Multiscale effects of the calcimimetic drug, etelcalcetide on bone health of rats with secondary hyperparathyroidism induced by chronic kidney disease.

Chronic kidney disease-induced secondary hyperparathyroidism (CKD-SHPT) heightens fracture risk through impaired mineral homeostasis and elevated levels of uremic toxins (UTs), which in turn enhance bone remodeling. Etelcalcetide (Etel), a calcium-sensing receptor (CaSR) agonist, suppresses parathyroid hormone (PTH) in hyperparathyroidism to reduce excessive bone resorption, leading to increased bone mass. However, Etel's effect on bone quality, chemical composition, and strength is not well understood. To address these gaps, we established a CKD-SHPT rat model and administered Etel at a human-equivalent dose concurrently with disease induction. The effects on bone and mineral homeostasis were compared with a CKD-SHPT (vehicle-treated group) and a control group (rats without SHPT). Compared with vehicle-treated CKD-SHPT rats, Etel treatment improved renal function, reduced circulating UT levels, improved mineral homeostasis parameters, decreased PTH levels, and prevented mineralization defects. The upregulation of mineralization-promoting genes by Etel in CKD-SHPT rats might explain its ability to prevent mineralization defects. Etel preserved both trabecular and cortical bones with attendant suppression of osteoclast function, besides increasing mineralization. Etel maintained the number of viable osteocytes to the control level, which could also contribute to its beneficial effects on bone. CKD-SHPT rats displayed increased carbonate substitution of matrix and mineral, decreased crystallinity, mineral-to-matrix ratio, and collagen maturity, and these changes were mitigated by Etel. Further, Etel treatment prevented CKD-SHPT-induced deterioration in bone strength and mechanical behavior. Based on these findings, we conclude that in CKD-SHPT rats, Etel has multiscale beneficial effects on bone that involve remodeling suppression, mineralization gene upregulation, and preservation of osteocytes.

Oral Administration of a Specific p300/CBP Lysine Acetyltransferase Activator Induces Synaptic Plasticity and Repairs Spinal Cord Injury.

TTK21 is a small-molecule activator of p300/creb binding protein (CBP) acetyltransferase activity, which, upon conjugation with a glucose-derived carbon nanosphere (CSP), can efficiently cross the blood-brain barrier and activate histone acetylation in the brain. Its role in adult neurogenesis and retention of long-term spatial memory following intraperitoneal (IP) administration is well established. In this study, we successfully demonstrate that CSP-TTK21 can be effectively administered via oral gavage. Using a combination of molecular biology, microscopy, and electrophysiological techniques, we systematically investigate the comparative efficacy of oral administration of CSP and CSP-TTK21 in wild-type mice and evaluate their functional effects in comparison to intraperitoneal (IP) administration. Our findings indicate that CSP-TTK21, when administered orally, induces long-term potentiation in the hippocampus without significantly altering basal synaptic transmission, a response comparable to that achieved through IP injection. Remarkably, in a spinal cord injury model, oral administration of CSP-TTK21 exhibits efficacy equivalent to that of IP administration. Furthermore, our research demonstrates that oral delivery of CSP-TTK21 leads to improvements in motor function, histone acetylation dynamics, and increased expression of regeneration-associated genes (RAGs) in a spinal injury rat model, mirroring the effectiveness of IP administration. Importantly, no toxic and mutagenic effects of CSP-TTK21 are observed at a maximum tolerated dose of 1 g/kg in Sprague-Dawley (SD) rats via the oral route. Collectively, these results underscore the potential utility of CSP as an oral drug delivery system, particularly for targeting the neural system.

On-demand release of a selective MMP-13 blocker from an enzyme-responsive injectable hydrogel protects cartilage from degenerative progression in osteoarthritis.

In osteoarthritis (OA), the degradation of cartilage is primarily driven by matrix metalloprotease-13 (MMP-13). Hence, the inhibition of MMP-13 has emerged as an attractive target for OA treatment. Among the various approaches that are being explored for MMP-13 regulation, blocking of the enzyme with specific binding molecules appears to be a more promising strategy for preventing cartilage degeneration. To enhance effectiveness and ensure patient compliance, it is preferable for the binding molecule to exhibit sustained activity when administered directly into the joint. Herein, we present an enzyme-responsive hydrogel that was designed to exhibit on-demand, the sustained release of BI-4394, a potent and highly selective MMP-13 blocker. The stable and compatible hydrogel was prepared using triglycerol monostearate. The efficacy of the hydrogel to prevent cartilage damage was assessed in a rat model of OA induced by anterior cruciate ligament transection (ACLT). The results revealed that in comparison to the rats administrated weekly with intra-articular BI-4394, the hydrogel implanted rats had reduced levels of inflammation and bone erosion. In comparison to untreated control, the cartilage in animals administered with BI-4394/hydrogel exhibited significant levels of collagen-2 and aggrecan along with reduced MMP-13. Overall, this study confirmed the potential of BI-4394 delivery using an enzyme-responsive hydrogel as a promising treatment option to treat the early stages of OA by preventing further cartilage degradation.

ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome.

Genome-wide association studies in inflammatory bowel disease have identified risk loci in the orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) gene to confer susceptibility to ulcerative colitis (UC), but the underlying functional relevance remains unexplored. Here, we found that a subpopulation of the UC patients who had higher disease activity shows enhanced expression of ORMDL3 compared to the patients with lower disease activity and the non-UC controls. We also found that the patients showing high ORMDL3 mRNA expression have elevated interleukin-1ß cytokine levels indicating positive correlation. Further, knockdown of ORMDL3 in the human monocyte-derived macrophages resulted in significantly reduced interleukin-1ß release. Mechanistically, we report for the first time that ORMDL3 contributes to a mounting inflammatory response via modulating mitochondrial morphology and activation of the NLRP3 inflammasome. Specifically, we observed an increased fragmentation of mitochondria and enhanced contacts with the endoplasmic reticulum (ER) during ORMDL3 over-expression, enabling efficient NLRP3 inflammasome activation. We show that ORMDL3 that was previously known to be localized in the ER also becomes localized to mitochondria-associated membranes and mitochondria during inflammatory conditions. Additionally, ORMDL3 interacts with mitochondrial dynamic regulating protein Fis-1 present in the mitochondria-associated membrane. Accordingly, knockdown of ORMDL3 in a dextran sodium sulfate -induced colitis mouse model showed reduced colitis severity. Taken together, we have uncovered a functional role for ORMDL3 in mounting inflammation during UC pathogenesis by modulating ER-mitochondrial contact and dynamics.

High prevalence of CD44 and its ligand low molecular weight hyaluronan in plasma of HNSCC patients: clinical significance.

BACKGROUND: This study aims to evaluate the role of cancer stem cell marker, CD44, and its ligand HA as potential molecular biomarker for early detection of HNSCC. METHODS AND RESULTS: The expression profile (mRNA/Protein) of CD44 variants were analysed in primary HNSCC lesions and plasma of the patients. Then, prevalence of HA variants was analysed in plasma of the patients. The mRNA expression of CD44 variants, CD44S and CD44v3, were significantly high in both early (stage I/II) and late (stage III/IV) invasive lesions, with predominant expression of CD44v3 in the late-stage lesions. In plasma of HNSCC patients, increased levels of SolCD44, CD44-ICD and unique 62 KD CD44 variants with respect to standard CD44S were seen, in comparison to their prevalence in plasma of normal individuals. The abundance of CD44-ICD and 62 KD variants were significantly high in plasma of late stage HNSCC patients. Interestingly, significantly high level of low molecular weight HA(LMW HA) with respect to high molecular weight HA(HMW HA) was seen in plasma of HNSCC patients irrespective of clinical stages. On the contrary, high HMW HA level in plasma of normal individuals was seen. The high level of LMW HA in plasma of HNSCC patients might be due to combinatorial effect of increased mRNA expression of HA synthesizing enzyme HAS1/2/3 and HA degrading enzyme HYAL1/2, as seen in the primary HNSCC samples. CONCLUSION: Thus, our data revealed the importance of specific CD44 and HA variants in plasma of HNSCC patients during its development as potential non-invasive molecular biomarker of the disease.

Insights on discovery, efficacy, safety and clinical applications of ghrelin receptor agonist capromorelin in veterinary medicine.

Growth hormone and insulin like growth factor-1 plays an important role in the regulation of body composition and metabolism. Growth Hormone is released from the pituitary through a specific G-protein coupled receptor (GPCR) called growth hormone secretagogue receptor 1a expressed in the hypothalamus. Ghrelin is a peptide hormone released from the cells in the stomach, which stimulates appetite and food intake in mammals, regulates gut motility, gastric acid secretion, taste sensation, circadian rhythm, learning and memory, oxidative stress, autophagy, glucose metabolism etc. When the release of the endogenous ligand GHSR-1a, i.e., ghrelin is malfunctioned or stopped, external substitutes are administrated to induce the stimulation of growth hormone and appetite. A class of compound known as ghrelin receptor agonists are developed as an external substitute of ghrelin for regulation and stimulation of growth hormone in frailty, for body weight gain, muscle mass gain, prevention of cachexia and for the treatment of chronic fatigue syndromes. Capromorelin [Entyce™ (Aratana Therapeutics, Leawood, KS, USA)] is the only FDA (Food and Drug Administration) approved (May 2016) drug used for stimulating appetite in dogs and was marketed in the fall of 2017. In 2020, USFDA approved Capromorelin [Elura™ (Elanco US Inc.)] for the management of weight loss in chronic kidney disease of cats. This article reviews the discovery of the ghrelin receptor agonist capromorelin, its efficacy, safety, clinical applications and aims to delineate its further scope of use in veterinary practice.

Pectoralis Major Myofascial (PMMF) Flap as a Valuable Alternative to Microvascular Free Flaps (MFF) in Females with Advanced Oral Squamous Cell Carcinomas: A Retrospective Institutional Analysis.

India contributes 60% of HNC cases worldwide among which OSCC has become the most common cancer in males and second most common in females (NCRCR 2020). As most cases present in advanced stage, surgical excision followed by flap reconstruction becomes mandatory to achieve functionality. Due to various logistics and financial issues, microvascular free flap reconstruction is not feasible in every case. Also in females, reconstruction with PMMC is challenging as it violates normal breast contour. As an alternative, we have explored the affectivity of pectoralis major myofascial (PMMF) flaps. A retrospective analysis was undertaken only in female patients with advanced stage oral malignancies who underwent surgery between September 2021 and January 2023. Patients having cutaneous involvement or requiring local flap reconstruction were excluded. Total 43 female patients were included in the study. Among them 8 had Tongue carcinoma and 35 had Alveobuccal carcinoma. 24 patients underwent PMMF reconstruction, whereas 19 patients underwent MFF reconstruction. The complication rates were 12.1% (3 out of 24) in PMMF and 89.4% (17 out of 19 cases)in MFF. Among PMMF group, 1 major complication (death, unrelated to flap) and 2 minor complications (wound infection) occured. Among the MFF group, major complications were e.g. Flap failure requiring re-exploration surgery (n = 4), wound dehiscence (n = 2), bleeding/hematoma (n = 1), donor site complications (n = 6). The minor complications being wound infections (n = 4). The goals of reconstruction of defects in oral cavity cancers are mainly functional and cosmetic integrity. Although MFF's provide a wide range of options for reconstruction of complex defects, as per our study the PMMF flap was more reliable and had lesser complications. PMMF flap is an invaluable alternative to MFF's in female patients for both reconstruction and breast contour preservation.

Efficient Nitric Oxide Scavenging by Urea-Functionalized Push-Pull Chromophore Modulates NO-Mediated Diseases.

The excess nitric oxide (NO) produced in the body in response to bacterial/proinflammatory stimuli is responsible for several pathological conditions. The current approaches that target the production of excess NO, either through the inhibition of nitric oxide synthase enzyme or its downstream mediators have been clinically unsuccessful. With an aim to regulate the excess NO, urea-functionalized push-pull chromophores containing 1,1,4,4-tetracyanobuta-1,3-dienes (TCBD) or expanded TCBD (eTCBD) were developed as NO scavengers. The NMR mechanistic studies revealed that upon NO binding, these molecules are converted to uncommon stable NONOates. The unique emissive property of Urea-eTCBD enables its application in vitro, as a NO-sensor. Furthermore, the cytocompatible Urea-eTCBD, rapidly inactivated the NO released from LPS-activated cells. The therapeutic efficacy of the molecule in modulating NO-mediated pathological condition was confirmed using a carrageenan-induced inflammatory paw model and a corneal injury model. While the results confirm the advantages of scavenging the excess NO to address a multitude of NO-mediated diseases, the promising sensing and bioactivity of Urea-eTCBD can motivate further exploration of such molecules in allied areas of research.

Discovery, SAR and mechanistic studies of quinazolinone-based acetamide derivatives in experimental visceral leishmaniasis.

Towards identification of novel therapeutic candidates, a series of quinazolinone-based acetamide derivatives were synthesized and assessed for their anti-leishmanial efficacy. Amongst synthesized derivatives, compounds F12, F27 and F30 demonstrated remarkable activity towards intracellular L. donovani amastigotes in vitro, with IC50 values of 5.76 ± 0.84 µM, 3.39 ± 0.85 µM and 8.26 ± 1.23 µM against promastigotes, and 6.02 µM ± 0.52, 3.55 ± 0.22 µM and 6.23 ± 0.13 µM against amastigotes, respectively. Oral administration of compounds F12 and F27 entailed >85% reduction in organ parasite burden in L. donovani-infected BALB/c mice and hamsters, by promoting host-protective Th1 cytokine response. In host J774 macrophages, mechanistic studies revealed inhibition of PI3K/Akt/CREB axis, resulting in a decrease of IL-10 versus IL-12 release upon F27 treatment. In silico docking studies conducted with lead compound, F27 demonstrated plausible inhibition of Leishmania prolyl-tRNA synthetase, which was validated via detection of decreased proline levels in parasites and induction of amino acid starvation, leading to G1 cell cycle arrest and autophagy-mediated programmed cell death of L. donovani promastigotes. Structure-activity analysis and study of pharmacokinetic and physicochemical parameters suggest oral availability and underscore F27 as a promising lead for anti-leishmanial drug development.

Post-Implantation Stiffening by a Bioinspired, Double-Network, Self-Healing Hydrogel Facilitates Minimally Invasive Cell Delivery for Cartilage Regeneration.

Injectable hydrogels have demonstrated advantages in cartilage repair by enabling the delivery of cells through a minimally invasive approach. However, several injectable hydrogels suffer from rapid degradation and low mechanical strength. Moreover, higher mechanical stiffness in hydrogels can have a detrimental effect on post-implantation cell viability. To address these challenges, we developed an in situ forming bioinspired double network hydrogel (BDNH) that exhibits temperature-dependent stiffening after implantation. The BDNH mimics the microarchitecture of aggrecan, with hyaluronic acid-conjugated poly(N-isopropylacrylamide) providing rigidity and Schiff base crosslinked polymers serving as the ductile counterpart. BDNHs exhibited self-healing property and enhanced stiffness at physiological temperature. Excellent cell viability, long time cell proliferation, and cartilage specific matrix production were observed in the chondrocytes cultured in the BDNH hydrogel. Evidence of cartilage regeneration in a rabbit cartilage defect model using chondrocyte-laden BDNH has suggested it to be a potential candidate for cartilage tissue engineering.

Injectable Bone Cement Reinforced with Gold Nanodots Decorated rGO-Hydroxyapatite Nanocomposites, Augment Bone Regeneration.

Interest in the development of new generation injectable bone cements having appropriate mechanical properties, biodegradability, and bioactivity has been rekindled with the advent of nanoscience. Injectable bone cements made with calcium sulfate (CS) are of significant interest, owing to its compatibility and optimal self-setting property. Its rapid resorption rate, lack of bioactivity, and poor mechanical strength serve as a deterrent for its wide application. Herein, a significantly improved CS-based injectable bone cement (modified calcium sulfate termed as CSmod ), reinforced with various concentrations (0-15%) of a conductive nanocomposite containing gold nanodots and nanohydroxyapatite decorated reduced graphene oxide (rGO) sheets (AuHp@rGO), and functionalized with vancomycin, is presented. The piezo-responsive cement exhibits favorable injectability and setting times, along with improved mechanical properties. The antimicrobial, osteoinductive, and osteoconductive properties of the CSmod cement are confirmed using appropriate in vitro studies. There is an upregulation of the paracrine signaling mediated crosstalk between mesenchymal stem cells and human umbilical vein endothelial cells seeded on these cements. The ability of CSmod to induce endothelial cell recruitment and augment bone regeneration is evidenced in relevant rat models. The results imply that the multipronged activity exhibited by the novel-CSmod cement would be beneficial for bone repair.

Quinolinyl ß-enaminone derivatives exhibit leishmanicidal activity against Leishmania donovani by impairing the mitochondrial electron transport chain complex and inducing ROS-mediated programmed cell death.

OBJECTIVES: Previously, a series of side chain-modified quinolinyl ß-enaminones was identified to possess significant activity against chloroquine-sensitive or -resistant Plasmodium falciparum and Brugia malayi microfilariae. The present study evaluates in vitro and in vivo activity of the series against Leishmania donovani and reports their mode of action. METHODS: The in vitro activity of 15 quinolinyl ß-enaminone derivatives against Leishmania promastigotes and amastigotes was assessed by luciferase assay. The reduction of organ parasite burden was assessed by Giemsa staining in L. donovani-infected BALB/c mice and hamsters. Intracellular Ca2+ and ATP level in active derivative (3D)-treated promastigotes were determined by fluorescence and luminescence assays. Flow cytometry was performed to determine loss of mitochondrial membrane potential (MMP) using JC-1 dye, reactive oxygen species (ROS) generation using 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) dye, phosphatidylserine externalization by Annexin V-FITC staining and cell-cycle arrest by propidium iodide (PI) staining. RESULTS: Compounds 3A, 3B and 3D showed significant in vitro efficacy against L. donovani with IC50 < 6 µM and mild cytotoxicity (∼75% viability) at 25 µM on J774 macrophages. 3A and 3D at 50 mg/kg and 100 mg/kg reduced parasite burden (>84%) in infected mice and hamsters, respectively, whereas 3D-treated animals demonstrated maximum parasite burden reduction without organ toxicity. Mode-of-action analysis revealed that 3D induced apoptosis by inhibiting mitochondrial complex II, reducing MMP and ATP levels, increasing ROS and Ca2+ levels, ultimately triggering phosphatidylserine externalization and sub-G0/G1 cell-cycle arrest in promastigotes. CONCLUSIONS: Compound 3D-mediated inhibition of L. donovani mitochondrial complex induces apoptosis, making it a promising therapeutic candidate for visceral leishmaniasis.

Butyrylation Meets Adipogenesis-Probed by a p300-Catalyzed Acylation-Specific Small Molecule Inhibitor: Implication in Anti-obesity Therapy.

The enzyme p300, besides having acetyltransferase activity, can also catalyze other acylation modifications, whose physiological implications are still being investigated. Here, we report that the level of histone butyrylation increases globally as well as locally in the promoters of pro-adipogenic genes during adipogenesis. To delineate the role of p300-catalyzed butyrylation from acetylation in adipogenesis, we identified a semisynthetic derivative (LTK-14A) of garcinol, which specifically inhibited histone butyrylation without affecting acetylation. Treatment of 3T3L1 cells with LTK-14A abolished adipogenesis with downregulation of pro-adipogenic genes along with inhibition of H4K5 butyrylation. Administering LTK-14A to high-fat diet-fed and genetically obese db/db mice led to attenuation/decrease in their weight gain. The reduced obesity could be partially attributed to the inhibition of H4K5 butyrylation in adipocytes and liver. This report therefore not only, for the first time, causally links histone butyrylation with adipogenesis but also presents a probable candidate for anti-obesity therapeutics.

Diosmin, a citrus fruit-derived phlebotonic bioflavonoid protects rats from chronic kidney disease-induced loss of bone mass and strength without deteriorating the renal function.

Kidney Disease Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline has recommended treatment decisions for patients with chronic kidney disease (CKD) with osteoporosis and/or high risk of fracture. Bisphosphonates, the first-line anti-osteoporosis drugs have the concern of worsening kidney functions. Moreover, despite impaired bone formation in CKD patients, teriparatide, the formation-stimulating drug is not recommended. Thus, there is an urgent need for safe and effective treatment of osteoporosis in CKD patients. Here, in CKD rats, we tested the osteoprotective effect of diosmin, a citrus-derived bioflavonoid used as a phlebotonic in chronic venous insufficiency and has a renoprotective effect. CKD was developed by 5/6th nephrectomy and diosmin at the human equivalent dose (100 mg kg-1) did not advance renal failure but reduced blood pressure to the level of sham control. Fibroblast growth factor-23 and parathyroid hormone were increased in CKD and diosmin suppressed both. CKD reduced bone mass and deteriorated the microarchitecture of trabecular bones, and diosmin maintained both to control levels. Bone formation and strength were impaired in the CKD and diosmin maintained these levels to control levels. Nanoindentation of bone showed that diosmin significantly increased tissue hardness over the control. Diosmetin, the metabolic surrogate of diosmin had comparable pharmacokinetic profiles between the control and CKD groups. Furthermore, diosmetin (50 mg kg-1) protected against CKD-induced bone loss. These data suggest that diosmin and its metabolic surrogate, diosmetin protect against CKD-induced osteopenia. Since diosmin has no renal adverse effect and protected bone mass and strength in CKD rats, we propose assessing its anti-osteoporosis effect in CKD patients.

An injectable hydrogel having proteoglycan-like hierarchical structure supports chondrocytes delivery and chondrogenesis.

The ECM of cartilage is composed of proteoglycans (PG) that contain glycosaminoglycan (GAG), aggrecan, hyaluronic acid (HA) and other molecular components which play an important role in regulating chondrocyte functions via cell-matrix interactions, integrin-mediated signalling etc. Implantation of chondrocytes encapsulated in scaffolds that mimic the micro-architecture of proteoglycan, is expected to enhance cartilage repair. With an aim to create a hydrogel having macromolecular structure that resembles the cartilage-specific ECM, we constructed a hierarchal structure that mimic the PG. The bottle brush structure of the aggrecan was obtained using chondroitin sulphate and carboxymethyl cellulose which served as GAG and core protein mimic respectively. A proteoglycan-like structure was obtained by cross-linking it with modified chitosan that served as a HA substitute. The physico-chemical characteristics of the above cross-linked injectable hydrogel supported long term human articular chondrocyte subsistence and excellent post-injection viability. The chondrocytes encapsulated in the PMH expressed significant levels of articular cartilage specific markers like collagen II, aggrecan, GAGs etc., indicating the ability of the hydrogel to support chondrocyte differentiation. The biocompatibility and biodegradability of the hydrogels was confirmed using suitable in vivo studies. The results revealed that the PG-mimetic hydrogel could serve as a promising scaffold for chondrocyte implantation.

Tunable, conductive, self-healing, adhesive and injectable hydrogels for bioelectronics and tissue regeneration applications.

Conductive hydrogels are attracting considerable interest in view of their potential in a wide range of applications that include healthcare and electronics. Such hydrogels are generally incorporated with conductive materials/polymers. Herein, we present a series of conductive hydrogels (Ch-CMC-PDA), prepared with no additional conductive material. The hydrogels were synthesized using a combination of chitosan, cellulose (CMC) and dopamine (DA). The conductivity (0.01-3.4 × 10-3 S cm-1) in these gels is attributed to ionic conductivity. Very few conductive hydrogels are endowed with additional properties like injectability, adhesiveness and self-healing, which would help to widen their scope for applications. While the dynamic Schiff base coupling in our hydrogels facilitated self-healing and injectable properties, polydopamine imparted tissue adhesiveness. The porosity, rheological, mechanical and conductive properties of the hydrogels are regulated by the CMC-dialdehyde-polydopamine (CMC-D-PDA) content. The hydrogel was evaluated in various bioelectronics applications like ECG monitoring and triboelectric nanogenerators (TENG). The ability of the hydrogel to support cell growth and serve as a template for tissue regeneration was confirmed using in vitro and in vivo studies. In summary, the integration of such remarkable features in the ionic-conductive hydrogel would enable its usage in bioelectronics and biomedical applications.

Partially saturated canthaxanthin alleviates aging-associated oxidative stress in D-galactose administered male wistar rats.

It has been earlier reported that partially saturated canthaxanthin (PSC) from Aspergillus carbonarius mutant is non-toxic, has anti-lipid peroxidation activity and can induce apoptosis in prostate cancer cell lines. In the present study, the antiaging effect of PSC was explored in D-galactose administered male wistar rats. 8-10 weeks old, male wistar rats were randomly divided into (i) Vehicle Control Group (VCG), (ii) Aged Control Group (ACG), (iii) Aged + α Lipoic Acid Group (ALG) and (iv) Aged + Partially saturated canthaxanthin Group (APG). Rats received D-galactose (300 mg /kg bwt/day; i.p.) alone (ACG) or together with PSC (APG) (20 mg/kg bwt/day; oral) and α Lipoic Acid (ALG) (80 mg/kg bwt/day; oral) for 10 weeks. Rats in VCG were injected with the same volume of physiological saline (i.p.) and fed with olive oil (vehicle). In vitro protein oxidation and DNA oxidation inhibition, in vivo malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), acetylcholinesterase (AChE) and monoamine oxidase (MAO) activities were determined. In addition, brain neurotransmitters, dopamine and serotonin were estimated by NMR. PSC treatment showed inhibition against protein and DNA oxidation. PSC effectively improved D-galactose induced aging rats by inducing a protective effect through up-regulation of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT) and brain neurotransmitters and downregulated malondialdehyde (MDA) and monoamineoxidase (MAO) levels. Thus, PSC appears to be a functional compound having antioxidant and antiaging properties.

Infectivity, virulence, pathogenicity, host-pathogen interactions of SARS and SARS-CoV-2 in experimental animals: a systematic review.

The outbreak of the SARS-CoV-2 in mainland China with subsequent human to human transmission worldwide had taken up the shape of a devastating pandemic. The ability of the virus to infect multiple species other than humans has currently been reported in experimental conditions. Non-human primates, felines, ferrets, rodents and host of other animals could previously be infected in experimental conditions with SARS-CoV and recently with SARS-CoV-2, both virus using Angiotensin-converting-enzyme 2 receptor for cellular entry. The variations in sequence homology of ACE2 receptor across species is identified as one of the factors determining virulence and pathogenicity in animals. The infection in experimental animals with SARS-CoV or SARS-CoV-2 on most occasions are asymptomatic, however, the virus could multiply within the respiratory tract and extra-pulmonary organs in most of the species. Here, we discuss about the pathogenicity, transmission, variations in angiotensin-converting-enzyme 2 receptor-binding across species and host pathogen interactions of SARS and SARS-CoV-2 in laboratory animals used in research.

Long acting GLP-1 analog liraglutide ameliorates skeletal muscle atrophy in rodents.

BACKGROUND: Skeletal muscle atrophy is characterized by muscle wasting with partial or complete functional loss. Skeletal muscle atrophy severely affects the quality of life and currently, there is no available therapy except for spinal muscular atrophy. OBJECTIVE: Drug repositioning is a promising strategy that reduces cost and time due to prior availability of safety and toxicity details. Here we investigated myogenic and anti-atrophy effects of glucagon-like peptide-1 (GLP-1) analog liraglutide. METHODS: We used several in vitro atrophy models in C2C12 cells and in vivo models in Sprague Dawley rats to study Liraglutide's efficacy. Western blotting was used to assess cAMP-dependent signaling pathways specifically activated by liraglutide. Therapeutic efficacy of liraglutide was investigated by histological analysis of transverse muscle sections followed by morphometry. Myogenic capacity was investigated by immunoblotting for myogenic factors. RESULTS: Liraglutide induced myogenesis in C2C12 myoblasts through GLP-1 receptor via a cAMP-dependent complex network of signaling events involving protein kinase A, phosphoinositide 3-kinase/protein kinase B, p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. Liraglutide imparted protection against freeze injury, denervation, and dexamethasone -induced skeletal muscle atrophy and improved muscular function in all these models. In a therapeutic model, liraglutide restored myofibrillar architecture in ovariectomy-induced atrophy. Anti-atrophy actions of liraglutide involved suppression of atrogene expression and enhancement in expression of myogenic factors. CONCLUSION: Liraglutide imparted protection and restored myofibrillar architecture in diverse models of muscle atrophy. Given its potent anti-atrophy, and recently reported osteoanabolic effects, we propose liraglutide's clinical evaluation in skeletal muscle atrophy and musculoskeletal disorders associated with diverse pathologies.

Cautery Burns: Prevention Better than Cure!

The electrocautery is an integral part of head and neck surgeries both for the primary lesion as well as for neck dissection. However, it is fraught with dangers of inadvertent burns to unintended areas, especially by the proximal end of the diathermy blade while working in deep narrow spaces. We devised a simple, cost effective, and easily reproducible method to eliminate this risk.