A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties.

New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms. In vivo experiments showed that this compound reduced blood glucose and lipid levels in a diabetic mice model displaying no toxicity on bone, kidney, and liver. To our knowledge, this is the first example of dual PPARα/γ partial agonist showing these combined effects representing, therefore, the potential lead of new drugs for treatment of dyslipidemic type 2 diabetes.

Elucidating the anti-obesity potential of bioactive fractions of kalanchoe pinnata (lam.) leaves extract using a combination of in vitro, in vivo and in silico methods along with characterisation of lead compounds through an HPTLC ms-MSn analytical study.

Fractions were isolated from the leaves extract of Kalanchoe pinnata and subjected to scrutiny for their prospective anti-obesity properties. An array of preliminary phytochemical, invitro antioxidant, and enzyme inhibition assays were executed, which discerned fractions F1 and F2 as the most effective fractions. These fractions were subsequently studied through invivo experiments, affirming that F2 as the most potent fraction. Further characterisation of F2 was conducted via HPTLC-Mass spectrometry (MS-MSn) techniques. The outcomes demonstrated that F2 produced a notable anti-obesity effect in obese mice, reducing their body weight and lipid metrics, and leading to advantageous changes in their organs. An analytical examination of F2 revealed the existence of four principal compounds, which were subsequently subjected to insilico molecular docking and dynamic analysis, confirming their aptitude for binding to selected proteins. These findings imply that the utilisation of Kalanchoe pinnata leaves could provide a promising therapeutic strategy for the treatment of obesity.

Anti-obesity potential of bioactive guided fractions of Annona squamosa linn. leaves extract: a combination of in-vitro, in-vivo and in-silico studies along with profiling of lead compounds by HPTLC MS-MSn method.

The antiobesity potential of bioactive fractions derived from Annona squamosa was approached using a combination of in vitro, in silico and in-vivo studies. The study was analyzed to validate and select the potent bioactive fractions of A. squamosa leaves extract through in vitro and in vivo activities targeting obesity. The phytochemical properties of the bioactive fractions were investigated utilizing total flavonoid, total phenolic and total steroidal content. Further, in vitro antioxidant assays such as nitric oxide (NO2), DPPH, ABTS, and Hydrogen peroxide (H2O2) scavenging assays were performed whereas pancreatic lipase, Alpha-amylase and Alpha glucosidase assays were carried out for enzyme inhibition activities. The overall study revealed that fractions F2 and F3 had shown significant in vitro activities targeting obesity. The selected potent fractions (F2 and F3) were orally bio-screened for efficacy in MSG-HFD-induced obese mice at 80 mg/kg/bw. The invivo study confirmed that fractions 2 and 3 with a dose of 80 mg/kg/bw had a significant potency compared to obese control and standard for various parameters. Body weight and lipid metrics were significantly reduced, and histological examinations revealed considerable beneficial alterations in the organs of the animals. Further HPTLC MS-MSn was used to characterize and identify the major compounds in the potent bioactive fractions, which confirmed the presence of seven major compounds: Ascorbic acid, Gallic acid, Quercetin, ß-sitosterol, Stigmasterol, Caffeine and Epigallocatechin gallate. An in silico model was then employed to determine the best binding activity of the identified compound towards the specific receptors targeting obesity, confirming the most effective docking score towards stigmasterol and sitosterol. The in vitro and in vivo studies of derived bioactive fractions of A. squamosa leaves extract revealed a possible therapeutic approach towards anti-obesity activity for the first time.

Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry Estimation of Quercetin-Loaded Nanoemulsion in Rabbit Plasma: In Vivo-In Silico Pharmacokinetic Analysis Using GastroPlus.

In the present study, we developed and validated a rapid, specific, sensitive, and reproducible liquid chromatography-electrospray ionization tandem mass spectrometry method for quantifying quercetin (QT) in rabbit plasma using hydrochlorothiazide as the internal standard. Animals were orally administered with optimized QT-loaded nanoemulsion (QTNE) and QT suspension (QTS), equivalent to 30 mg/kg, to the test and control group, respectively. The blood samples were collected at pre-determined time points up to 48 h. The linearity range was from 5 to 5000 ng mL-1 with R 2 = 0.995. Further, we analyzed the various pharmacokinetic parameters and established the in vitro-in vivo correlation (IVIVC) of QTNE using GastroPlus software. The method was successfully developed and validated, and when applied for the determination of QT in rabbit plasma, it exhibited an increase in C max from 122.56 ng mL-1 (QTS) to 286.51 ng mL-1 (QTNE) (2.34-fold) and AUC0-48 from 976 ng h mL-1 (QTS) to 4249 ng h mL-1 (QTNE) (4.35-fold), indicating improved oral bioavailability QT when administered as QTNE. Statistical analysis revealed that the Loo-Riegelman method (two-compartmental method) best fitted the deconvolution approach (R 2 = 0.998, SEP = 4.537, MAE = 2.759, and AIC = 42.38) for establishing the IVIVC. In conclusion, the established bioanalytical method and IVIVC studies revealed that QTNE is a potential carrier for the effective delivery of QT with enhanced oral bioavailability.

A New Antidiabetic Agent Showing Short- and Long-Term Effects Due to Peroxisome Proliferator-Activated Receptor Alpha/Gamma Dual Agonism and Mitochondrial Pyruvate Carrier Inhibition.

A new series of analogues or derivatives of the previously reported PPARα/γ dual agonist LT175 allowed the identification of ligand 10, which was able to potently activate both PPARα and -γ subtypes as full and partial agonists, respectively. Docking studies were performed to provide a molecular explanation for this different behavior on the two different targets. In vivo experiments showed that this compound induced a significant reduction in blood glucose and lipid levels in an STZ-induced diabetic mouse model displaying no toxic effects on bone, kidney, and liver. By examining in depth the antihyperglycemic activity of 10, we found out that it produced a slight but significant inhibition of the mitochondrial pyruvate carrier, acting also through insulin-independent mechanisms. This is the first example of a PPARα/γ dual agonist reported to show this inhibitory effect representing, therefore, the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.

In vivo morphological study of obese development in mice model guided by swept-source optical coherence tomography (SSOCT).

This article shows the adequacy of the custom-built optical imaging system in the advancement investigation of obese mice. Obesity is defined as increased adipose/fatty mass resulting from a chronic imbalance between energy intake and expenditure. The in vivo investigation was performed for the tissue characterization of obese mice utilizing swept-source optical coherence tomography (SSOCT) for in situ examination and histology of delicate tissues in mice skin. It provides a noninvasive, painless visualization of the subsurface in life systems. Our SSOCT system's data is comparable to the regular invasive histology. Cross-assessment is done in various skin layers in obese mice like epidermis, papillary dermis, dermis, and fat tissue, which are likewise separated from the nonobese mice group. Histopathology results were further assessed with the obtained SSOCT results. This high precision of characterizing tissues using SSOCT helps us perform in vivo imaging and can also be used for the variable purpose of clinical practice.

A Series of Ferulic Acid Amides Reveals Unexpected Peroxiredoxin 1 Inhibitory Activity with in†vivo Antidiabetic and Hypolipidemic Effects.

Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes (T2DM). Ferulic acid is known for attenuating the insulin resistance and reducing the blood glucose in T2DM rats. In this work, we designed and synthesized a library of new ferulic acid amides (FAA), which could be considered as ring opening derivatives of the antidiabetic PPARγ agonists Thiazolidinediones (TZDs). However, since these compounds displayed weak PPAR transactivation capacity, we employed a proteomics approach to unravel their molecular target(s) and identified the peroxiredoxin 1 (PRDX1) as a direct binding target of FAAs. Interestingly, PRDX1, a protein with antioxidant and chaperone activity, has been implied in the development of T2DM by inducing hepatic insulin resistance. SPR, mass spectrometry-based studies, docking experiments and in vitro inhibition assay confirmed that compounds VIe and VIf bound PRDX1 and induced a dose-dependent inhibition. Furthermore, VIe and VIf significantly improved hyperglycemia and hyperlipidemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats as confirmed by histopathological examinations. These results provide guidance for developing the current FAAs as new potential antidiabetic agents.

Evaluation of wound healing and antimicrobial potentials of Ixora coccinea root extract.

OBJECTIVE: To evaluate the wound healing and antimicrobial activity of root extracts of Ixora coccinea (I. coccinea). METHODS: To investigate the wound healing efficacy of root extract of I. coccinea Linn, five groups of animals were divided each containing six animals. Two wound models including incision and excision wound models were used in this study. The parameters studied were tensile strength on incision wound model and in terms of wound contraction for excision wound model were compared with standard Nitrofurazone (NFZ) ointment (0.2% w/w). Six extracts (ethanol, aqueous, petroleum ether, benzene, chloroform and ethyl acetate) of I. coccinea were screened for in vitro growth inhibiting activity against different bacterial strains viz, Staphylococcus aureus, Bacillus pumilius, Enterococcus faecalis, Escherichia coli, Salmonella typhi and Pseudomonas aeruginosa and fungi Candida albicans and Aspergillus niger were compared with the standard drugs ciprofloxacin and chloramphenicol for antibacterial and griseofulvin for antifungal screening. The serial dilution and cup (or) well plate methods were used for the antimicrobial study and MIC was determined. RESULTS: The ethanolic extract showed significant (P<0.001) wound healing activity when compared to standard drug NFZ with respect to normal control group. Amongst all, ethanolic extract showed highly significant antibacterial activity against all bacterial strains used in this study when compared to standard. The aqueous extract showed moderate significant inhibition against all bacterial strains when compared to standard. All the extracts were shown negligible activity against the fungal strains used in this study. CONCLUSIONS: The ethanolic root extract of I. coccinea showed pronounced wound healing and antibacterial activity. The probable reason to heal the wound was that the external application of the extract prevented the microbes to invade through the wound thus the protection of wound occurs against the infection of the various organisms.

Stem cells: An overview with respect to cardiovascular and renal disease.

In recent years, there has been a tremendous increase in the understanding of stem cell biology. Stem cells have clonogenic and self-renewing capabilities, and under certain conditions, can differentiate into multiple lineages of mature cells. Recent studies have shown that adult stem cells can be isolated from a wide variety of tissues, including bone marrow, peripheral blood, muscle, and adipose tissue. The potential clinical applications lead to an extended interest in the use of stem cells in many medical disciplines. In this article, we present an overview of stem cells with special reference to cardiovascular and renal diseases treatments by stem cells.