•Guar gum based pH-responsive hydrogel was synthesized as a colon drug carrier.•The prepared hydrogel was characterized with FT-IR, 1H NMR and XRD analysis.•This hydrogel showed a pH dependent ...swelling and drug release profile, which would be suitable for colon-targeted drug delivery.•This hydrogel showed no cytotoxicity against the MSC stem cells and therefore it would be safe material for colon-drug delivery.
A novel type of ethylene glycol dimethacrylate (EGDMA) cross-linked guar gum oleate-graft-poly(methacrylic acid) (GGO-g-PMAc) hydrogel was prepared as a pH-responsive controlled release carrier for colon-specific drug delivery. The structure of GGO-g-PMAc hydrogel was characterized by FT-IR, 1H NMR and X-ray diffraction (XRD) analysis. The swelling degree of the GGO-g-PMAc hydrogel at pH 7.4 was found to be higher than that at pH 1.2. The drug release studies performed in pH 7.4 and 1.2 buffer solutions at 37°C revealed that the rate and amount of drug released from the GGO-g-PMAc hydrogel at pH 7.4 were higher than that at pH 1.2. The MTT assay revealed that there is no noticeable cytotoxicity of GGO-g-PMAc hydrogel at the concentration range of 0–100μg/ml against the mouse mesenchymal stem cell line (C3H10T1/2). These results suggested that GGO-g-PMAc hydrogel can be a prospective pH-sensitive carrier for colon-targeted drug delivery.
The agonists of peroxisome proliferator–activated receptor gamma (PPARγ) from natural victual products were used as antidiabetic agents. Faba bean (Vicia faba L.) is a consequential legume that was ...known to possess potential antidiabetic activity, whose mechanism of action was unknown. The current study was focused to ascertain gene expression of the nuclear receptor PPARγ by Faba bean pod extract in rat cell lines (RINm5F).The real‐time polymerase chain reaction analysis demonstrated that Faba bean pod extract in concentrations of 160 µg/mL have shown 4.97‐fold stimulation compared with control. The cells treated with 320 µg/mL has shown 5.89‐fold upregulation, respectively. Furthermore, in silico docking analysis was carried out against PPARγ, using the bioactive compounds identified from Faba bean pod extracts, which were known reported compounds from the literature. The results suggest that gene expression of PPARγ was inhibited by the constituents in Faba bean. In silico analysis prognosticates, butein has a high binding energy (−8.6 kcal/mol) with an atomic contact energy of −214.10, followed by Apigenin and Quercetin against PPARγ. Similarly, the percentage of interaction was high for butein, followed by Apigenin and Quercetin than other compounds comparatively. Hence, the results conclude inhibition of PPARγ by the bioactive compounds from Faba bean, which may provide insights into developing future therapeutic molecules for diabetes mellitus.
The Faba bean has upregulated the expression of nuclear receptor peroxisome proliferator–activated receptor gamma in diabetic cell lines (RINm5F). The compounds present in Faba bean were responsible for this activity. Hence, we conclude that Faba bean exhibit antidiabetic activity by regulating the transcriptional factor peroxisome proliferator–activated receptor gamma.
Cardiovascular disease (CVD) is the most common co-morbidity associated with COVID-19 and the fatality rate in COVID-19 patients with CVD is higher compared to other comorbidities, such as ...hypertension and diabetes. Preliminary data suggest that COVID-19 may also cause or worsen cardiac injury in infected patients through multiple mechanisms such as ‘cytokine storm’, endotheliosis, thrombosis, lymphocytopenia etc. Autopsies of COVID-19 patients reveal an infiltration of inflammatory mononuclear cells in the myocardium, confirming the role of the immune system in mediating cardiovascular damage in response to COVID-19 infection and also suggesting potential causal mechanisms for the development of new cardiac pathologies and/or exacerbation of underlying CVDs in infected patients. In this review, we discuss the potential underlying molecular mechanisms that drive COVID-19-mediated cardiac damage, as well as the short term and expected long-term cardiovascular ramifications of COVID-19 infection in patients.
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Guar gum succinate − sodium alginate (GGS-SA) beads cross-linked with barium ions were prepared and characterized as a pH sensitive carrier for colon-specific drug delivery. The structure of GGS-SA ...beads was confirmed by FT-IR spectroscopy. Scanning Electron Microscope (SEM) studies revealed that the drug loaded GGS-SA beads prepared using 2:2 (w/v) weight percent of GGS and SA had a diameter about 1.4mm and roughly spherical in shape. X-ray diffraction (XRD) studies showed that the peaks corresponding to GGS and SA at 13.5°, 17.5°, 20.2° and 13.5°, 22°, 24.1°, respectively were destroyed in GGS-SA beads which show that these beads are more amorphous in nature. Swelling studies demonstrated the pH-dependent swelling behavior of GGS-SA beads. The beads showed higher swelling degrees in pH 7.4 than that in pH 1.2 due to the existence of anionic groups in the polymer chains. The drug release study showed that the amount of model drug, ibuprofen, released from the GGS-SA beads was higher in pH 7.4 than that in pH 1.2 due to the pH-dependent swelling behavior of the beads. MTT assay revealed that GGS-SA beads at a concentration range of 0–30μg/ml had no cytotoxic effect on the cultured mouse mesenchymal stem cells (C3H10T1/2). These results suggest that GGS-SA beads can be used as effective colon-specific drug delivery system with pH-dependent drug release ability.
BACKGROUND—Voltage-gated Na channels (Nav) are essential for myocyte membrane excitability and cardiac function. Nav current (INa) is a large-amplitude, short-duration spike generated by rapid ...channel activation followed immediately by inactivation. However, even under normal conditions, a small late component of INa (INa,L) persists because of incomplete/failed inactivation of a subpopulation of channels. Notably, INa,L is directly linked with both congenital and acquired disease states. The multifunctional Ca/calmodulin-dependent kinase II (CaMKII) has been identified as an important activator of INa,L in disease. Several potential CaMKII phosphorylation sites have been discovered, including Ser571 in the Nav1.5 DI-DII linker, but the molecular mechanism underlying CaMKII-dependent regulation of INa,L in vivo remains unknown.
METHODS AND RESULTS—To determine the in vivo role of Ser571, 2 Scn5a knock-in mouse models were generated expressing either(1) Nav1.5 with a phosphomimetic mutation at Ser571 (S571E), or (2) Nav1.5 with the phosphorylation site ablated (S571A). Electrophysiology studies revealed that Ser571 regulates INa,L but not other channel properties previously linked to CaMKII. Ser571-mediated increases in INa,L promote abnormal repolarization and intracellular Ca handling and increase susceptibility to arrhythmia at the cellular and animal level. Importantly, Ser571 is required for maladaptive remodeling and arrhythmias in response to pressure overload.
CONCLUSIONS—Our data provide the first in vivo evidence for the molecular mechanism underlying CaMKII activation of the pathogenic INa,L. Relevant for improved rational design of potential therapies, our findings demonstrate that Ser571-dependent regulation of Nav1.5 specifically tunes INa,L without altering critical physiological components of the current.
A novel type of pH-sensitive colon-specific controlled drug delivery carrier based on guar gum succinate (GGS) was prepared by reacting guar gum (GG) with succinic anhydride (SA) in the presence of ...4-dimethylaminopyridine (DMAP). The formation of GGS was confirmed by FT-IR and 1H NMR and characterized using XRD techniques. GGS microparticles with 460–740μm in size were prepared using sodium trimetaphosphate (STMP) as a cross-linking agent. The size and morphologies of GGS microparticles were assessed by scanning electron microscopy (SEM). The swelling degree of the GGS microparticles was found to be higher in pH 7.4 than in pH 1.2. In addition, GGS microparticles showed a pH dependent drug release profile when compared to the GG microparticles. The MTT assay revealed that there is no apparent cytotoxicity of GGS against a mouse mesenchymal stem cell line at a concentration range of 0–200μg/ml. These results confirm that GGS could be used as a carrier for colon-specific drug delivery.
Wound dressings play a vital role in the wound healing process. Although a variety of wound dressings have been developed so far, most of them still have many drawbacks such as rigidity, ...non-porosity, low mechanical strength, an affinity to stick onto the injury surface and less antimicrobial activity. To overcome these issues, a novel type of porous three-dimensional (3D) film was fabricated using chitosan/carboxymethyl pullulan polyelectrolyte complex (PEC) loaded with 45S5 bioglass (CCMPBG) by the freeze-drying method for wound healing application. The developed films were analysed by FTIR, XRD, EDS and SEM to confirm their chemical nature, microstructure and surface morphologies. The CCMPBG films exhibited rough surface morphology and well-interconnected micropores with an average size range of 101–74 μm. Compared to the control chitosan/carboxymethyl pullulan (CCMP) film, the CCMPBG films showed an enhanced mechanical strength and controlled rate of swelling and biodegradation behaviours due to the interaction of polymer matrix and 45S5 bioglass (BG). Furthermore, CCMPBG films presented the improved biocompatibility, antimicrobial activity and wound closure ability because of the synergistic effects of chitosan, carboxymethyl pullulan (CMP) and BG. The results demonstrated that CCMPBG films can be an effective dressing material for wound therapy.
Type 2 diabetes mellitus (T2DM) is a metabolic disorder caused due to varied genetic and lifestyle factors. The search for a potential natural compound to enhance the treatment of diabetes is the ...need of the hour. Butein, a flavonoid, found sufficiently in Faba bean, is said to possess an anti-diabetic property. In-silico analysis, Butein is predicted as a potential anti-diabetic compound, due to its regulatory action on PPAR-Gamma. Based on this evidence, the Butein’s anti-diabetic action is studied in diabetic induced rat models. The drug property of Butein is studied through in-silico analysis to determine the metabolic properties. In animal models, the biochemical analysis, histopathological and gene expression against PPAR-Gamma were studied comparatively. Butein being a hydrophobic compound, the bioavailability is said to be minimum. Hence, Butein formulation was made using biopolymer Chitosan for the synergistic anti-diabetic action. The Butein Chitosan formulation was optimized and characterized using analytical techniques. Further, the anti-diabetic activity of Butein and Butein Chitosan formulation was studied in diabetic induced rats. The obtained in-silico analysis results showed that Butein is the most favorable drug. Apparently, in the rat model, Butein and Butein Chitosan formulation effectively controlled the blood glucose levels without any side effects. The histopathological observations of the tissue samples showed nontoxic activity. Additionally, the gene expression analysis predicted the possible mechanism of anti-diabetic action exhibited through the down regulation of PPAR-Gamma. Whereas, the Butein Chitosan formulation failed, to show synergetic anti-diabetic activity as expected. This study is vital in introducing Butein as a safe anti-diabetic compound, which can be used in the treatment of T2DM.
Congenital myopathies are a heterogeneous group of muscle disorders that are often genetically determined. Here, we investigated a boy with congenital myopathy, deafness, and neuropathy from a ...consanguineous Kurdish family by autozygosity mapping and whole exome sequencing. We found a homozygous nonsense mutation in
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c.1597C>T, NM_020971.2; p.(Q533*), NP_066022.2; ClinVar SUB2292235 encoding βIV-spectrin, a non-erythrocytic member of the β-spectrin family. Western blot confirmed the absence of the full-length 288 kDa isoform in muscle and of a specific 72 kDa isoform in fibroblasts. Clinical symptoms of the patient largely corresponded to those described for the quivering mouse, a loss-of-function animal model. Since the human phenotype of βIV-spectrin deficiency included a myopathy with incomplete congenital fiber-type disproportion, we investigated muscle of the quivering (qv4J) mouse and found complete absence of type 1 fibers (fiber-type 2 uniformity). Immunohistology confirmed expression of βIV-spectrin in normal human and mouse muscle at the sarcolemma and its absence in patient and quivering (qv4J) mouse.
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mRNA-expression levels in healthy skeletal muscle were found in the range of other regulatory proteins. More patients have to be described to confirm the triad of congenital myopathy, neuropathy and deafness as the defining symptom complex for βIV-spectrin deficiency.
Normal heart rhythm (sinus rhythm) depends on regular activity of the sinoatrial node (SAN), a heterogeneous collection of specialized myocytes in the right atrium. SAN cells, in general, possess a ...unique electrophysiological profile that promotes spontaneous electrical activity (automaticity). However, while automaticity is required for normal pacemaking, it is not necessarily sufficient. Less appreciated is the importance of the elaborate structure of the SAN complex for proper pacemaker function. Here, we review the important structural features of the SAN with a focus on how these elements help manage a precarious balance between electrical charge generated by the SAN ("source") and the charge needed to excite the surrounding atrial tissue ("sink"). We also discuss how compromised "source-sink" balance due, for example to fibrosis, may promote SAN dysfunction, characterized by slow and/or asynchronous pacemaker activity and even failure, in the setting of cardiovascular disease (e.g., heart failure, atrial fibrillation). Finally, we discuss implications of the "source-sink" balance in the SAN complex for cell and gene therapies aimed at creating a biological pacemaker as replacement or bridge to conventional electronic pacemakers.
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