Suitable Therapeutic Agent Research Articles

Cardio- and Hepatoprotective Effects of Hydrogen Sulfide in a High-Fat Diet and Low-Dose Streptozotocin-Induced Type 2 Diabetic Rats

Background: Hydrogen sulfide (H2 S) is the third most crucial gas that is produced inside the body, and at physiological levels, it increases a wide range of health properties, such as anti-inflammatory antioxidant effects. Objectives: This study aimed at evaluating the impact of H2 S administration on oxidative stress (OS) in the heart and liver tissues of diabetic rats. Methods: Twenty-eight Wistar rats were randomly divided into 4 groups, namely, the healthy control group, the diabetic group, and diabetic groups treated with 50 µM/kg and 100 µM/kg of H2 S. After 60 days of treatment, the animals were sacrificed, and biochemical and OS markers were determined using colorimeter methods. In addition, the liver tissue underwent histological assessment. Results: The findings revealed that H2 S controlled the weight of rats and significantly decreased fasting blood sugar (FBS) in the treatment group with a dose of 50 µM/kg and 100 µM/kg (P<0.05) compared to the diabetic animals. Further, insulin concentration and insulin resistance in the H2 S 100 µM/kg group decreased in comparison to the diabetic group (P<0.05). The levels of triglyceride, cholesterol, atherogenic index, and low-density lipoprotein in H2 S-treated animals were markedly lower than in the diabetic group (P<0.05). The results of OS parameters demonstrated that H2 S 100 µM/kg reduced the malondialdehyde in the heart tissue compared to the diabetic group (P<0.05). The histological assessment also confirmed the effectiveness of H2 S in improving liver morphology and parenchymal structure. Conclusion: According to the results of this study, H2 S can be considered a suitable therapeutic agent to prevent diabetes complications.

Astragaloside IV inhibits cell viability and glycolysis of hepatocellular carcinoma by regulating KAT2A-mediated succinylation of PGAM1

BackgroundAstragaloside IV (AS-IV) is one of the basic components of Astragali radix, that has been shown to have preventive effects against various diseases, including cancers. This study aimed to explore the role of AS-IV in hepatocellular carcinoma (HCC) and its underlying mechanism.MethodsThe cell viability, glucose consumption, lactate production, and extracellular acidification rate (ECAR) in SNU-182 and Huh7 cell lines were detected by specific commercial kits. Western blot was performed to analyze the succinylation level in SNU-182 and Huh7 cell lines. The interaction between lysine acetyltransferase (KAT) 2 A and phosphoglycerate mutase 1 (PGAM1) was evaluated by co-immunoprecipitation and immunofluorescence assays. The role of KAT2A in vivo was explored using a xenografted tumor model.ResultsThe results indicated that AS-IV treatment downregulated the protein levels of succinylation and KAT2A in SNU-182 and Huh7 cell lines. The cell viability, glucose consumption, lactate production, ECAR, and succinylation levels were decreased in AS-IV-treated SNU-182 and Huh7 cell lines, and the results were reversed after KAT2A overexpression. KAT2A interacted with PGAM1 to promote the succinylation of PGAM1 at K161 site. KAT2A overexpression promoted the viability and glycolysis of SNU-182 and Huh7 cell lines, which were partly blocked following PGAM1 inhibition. In tumor-bearing mice, AS-IV suppressed tumor growth though inhibiting KAT2A-mediated succinylation of PGAM1.ConclusionAS-IV inhibited cell viability and glycolysis in HCC by regulating KAT2A-mediated succinylation of PGAM1, suggesting that AS-IV might be a potential and suitable therapeutic agent for treating HCC.

Silver nanoparticles green-formulated by Scrophulariastriata: A novel chemotherapeutic drug for the treatment of nerve cancer

The plants use because of their compatibility with the abundance and environment are usually prioritized in synthesizing the silver nanoparticles. In addition, because of their abundance and need lack for special conditions and growth nutrients, plants are suitable options for the production of silver nanoparticles using biological methods. One of these plants is Scrophularia striata. It belongs to the Scrophulariacae family family and has many medicinal properties in traditional medicine. It has been traditionally consumed by local people recently for helping to heal wounds and disinfecting them, however, there have not been many studies on it. We herein demonstrate a novel Ag NPs green mediated by S. striata aqueous extract for the nerve cancer treatment under in vitro conditions. Physicochemical and structural properties of the nanoparticles biomaterial were determined by UV-Vis spectrum, FT-IR, and FE-SEM. The IC50 of Ag NPs against DPPH was 114 μg/mL. In the oncological part of this research, the statue of normal and human peripheral nerve sheath tumor (BL1391 and S462) cells was determined. The IC50 of Ag NPs was 191 and 172 μg/mL against S462 and BL1391. It seems that the prepared nanoparticles have stopped the nerve cancer cells growth and the recent cancer cells have removed with high concentration of nanoparticles. According to the results of this research, it is suggested that the synthesized Ag NPs may be used as a suitable therapeutic agent against several nervous system tumors.

Protective effects of cell permeable Tat-PIM2 protein on oxidative stress induced dopaminergic neuronal cell death

BackgroundOxidative stress is considered as one of the main causes of Parkinson's disease (PD), however the exact etiology of PD is still unknown. Although it is known that Proviral Integration Moloney-2 (PIM2) promotes cell survival by its ability to inhibit formation of reactive oxygen species (ROS) in the brain, the precise functional role of PIM2 in PD has not been fully studied yet. ObjectiveWe investigated the protective effect of PIM2 against apoptosis of dopaminergic neuronal cells caused by oxidative stress-induced ROS damage by using the cell permeable Tat-PIM2 fusion protein in vitro and in vivo. MethodsTransduction of Tat-PIM2 into SH-SY5Y cells and apoptotic signaling pathways were determined by Western blot analysis. Intracellular ROS production and DNA damage was confirmed by DCF-DA and TUNEL staining. Cell viability was determined by MTT assay. PD animal model was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and protective effects were examined using immunohistochemistry. ResultsTransduced Tat-PIM2 inhibited the apoptotic caspase signaling and reduced the production of ROS induced by 1-methyl-4-phenylpyridinium (MPP+) in SH-SY5Y cells. Furthermore, we confirmed that Tat-PIM2 transduced into the substantia nigra (SN) region through the blood-brain barrier and this protein protected the Tyrosine hydroxylase-positive cells by observation of immunohistostaining. Tat-PIM2 also regulated antioxidant biomolecules such as SOD1, catalase, 4-HNE, and 8-OHdG which reduce the formation of ROS in the MPTP-induced PD mouse model. ConclusionThese results indicated that Tat-PIM2 markedly inhibited the loss of dopaminergic neurons by reducing ROS damage, suggesting that Tat-PIM2 might be a suitable therapeutic agent for PD.

An integrated in-silico Pharmaco-BioInformatics approaches to identify synergistic effects of COVID-19 to HIV patients

BackgroundWith high inflammatory states from both COVID-19 and HIV conditions further result in complications. The ongoing confrontation between these two viral infections can be avoided by adopting suitable management measures. PurposeThe aim of this study was to figure out the pharmacological mechanism behind apigenin's role in the synergetic effects of COVID-19 to the progression of HIV patients. MethodWe employed computer-aided methods to uncover similar biological targets and signaling pathways associated with COVID-19 and HIV, along with bioinformatics and network pharmacology techniques to assess the synergetic effects of apigenin on COVID-19 to the progression of HIV, as well as pharmacokinetics analysis to examine apigenin's safety in the human body. ResultStress-responsive, membrane receptor, and induction pathways were mostly involved in gene ontology (GO) pathways, whereas apoptosis and inflammatory pathways were significantly associated in the Kyoto encyclopedia of genes and genomes (KEGG). The top 20 hub genes were detected utilizing the shortest path ranked by degree method and protein-protein interaction (PPI), as well as molecular docking and molecular dynamics simulation were performed, revealing apigenin's strong interaction with hub proteins (MAPK3, RELA, MAPK1, EP300, and AKT1). Moreover, the pharmacokinetic features of apigenin revealed that it is an effective therapeutic agent with minimal adverse effects, for instance, hepatoxicity. ConclusionSynergetic effects of COVID-19 on the progression of HIV may still be a danger to global public health. Consequently, advanced solutions are required to give valid information regarding apigenin as a suitable therapeutic agent for the management of COVID-19 and HIV synergetic effects. However, the findings have yet to be confirmed in patients, suggesting more in vitro and in vivo studies.

Optimization of Extraction Conditions using Response Surface Methodology and HPTLC Fingerprinting Analysis of Indian Propolis

The potential of Indian propolis as a suitable therapeutic agent is still to be explored to the fullest. As variation in the chemical composition across different geographical regions has been a major concern, it is, therefore, worthwhile to systematically investigate, and assess the quality of Indian propolis and set nationalized standards. The propolis collected from three different regions were authenticated for the major plant source, followed by the evaluation of physicochemical properties. Different extraction methods were compared, with their influence on balsam content, polyphenol, and flavonoid content. The sample coded HAR using ultrasonication gave the highest extraction yield of 71.87%. Further, the process variables in the ultrasonication method (i.e. Amplitude, extraction time, the concentration of ethanol) at three levels were optimized using the Box-Behnken response design. The model was found significant with the concentration of ethanol having a maximum influence on the responses. The model was successfully verified by setting the amplitude at 48%, extraction time to 5.6 mins, and ethanol concentration to 87% v/v. The extraction efficiency of 83.86±1.17% was achieved with a substantial diminution of extraction time. The total phenolic, total flavonol, and total flavanone content of the optimized batch were 28.74±0.13 mgGAE/g, 4.66±0.78 mgQE/g, and 3.16±0.14 mgPE/g of propolis respectively. Further HPTLC fingerprint image of the optimized extract revealed the presence of quercetin, p-coumaric acid, kaempferol, chrysin, pinocembrin, and galangin.

Cyclic-di-GMP stimulates keratinocyte innate immune responses and attenuates methicillin-resistant Staphylococcus aureus colonization in a murine skin wound infection model

BackgroundStaphylococcus aureus is a leading cause for morbidity and mortality associated with skin and burn wound infections. Therapeutic options for methicillin-resistant S. aureus (MRSA) have dwindled and therefore alternative treatments are urgently needed. In this study, the immuno-stimulating and anti-MRSA effects of cyclic di-guanosine monophosphate (c-di-GMP), a uniquely bacterial second messenger and immuno-modulator, were investigated in HaCaT human epidermal keratinocytes and a murine skin wound infection model.ResultsStimulation of HaCaT cells with 125 μM c-di-GMP for 12 h prior to MRSA challenge resulted in a 20-fold reduction in bacterial colonization compared with untreated control cells, which was not the result of a direct c-di-GMP toxic effect, since bacterial viability was not affected by this dose in the absence of HaCaT cells. C-di-GMP-stimulated or MRSA-challenged HaCaT cells displayed enhanced secretion of the antimicrobial peptides human β-defensin 1 (hBD-1), hBD-2, hBD-3 and LL-37, but for hBD1 and LL-37 the responses were additive in a c-di-GMP-dose-dependent manner. Secretion of the chemokines CXCL1 and CXCL8 was also elevated after stimulation of HaCaT cells with lower c-di-GMP doses and peaked at a dose of 5 μM. Finally, pre-treatment of mice with a 200 nmol dose of c-di-GMP 24 h before a challenge with MRSA in skin wound infection model resulted in a major reduction (up to 1,100-fold by day 2) in bacterial CFU counts recovered from challenged skin tissue sections compared PBS-treated control animals. Tissue sections displayed inflammatory cell infiltration and enhanced neutrophil influx in the c-di-GMP pre-treated animals, which might account for the reduced ability of MRSA to colonize c-di-GMP pre-treated mice.ConclusionsThese results demonstrate that c-di-GMP is a potent immuno-modulator that can stimulate anti-MRSA immune responses in vivo and might therefore be a suitable alternative prophylactic or therapeutic agent for MRSA skin or burn wound infections.

Putative Mechanisms Underlying the Beneficial Effects of Polyphenols in Murine Models of Metabolic Disorders in Relation to Gut Microbiota.

The beneficial effects of polyphenols on metabolic disorders have been extensively reported. The interaction of these compounds with the gut microbiota has been the focus of recent studies. In this review, we explored the fundamental mechanisms underlying the beneficial effects of polyphenols in relation to the gut microbiota in murine models of metabolic disorders. We analyzed the effects of polyphenols on three murine models of metabolic disorders, namely, models of a high-fat diet (HFD)-induced metabolic disorder, dextran sulfate sodium (DSS)-induced colitis, and a metabolic disorder not associated with HFD or DSS. Regardless of the model, polyphenols ameliorated the effects of metabolic disorders by alleviating intestinal oxidative stress, improving inflammatory status, and improving intestinal barrier function, as well as by modulating gut microbiota, for example, by increasing the abundance of short-chain fatty acid-producing bacteria. Consequently, polyphenols reduce circulating lipopolysaccharide levels, thereby improving inflammatory status and alleviating oxidative imbalance at the lesion sites. In conclusion, polyphenols likely act by regulating intestinal functions, including the gut microbiota, and may be a safe and suitable therapeutic agent for various metabolic disorders.

Synthesis and biological evaluation of novel coumarin derivatives in rhabdoviral clearance.

Diseases caused by rhabdoviruses have had a huge impact on the productive lives of the entire human population. The main problem is the lack of drugs for the treatment of this family of viruses. Infectious hematopoietic necrosis virus (IHNV), the causative agent of IHN, is a typical rhabdovirus which has caused huge losses to the salmonid industry. Therefore, in this study, IHNV was studied as a model to evaluate the antiviral activity of 35 novel coumarin derivatives. Coumarin A9 was specifically selected for further validation studies upon comparing the half maximum inhibitory concentration (IC50) of four screened candidate derivatives in epithelioma papulosum cyprinid (EPC) cells, as it exhibited an IC50 value of 2.96μM against IHNV. The data revealed that A9 treatment significantly suppressed the virus-induced cytopathic effect (CPE) in EPC cells. In addition, A9 showed IC50 values of 1.68 and 2.12μM for two other rhabdoviruses, spring viremia of carp virus and micropterus salmoides rhabdovirus, respectively. Furthermore, our results suggest that A9 exerts antiviral activity, but not by destroying the virus particles and interfering with the adsorption of IHNV. Moreover, we found that A9 had an inhibitory effect on IHNV-induced apoptosis in EPC cells, as reflected by the protection against cell swelling, formation of apoptotic bodies, and loss of cell morphology and nuclear division. There was a 19.05% reduction in the number of apoptotic cells in the A9 treatment group compared with that in the IHNV group. In addition, enzyme activity assays proved that A9 suppressed the expression of caspase 3, 8 and 9. These results suggested that A9 inhibit viral replication, to some extent, by blocking IHNV-induced apoptosis. In an invivo study, A9 exhibited an anti-rhabdovirus effect in virus-infected fish by substantially enhancing the survival rate. Consistent with the above results, A9 repressed IHNV gene expression in virus-sensitive tissues (brain, kidney and spleen) in the early stages of virus infection. Importantly, the data showed that horizontal transmission of IHNV was reduced by A9 in a static cohabitation challenge model, especially in fish that underwent bath treatment, suggesting that A9 might be a suitable therapeutic agent for IHNV in aquaculture. Therefore, coumarin derivatives can be developed as antiviral agents against rhabdoviruses.

Isolation and Purification of Thrombolytic Enzyme Extracted from Earthworm Punjab, Pakistan

The Cardiovascular disease due to thrombus (clot) formation is the major factor of death throughout the world. Earthworms being the eco engineers has thrombolytic enzyme that can be used for thrombolysis. The thrombolytic enzyme was isolated and purified from supernatant of earthworm Apporectodea longa by column chromatography. Six Strain BKT 11, BKT 15, BKT 17, BKT 26, BKT 27 and BKT 28 shows the thrombolytic activity 791.64 U/mg, 1362.39 U/mg, 1205.4 U/mg, 710.63 U/mg, 529.66 U/mg and 625.00 U/mg respectively. Thrombolytic activity was confirmed by blood clot lysis method. Different concentrations 50 ?l,100 ?l, 150 ?l, 200 ?l and 250 ?l of extracted enzyme were applied on 25mg of wet blood clot along with control where distill water used. These fractions of extracted enzymes represent the dissolution of clot (thrombolysis). The molecular weight 32 KDa was determined by sodium dodecyl sulphate gel electrophoresis (SDS-PAGE). Results show that extracted elute have potential of fibrinolytic activity in this specie of earthworm and it can serve as a suitable therapeutic agent. Keywords: Thrombolytic activity, Casein plate assay, Blood clot lysis, spectrophotometry, Gel electrophoresis.

Synthesis of methoxy poly(ethylene glycol)-poly(ε-caprolactone) diblock copolymers hybridized with DDAB cationic lipid as the efficient nanocarriers for in vitro delivery of lycopene into MCF-7 breast cancer cells

Given the high rate of cancer mortality in the world, trying to find appropriate therapeutic strategies is a very crucial issue. Since insulin-like growth factor −1(IGF-1) and its receptor (IGF-1R) play a significant role in tumor formation and progression, targeting them can have a vital effect on cancer treatment. Lycopene is a natural antioxidant that exerts its anti-tumor effect by regulating IGF-I signaling and cell cycle arrest, making it a suitable therapeutic agent for reducing tumor induction. However, the utilization of lycopene is limited due to its high lipophilicity and very low solubility in biological body fluids. To overcome this problem, polymer lipid hybrid nanocarriers that have a core-shell structure have received much attention in recent years. In this study, to produce lipid-hybrid nanoparticles (NPs), methoxypolyethylene glycol-polycaprolactone (mPEG-PCL) copolymers were applied for lycopene loading due to biocompatibility, biodegradability, non-toxic nature, small size, amphiphilic properties, and stability of these NPs in the circulatory system. Furthermore, the use of the cationic lipid of Dimethyldioctadecylammonium bromide (DDAB) increased the cellular uptake of nanocarriers. This study proposed mPEG-PCL-DDAB as a potent nanocarrier for drug delivery to MCF-7 breast cancer cell lines, in vitro, and their applicability for the IGF-1R silencing, as a promising anti-cancer therapeutic approach, for the first time.

Melatonin: a pleiotropic hormone as a novel potent therapeutic candidate in arsenic toxicity

Arsenic is a natural element which exists in the environment in inorganic and organic forms. In humans, the main reason for the toxicity of arsenic is its uptake via water sources. As polluted water and the problems associated with it can be found in many countries. Therefore, considering all these positive effects of melatonin, this review is aimed at melatonin supplementation therapy on arsenic toxicity which seems to be a suitable therapeutic agent to eliminate the adverse effects of arsenic. It is seen in previous studies that chronic exposure to arsenic could cause serious dys functions of organs and induce different degrees of toxicities that is one of the first hazardous materials in the classification of substances by the United States Environmental Protection Agency so leads to costly cleanup operations burdening the economy. Arsenic harmfulness degree depends on the bioavailability, chemical form, valence state, detoxification, and metabolism of human body. The oxidative stress has a major role in arsenic-induced toxicity; on the other hand, it was discovered that melatonin is a powerful scavenger for free radical and it's an extensive-spectrum antioxidant. Due to its highly lipophilic and small size properties, melatonin accesses all intracellular organs by easily passing via the cell membrane and prevents protein, DNA damage, and lipid peroxidation. In particular, melatonin, by protecting and reducing oxidative stress in mitochondria, can normalize homeostasis and mitochondrial function and ultimately prevent apoptosis and cell death.

In-silico Study to Identify Dietary Molecules as Potential SARS-CoV-2 Agents

Background: Recently, Coronavirus Disease-2019 (COVID-19), caused by a fatal strain of coronavirus named Severe Acute Respiratory Syndrome-2 (SARS-CoV-2), has been declared as a pandemic by the World Health Organisation (WHO) on 11 March 2020. Globally, no therapy such as vaccines and specific therapeutic agents is available so far despite some protease inhibitors and antiviral agents. Introduction: Due to no therapeutic drug or vaccine against SARS-CoV-2 so far, phytomedicine may be developed as therapeutic agents in the prevention and treatment of current COVID-19 disease. Thus, the aim of this study was to find out a suitable therapeutic agent from selected 17 dietary molecules, which could target SARS-CoV-2 encoded proteins. Materials and Methods: In this study, 3D structures of selected dietary molecules were obtained from the PubChem database, which have previously been reported for their antiviral and anti-inflammatory effects. Then, molecular docking analysis by using AutoDoc4 and AutoDockVina software was conducted to evaluate their anti-SARS-CoV-2 activity. Lipinski’s rule of five and drug-likeness properties were also discussed with the help of Molinspiration and the OSIRIS property explorer methods. Results: Our results revealed that, among all, epigallocatechin gallate (EGCG) (7) is a lead compound that could fit well into the binding sites of docked proteins of SARS-CoV-2. EGCG showed very strong molecular interactions with the free enzyme of main protease (6y2e), chimeric receptorbinding domain complexed with human ACE2 (6vw1), and NSP15 endoribonuclease (6vww) encoded proteins of SARS-CoV-2, by showing binding energies -9.30, -8.66, and -8.38, kcal/mole, respectively. Conclusion: In the present study, EGCG (7) is more active than two standard drugs that are currently being used in COVID 19, namely remdesivir and nafamostat. Therefore, EGCG (7), as per our results, might be explored as a therapeutic agent for the treatment of COVID-19.

Regorafenib inhibits migration, invasion, and vasculogenic mimicry of hepatocellular carcinoma via targeting ID1-mediated EMT.

Regorafenib is approved for patients with unresectable hepatocellular carcinoma (HCC) following sorafenib. However, the effect of regorafenib on HCC metastasis and its mechanism are poorly understood. Here, our data showed that regorafenib significantly restrained the migration, invasion and vasculogenic mimicry (VM) of HCC cells, and downregulated the expression of epithelial-to-mesenchymal transition (EMT)/VM-related molecules. Using RNA-seq and cellular thermal shift assays, we found that inhibitor of differentiation 1 (ID1) was a key target of regorafenib. In HCC tissues, the protein expression of ID1 was positively correlated with EMT and VM formation (CD34- /PAS+ ). Functionally, ID1 knockdown inhibited HCC cell migration, invasion, metastasis, and VM formation in vitro and in vivo, with upregulation of E-cadherin and downregulation of Snail and VE-cadherin. Moreover, Snail overexpression promoted the migration, invasion, and VM formation of ID1 knockdown cells. Snail knockdown reduced the migration, invasion, and VM formation of ID1 overexpression cells. Finally, regorafenib suppressed VM formation and decreased the expression of ID1, VE-cadherin and Snail in HCC PDX model. In conclusion, we manifested that regorafenib distinctly inhibited EMT in HCC cells via targeting ID1, leading to the suppression of cell migration, invasion and VM formation. These findings suggest that regorafenib may be developed as a suitable therapeutic agent for HCC metastasis.

P0491THE ROUTE TO INDIVIDUALIZED THERAPIES IN PRIMARY MEMBRANOUS NEPHROPATHY: BMI AND KIDNEY OUTCOMES

Abstract Background and Aims A real progress in treating patients more than diseases, would rest on tailored medicine and go beyond the hypothesis that “one size fits all”. Glomerular diseases are not an exception to this consideration, and deserve case-by-case evaluation for choosing both the most suitable therapeutic agent and its appropriate dose, because a standardized treatment may result in worse prognosis. We analyzed the role of body mass index (BMI) in modifying renal outcomes of patients with nephrotic syndrome due to membranous nephropathy (MN) treated with immunosuppressive drugs. Method We performed a retrospective analysis of 29 MN patients related to our center (M 19, F 10), checking their anti PLA2R status at kidney biopsy time and any change in proteinuria, serum creatinine (SCr) and body mass index (BMI) between diagnosis and at last follow-up visit, in search of a correlation with their response to immunosuppressive treatment. Data with non normal distribution are expressed as median and interquartile range [IQR]. Results The median follow-up of our patients lasted 49 months [IQR 14-80]. At biopsy time, almost half of them was anti-PLA2R positive (n=14 subjects) while the other resulted to be negative and were thus screened for secondary causes of MN (n=15). Irrespective either of anti-PLA2R status or the administration of Ponticelli regimen or Rituximab, complete remission was achieved in 31% of patients, while 34.5% experienced a partial remission and 34.5% resulted non responder to at least a therapeutic protocol. Median proteinuria reduction was of 3.732g/24h [IQR 7.636-1.77 g/24h]. Median rise in SCr was 0.140 mg/dl [IQR -0.11 – 0.4 mg/dl]. Direct association between the proteinuria/BMI ratio at diagnosis and remission of proteinuria at last follow up was statistically significant (r=-0.7506; P<0.0001) (Fig.1). Conclusion Albeit remission is not directly correlated with basal BMI, our results appear to confirm that an appropriate drug posology, not only according to patients’ renal or hepatic function but also to their body mass, may result in more effective individualized therapies in MN; nevertheless, this recorded association must be confirmed by large scale randomized clinical trials.

Treatment with once-weekly alendronate oral jelly compared with once-weekly alendronate oral tablet for Japanese patients with primary osteoporosis: An open-label, prospective, observational study.

Background and aimsClinical data regarding alendronate jelly are limited. We compared the efficacy and safety of once‐weekly alendronate oral jelly with once‐weekly alendronate tablet formulations in the context of primary osteoporosis.MethodsIn this 6‐month, open‐label, prospective, observational study, Japanese patients aged ≥60 years with primary osteoporosis were included from 14 primary care centres in Japan. The effects of once‐weekly alendronate oral jelly and tablet formulations on bone mineral density (BMD), bone turnover markers, and quality of life related to gastrointestinal symptoms were assessed at baseline and 6 months. Treatment was allocated by patient preference. This potentially confounding factor was adjusted for statistically.ResultsIn total, 170 patients were enrolled (jelly, n = 97; tablet, n = 73). Mean percent changes in radius, lumbar spine, femoral neck, and hip BMD were similar in both treatment groups at 6 months. Both formulations decreased tartrate‐resistant acid phosphatase 5b (TRACP‐5b) and procollagen 1 N‐terminal peptide (P1NP) between baseline and 6 months (by about 50% and 60%, respectively); no significant differences in mean changes were noted in these markers between groups. At 6 months, no significant differences were noted in visual analogue scale or EuroQOL five‐dimension questionnaire scores between groups. The jelly group had significantly lower scores than the tablet group in the Izumo scale domains of heartburn (−0.81, P = 0.0040), epigastralgia (−0.94, P = 0.0003), and epigastric fullness (−0.49, P = 0.044). During treatment, more patients discontinued for upper gastrointestinal symptoms in the tablet group (n = 4) than the jelly group (n = 1).ConclusionsOnce‐weekly alendronate oral jelly 35 mg may be a suitable alternative therapeutic agent for primary osteoporosis in Japan.

Effects of toceranib compared with sorafenib on monocrotaline-induced pulmonary arterial hypertension and cardiopulmonary remodeling in rats

Sorafenib reverses pulmonary arterial hypertension (PAH) and cardiopulmonary remodeling (CPR), but the effects of toceranib are unknown. This study investigated anti-remodeling effects and determined optimal doses of toceranib and sorafenib on monocrotaline (MCT)-induced PAH and CPR in rats. MCT-treated rats were orally treated with a 14-day course of sorafenib (10, 30, or 100 mg/kg), toceranib (1, 3, or 10 mg/kg), or water. Both sorafenib and toceranib significantly reversed the right ventricular (RV) hypertrophy at 10 mg/kg, but only sorafenib significantly improved the RV systolic and mean pressures. Sorafenib significantly normalized the B-type natriuretic peptide mRNA level of the RV and increased the non-muscularized pulmonary artery percentage. However, these effects were only observed at the highest toceranib dose, and neither toceranib dose reduced the fully muscularized pulmonary artery percentage. Further, the inhibition on vascular endothelial growth factor (VEGF) signaling was stronger in sorafenib than in toceranib. Besides the stronger inhibition on mitogen-activated protein kinase signaling, the greater reversal ability of sorafenib may be also due to the simultaneous blockade on the C-X-C chemokine receptor type 4 and autophagy induction. Toceranib insignificantly reversed CPR, and a high-dose therapy did not improve the RV hemodynamic outcomes. Sorafenib significantly reversed CPR, and a low-dose sorafenib therapy may be a suitable therapeutic agent for PAH.

Isolation, identification and characterization of apigenin from Justicia gendarussa and its anti-inflammatory activity

Inflammatory responses during chronic diseases such as atherosclerosis, cancer etc., are harmful to host organisms. Generally NSAIDs are used to treat against these severe conditions but due to its adverse effects studies are going on with medicinal plants, since they are rich in bioactive compounds. Justicia gendarussa is one such plant which has been used as a remedial measure for treating inflammatory diseases since ancient time. Thus the present study involved in the isolation, characterization and identification of apigenin (flavonoid) from this plant and to elucidate its molecular mechanism against inflammation via TLR-NF-κB signaling pathway using ox-LDL induced hPBMCs in in vitro model. Methanolic extract was used for the isolation process and results showed that the F6 fraction collected from ethyl acetate through column chromatography showed 89% paw edema inhibition at a dose of 10 mg/kg in carrageenan induced rats. Purification of F6 by TLC with toluene: chloroform: acetone (8:5:7) and further characterization by 1HNMR indicated the presence of bioactive compound, apigenin. In vitro studies revealed that pretreatment of ox-LDL induced hPBMCs with apigenin (25 μM) significantly (P < 0.05) reduced the levels of TLR4, MyD88, TRIF, TRAF6, NF-κB, COX-2, PGE2, IL-1β and TNF-α responsible for generating inflammation and elevated the level of anti-inflammatory cytokine, IL-10. These results indicate the therapeutic efficacy of bioflavonoid apigenin which was isolated from Justicia gendarussa against ox-LDL induced inflammation. Therefore apigenin can be treated as a suitable therapeutic agent against inflammatory diseases.

Original paper: Efficacy and safety analysis of insulin degludec/insulin aspart compared with biphasic insulin aspart 30: A phase 3, multicentre, international, open-label, randomised, treat-to-target trial in patients with type 2 diabetes fasting during Ramadan

AimsTo compare the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) and biphasic insulin aspart 30 (BIAsp 30) before, during and after Ramadan in patients with type 2 diabetes mellitus (T2DM) who fasted during Ramadan. MethodsIn this multinational, randomised, treat-to-target trial, patients with T2DM who intended to fast and were on basal, pre- or self-mixed insulin ± oral antidiabetic drugs for ≥90 days were randomised (1:1) to IDegAsp twice daily (BID) or BIAsp 30 BID. Treatment period included pre-Ramadan treatment initiation (with insulin titration for 8–20 weeks), Ramadan (4 weeks) and post-Ramadan (4 weeks). Insulin doses were reduced by 30–50% for the pre-dawn meal (suhur) on the first day of Ramadan, and readjusted to the pre-Ramadan levels at the end of Ramadan. Hypoglycaemia was analysed as overall (severe or plasma glucose <3.1 mmol/L [56 mg/dL]), nocturnal (00:01–05:59) or severe (requiring assistance of another person). ResultsDuring the treatment period, IDegAsp (n = 131) had significantly lower overall and nocturnal hypoglycaemia rates with similar glycaemic efficacy, versus BIAsp 30 (n = 132). During Ramadan, despite achieving significantly lower pre-iftar (meal at sunset) self-measured plasma glucose (estimated treatment difference: −0.54 mmol/L [−1.02; −0.07]95% CI, p = .0247; post hoc) with similar overall glycaemic efficacy, IDegAsp showed significantly lower overall and nocturnal hypoglycaemia rates versus BIAsp 30. ConclusionsIDegAsp is a suitable therapeutic agent for patients who need insulin for sustained glucose control before, during and after Ramadan fasting, with a significantly lower risk of hypoglycaemia, versus BIAsp 30, an existing premixed insulin analogue.

The apoptotic and genomic studies on A549 cell line induced by silver nitrate.

Lung cancer is the leading cause of male cancer deaths worldwide. Metal-based anticancer drugs have evolved significantly during the past decades. Recently, silver ions have been investigated for their anticancer effects. We aimed to study the time-course cytotoxic effects of silver nitrate on A549 adenocarcinomic human alveolar basal epithelial cells to provide insights into the molecular-level understanding of growth suppression mechanism involved in apoptosis. The influences of silver nitrate were studied via MTT assay, flow cytometry, immunocytochemical, confocal and transmission electron microscopy, and microarray assays. Silver nitrate showed inhibitory effects against A549 cells in a dose- and time-dependent manner for 24, 48, and 72 h and induced apoptosis. The early and late apoptotic cells and depolarized mitochondrial membrane potential were determined by the half-maximal inhibitory concentration (IC50) value of silver nitrate treated for 72 h. But cysteinyl aspartate proteinase-3 was not activated for 72 h. Furthermore, IC50 value of silver nitrate also induced apoptosis according to immunocytochemical assays for 72 h. The downregulated CCNY, HNRNPL, ASF1B, PIAS4, HNRNPH1, EIF2C2, TAF15, FOXC1, LEP, and PCB2 genes administered with silver nitrate IC50 were identified as apoptosis-leading genes. Silver nitrate may be a suitable therapeutic agent against lung cancer.