inhibition potential of 79.38% was recorded in anti-arthritic complete Freund’s adjuvant-induced arthritic rat model. A substantial ameliorating effect on altered hematological and biochemical parameters in arthritic rats was also observed. Therefore, findings of the present study prospects fucoidan as a potential antioxidant that can effectively abrogate oxidative stress, edema and arthritis-mediated inflammation and mechanistic studies are recommended for observed activities. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The two plants investigated here ( Fagonia cretica L. and Hedera nepalensis K. Koch) have been previously reported as natural folk medicines for the treatment of diabetes but until now no scientific investigation of potential anti-diabetic effects has been reported. Materials and methods In vitro inhibitory effect of the two tested plants and their five isolated compounds on the dipeptidyl peptidase 4 (DPP-4) was studied for the assessment of anti-diabetic activity. Results A crude extract of Fagonia cretica possessed good inhibitory activity (IC 50 value: 38.1 μg/ml) which was also present in its n -hexane (FCN), ethyl acetate (FCE) or aqueous (FCA) fractions. A crude extract of Hedera nepalensis (HNC) possessed even higher inhibitory activity (IC 50 value: 17.2 μg/ml) and this activity was largely retained when further fractionated in either ethyl acetate (HNE; IC 50 : 34.4 μg/ml) or n -hexane (HNN; 34.2 μg/ml). Bioactivity guided isolation led to the identification of four known compounds (isolated for the first time) from Fagonia cretica : quinovic acid ( 1 ), quinovic acid-3 β -O- β - d -glycopyranoside ( 2 ), quinovic acid-3 β -O- β - d -glucopyranosyl-(28→1)- β - d -glucopyranosyl ester ( 3 ), and stigmasterol ( 4 ) all of which inhibited DPP-4 activity (IC 50 : 30.7, 57.9, 23.5 and >100 µM, respectively). The fifth DPP-4 inhibitor, the triterpenoid lupeol ( 5 ) was identified in Hedera nepalensis (IC 50 : 31.6 μM). Conclusion The experimental study revealed that Fagonia cretica and Hedera nepalensis contain compounds with significant DPP-4 inhibitory activity which should be further investigated for their anti-diabetic potential. [ABSTRACT FROM AUTHOR]

Abstract The present study for the first time reports facile in-situ room temperature synthesis of butterfly cluster like lamellar BiOBr deposited over TiO 2 nanoparticles for photocatalytic breakdown of ciprofloxacin (CIP). The butterfly cluster arrangement of BiOBr resulted in an increase in surface area from 124.6 to 160.797 m2·g−1 and subsequently increased incident light absorption by the composite photocatalyst. The XRD indicated the existence of TiO 2 as spherical ≈10–15 nm diameter particles with [101] preferential growth planes of anatase phase while the lamellar BiOBr showing growth along [110] and [102] preferential planes that were also confirmed by the HR-TEM images. DRS data implicated 2.76 eV as the energy band gap of the synthesized nanocomposite while PL spectroscopic analysis predicted it to be 2.81 eV. XPS measurements examined the chemical oxidation states of the constituents among the nanocomposite samples. The lameller structure of BiOBr in 15%BiOBr/TiO 2 acts as a manifold promoting both visible light (λ > 420 nm) and direct sunlight catalytic degradation of 25 mg·L−1 aqueous CIP up to 92.5% and 100%, respectively within 150 min. The rate constant values suggested that the visible light photocatalysis of CIP with 15%BiOBr/TiO 2 was 5.2 and 9.4 times faster compared to pristine TiO 2 and BiOBr, respectively. The free radical scavenging study demonstrated that although photogenerated superoxide ions and holes contribute to the overall photocatalytic activity, yet, hydroxyl radicals predominantly control the CIP oxidation. The synthesized nanocomposite was re-used up to five cycles and retained 82.98% efficiency even after 5th use cycle showing a decline of only 12%. The catalyst stability and easy recovery adds to its reusability and value of the photocatalytic process. Graphical abstract Unlabelled Image Highlights • Butterfly cluster shaped BiOBr/TiO 2 nanoparticles fabricated by in-situ deposition • 15%BiOBr/TiO 2 exhibited efficacy in photochemical degradation of ciprofloxacin. • The stable nanoparticles could efficiently enhance photo-induced electron hole pairs. • 100% degradation of 25 mg·L−1 CIP in 150 min under solar radiation • CIP degradation by 15%BiOBr/TiO 2 was 5.2 and 9.4 times faster than TiO 2 and BiOBr. [ABSTRACT FROM AUTHOR]

Abstract In current research, five series of mono- and di-substituted piperazine derivatives have been synthesized. For di-substituted derivatives, ciprofloxacin was selected and hybrids were synthesized via substitution at piperazinyl- N 4 . In vitro antibacterial studies of all synthesized compound were carried out against American Type Culture Collection (ATCC) strains; E. coli (ATCC 25922), P. aeruginosa (ATCC 15442), K. pneumoniae (ATCC 1705), B. subtilis (ATCC 6633) and S. aureus (ATCC 6538). The potent series of compounds were further evaluated for their potential against clinically isolated resistant strains of E. coli , P. aeruginosa , S. aureus , and S. hemolytic. The reaction of piperazinyl-NH of ciprofloxacin with selected drugs resulted in pronounced growth inhibition of standard as well as resistant bacterial strains. Hybrid compounds 14b , 16a , 16d and CGS-20 showed excellent bacterial growth inhibition against standard and resistant strains. In vitro results were further correlated by using in silico tools. Molecular docking studies were carried out using MOE (Molecular Operating Environment) software. DNA gyrase used as a target and all compounds were docked against this specific target. Graphical abstract Image 1 Highlights • Mono- and di-substituted piperazine derivatives were synthesized. • In di-substituted derivatives, ciprofloxacin-drug hybrids were synthesized. • Compounds were evaluated against normal and resistant bacterial strains. • Excellent in vitro bacterial strain inhibition by some compounds. • Molecular docking studies on DNA gyrase as target. [ABSTRACT FROM AUTHOR]

Graphical abstract A series of new triorganotin(IV) complexes of Schiff base ligands as benzylidene benzohydrazide and their hydrazone analogues have been synthesized. Then they were complexed with organotin(IV) moiety with general formula [R' 3 SnL] where L = C 4 H 3 O-CONH-N CH-R, R = C 6 H 5 O(I a), C 4 H 5 O(I b), C 6 H 3 Cl 2 (I c) and R' = –CH 3 (1 – 3), –CH 2 Ph(4 – 6), –Ph(7 – 9). The complexes (1 – 9) have been fully characterized by IR, NMR(1H, 13C and 119Sn) spectroscopy, combined with CHN and melting point determinations. Highlights • New substituted hydrazones have been synthesized. • Hydrazones, then, complexed with triorganotin(IV) moieties to get target compounds. • All compounds characterized by advanced analytical techniques. • These compounds were preliminary bio-assayed and found encouraging results. Abstract A series of Schiff base ligands as benzylidene benzohydrazide and their hydrazone analogues (I a -I c) have been synthesized and then complexed with organotin(IV) moiety having general formula [R' 3 SnL] to get the target compounds (1 – 9) , where L = C 4 H 3 OCONHN CHR, R = C 6 H 5 O(I a), C 4 H 5 O(I b), C 6 H 3 Cl 2 (I c) and R' = –CH 3 (1 – 3), –CH 2 Ph(4 – 6), –Ph(7 – 9). They were fully characterized using FT-IR, NMR(1H, 13C and 119Sn) spectroscopy, along with elemental analysis and melting point. One of the precursor (I b) has been analyzed by single crystal XRD to further authenticate the structure. The 119Sn NMR data suggest the molecular geometry of organotin derivatives as distorted pentagonal bipyramidal. They were also evaluated for their antibacterial, antifungal, α-amylase inhibition, DPPH, total reducing power and total antioxidant activities. Triaryltin(IV) derivatives show good antibacterial and antifungal activity. Whereas the data for antidiabetic activity demonstrated that the compounds may serve as moderately effective alpha amylase inhibitor. [ABSTRACT FROM AUTHOR]

Quercus dilatata Lindl. ex Royle was evaluated for in vitro polyphenol content and antioxidant potential as well as in vivo protective role against bisphenol A (BPA) induced hepatotoxicity. The distilled water-acetone (QDDAE) and methanol-ethyl acetate (QDMEtE) extracts were standardized and administered in high (300 mg/kg body weight (BW) and low (150 mg/kg BW) doses to Sprague Dawley rats, injected with BPA (25 mg/kg BW). Silymarin (50 mg/kg BW) was used as positive control. Subsequently, blood and liver homogenates were collected after four weeks of treatment, and the defensive effects of both extracts against oxidative damage and genotoxicity were assessed via hematological and biochemical investigations, determination of endogenous expression of enzymes as well as levels of free radicals and comet assay. Between the two extracts, maximum phenolics (213 ± 0.15 μg gallic acid equivalent/mg dry extract (DE) and flavonoids (55.6 ± 0.16 μg quercetin equivalent/mg DE) content, DPPH scavenging activity (IC 50 : 8.1 ± 0.5 μg/ml), antioxidant capacity (53.7 ± 0.98 μg ascorbic acid equivalent (AAE)/mg DE) and reducing potential (228.4 ± 2.4 μg AAE/mg DE) were observed in QDMEtE. In in vivo analysis, a dose dependent hepatoprotective activity was exhibited by both the extracts. QDDAE demonstrated maximum reduction in levels of alanine transaminase (49.77 ± 3.83 U/l), thiobarbituric acid reactant substances (33.46 ± 0.70 nM/min/mg protein), hydrogen peroxide (18.08 ± 0.01 ng/mg tissue) and nitrite (55.64 ± 1.79 μM/ml), along with decline in erythrocyte sedimentation rate (4.13 ± 0.072 mm/h), histopathological injuries and DNA damage in BPA intoxicated rats as compared with QDMEtE. Likewise, QDDAE also significantly restored activity levels of endogenous antioxidants, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (POD) and GSH with values of 6.46 ± 0.15 U/mg protein, 6.87 ± 0.1 U/min, 11.94 ± 0.17 U/min and 16.86 ± 1.56 nM/min/mg protein, respectively. Comparative results were obtained for QDMEtE. In conclusion, the present study endorses the significant hepatoprotective potential of standardized extracts of Q. dilatata with known polyphenolics content and validates the traditional use of this plant in natural medicine to manage disorders like hepatotoxicity. [ABSTRACT FROM AUTHOR]

Present work describes the in vitro antibacterial evaluation of some new amino acid conjugated antimicrobial drugs. Structural modification was attempted on the three existing antimicrobial pharmaceuticals namely trimethoprim, metronidazole, isoniazid. Twenty one compounds from seven series of conjugates of these drugs were synthesized by coupling with some selected Boc-protected amino acids. The effect of structural features and lipophilicity on the antibacterial activity was investigated. The synthesized compounds were evaluated against five standard American type culture collection (ATCC) i.e. Staphylococcus aureus , Bacillus subtilis, Escherichia coli , Pseudomonas aeruginosa and Salmonella typhi strains of bacteria. Our results identified a close relationship between the lipophilicity and the activity. Triazine skeleton proved beneficial for the increase in hydrophobicity and potency. Compounds with greater hydrophobicity have shown excellent activities against Gram-negative strains of bacteria than Gram-positive. 4-amino unsubstituted trimethoprim-triazine derivative 7b have shown superior activity with MIC = 3.4 μM (2 μg/mL) for S. aureus and 1.1 μM (0.66 μg/mL) for E. coli . The synthesized compounds were also evaluated for their urease inhibition study. Microbial urease from Bacillus pasteurii was chosen for this study. Triazine derivative 7a showed excellent inhibition with IC 50  = 6.23 ± 0.09 μM. Docking studies on the crystal structure of B. pasteurii urease (PDB ID 4UBP ) were carried out. [ABSTRACT FROM AUTHOR]

Diabetic neuropathic pain is one of the microvascular complications of diabetes mellitus characterized by symmetrical pain and sensory abnormalities. A steroidal lactone isolated from the datura innoxa plant, withametelin (WMT), exhibited significant neuroprotective, anti-inflammatory, antioxidant, and anticancer properties. The current study aimed to investigate anti-neuropathic pain activity and the molecular mechanism of WMT against streptozotocin (STZ)-induced diabetic neuropathy. Rats were given a single injection of STZ (60 mg/kg, intraperitoneally (i.p.)) for induction of diabetes on the first day of the study. After the onset of diabetic neuropathy, pregabalin (10 mg/kg, i.p.) and WMT (0.1 and 1 mg/kg, i.p.) treatments were started from day 14 up to day 42. It was found that STZ-induced neuropathic pain behaviors were markedly reduced by WMT. It inhibited the STZ-associated histopathological changes and genotoxicity in the sciatic nerve and spinal cord. Additionally, Fourier transforms infrared (FTIR) spectroscopy results revealed that STZ-induced alterations in the biochemical components of the sciatic nerve's myelin sheath were inhibited by WMT. In the spinal cord, it markedly reduced the immunoreactivity of mitogen-activated protein kinases (MAPKs) signaling components such as p38 - MAPK, c-Jun N-terminal kinase (JNK), extracellular-signal-regulated-kinase (ERK), and activator-protein 1 (AP-1). It also reduced the expression levels of nuclear factor-kappa-B (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). The production of inflammatory cytokines was considerably reduced by WMT. This study provides convincing evidence that WMT treatment attenuated STZ-induced diabetic neuropathic pain by inhibition of MAPK/NF-κB signaling. [Display omitted] • Withametelin alleviated STZ-induced neuropathic pain behaviors. • Withametelin restored STZ-associated histopathological changes. • Withametelin suppressed the STZ-induced inflammatory cytokines. • Withametelin reduced the immunoreactivity of MAPK/NF-kB signaling proteins. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) that remains incurable. Withametelin (WMT), a phytosterol, showed diverse biological activities isolated from the leaves of Datura innoxa. In the present study, we used an in vitro model of HT22 and BV - 2 cell lines and an in vivo murine model of MS, experimental autoimmune encephalomyelitis (EAE), to explore the antioxidant and anti neuroinflammatory potential of WMT. The results showed that pretreatment with WMT markedly inhibited H 2 O 2 - induced cytotoxicity and oxidative stress in a dose-dependent manner. Correspondingly, WMT post-immunization treatment significantly attenuated EAE-induced clinical score, weight loss, neuropathic pain behaviors, and motor dysfunction. It markedly lowers EAE-induced elevated circulating leucocytes, spinal deformity, and splenomegaly. It strikingly inhibited the Evans blue and FITC extravasation in the brain. It remarkably reversed the EAE-induced histopathological alteration of the brain, spinal cord, eye, and optic nerve. It significantly intensified the antioxidant defense mechanism by improving the expression level of nuclear factor-erythroid-related factor-2 (Nrf2), heme-oxygenase-1 (HO-1) but reducing the expression level of the Kelch-like-ECH-associated-protein-1 (keap-1), inducible-nitric-oxide-synthase (iNOS) in the CNS. Likewise, it markedly suppressed neuroinflammation by reducing the expression level of toll-like-receptor 4 (TLR4), nuclear-factor-kappa-B (NF-κB), activator-protein-1 (AP-1) but increased the expression level IkB-α in the CNS. Furthermore, molecular dynamics simulations and MMPBSA binding free energies were determined to validate the dynamic stability of complexes and shed light on the atomic level intermolecular interaction energies. Taken together, this study showed that WMT has significant neuroprotective potential in EAE via modulation of Nrf2 mediated-oxidative stress and NF-κB mediated inflammation. [Display omitted] • Withametelin ameliorated EAE-associated clinical symptoms. • Withametelin reversed EAE-associated histopathological alteration in the CNS. • Withametelin suppressed the BBB permeability, oxidative stress & neuroinflammation. • Withametelin inhibited the apoptosis, protein, and myelin damage in the EAE mice. • Withametelin modulates the expression of TLR4/IκB-α/NF-κB/AP-1 & Nrf2/Keap-1/HO-1/iNOS/Bcl-2. [ABSTRACT FROM AUTHOR]