Functionally graded hydrogels with opposing biochemical cues for osteochondral tissue engineering.

Osteochondral tissue (OC) repair remains a significant challenge in the field of musculoskeletal tissue engineering. OC tissue displays a gradient structure characterised by variations in both cell types and extracellular matrix components from cartilage to the subchondral bone. These functional gradients in the native tissue have been replicated to engineer osteochondral tissue in vitro. While diverse fabrication methods have been employed to create these microenvironments, emulating the natural gradients and effective regeneration of the tissue continues to present a significant challenge. In this study, we present the design and development of an interpenetrating (IPN) hydrogel with opposing dual biochemical gradients with the aim of regenerating the complete osteochondral unit. The gradients of biochemical cues were generated using an in-house built extrusion system in CMC-Silk IPN hydrogel having improved mechanical strength. Firstly, we fabricated a hydrogel that exhibits a smooth transition of sCMC and TGF-ß1 (SCT gradient hydrogel) from the upper to the lower region of the IPN hydrogel, with the intent of regenerating the cartilage layer. Secondly, a hydrogel with a HAp gradient (HAp gradient hydrogel) from the lower to the upper region was fabricated to facilitate the regeneration of the subchondral bone layer. Subsequently, we developed a dual biochemical gradient hydrogel with the goal of regenerating the entire osteochondral unit. The fabricated hydrogel demonstrated a smooth transition of sCMC + TGF-ß1 and HAp gradients in opposing directions, along with a blend of both the biochemical cues at the interface. The results showed that the hydrogels having biochemical cues corresponding to the three zones (i.e., cartilage, interface and bone) of dual biochemical gradient hydrogel led to differentiation of BMSCs towards their respective lineages, thereby demonstrating their efficacy in directing the fate of progenitor cells. The developed dual gradient hydrogel provided biochemical signals that have the potential to facilitate tissue growth and regeneration of the entire osteochondral tissue with a smooth transition from cartilage (soft) to bone (hard) tissues. In summary, our study provides a simple and innovative method for incorporating biochemical cues into hydrogels. This promising approach is translatable and has the potential to be extrapolated to other interface tissues. .

Early cutaneous inflammatory response at different degree of burn and its significance for clinical diagnosis and management.

A complete characterization of the burn wound based on cutaneous architectural changes and inflammatory response is extremely important to provide evidence for progressive changes in the burn wound. Burn wounds are highly susceptible to conversion into deeper wounds, which need special care and attention; thereby, the complete characterization of burn wound type and their subsequent inflammatory status in the cutaneous system at the earliest is of paramount importance. Inflammatory markers at different degrees will help clinicians devise better and more specific treatment strategies for each burn type. The present study is carried out to profile pro-inflammatory gene expression along with immune cell quantification, vascular perfusion, and histopathological assessment in the cutaneous system of murine models. The study revealed that burn injury caused an immediate increase in vascular perfusion in superficial and partial-thickness burns, whereas there was a decrease in vascular perfusion in full-thickness burns. An influx of lymphocytes at the edges of burn wounds in each type of burn injury was well-orchestrated with the event of vascular perfusion. Further, pro-inflammatory gene expression profiling revealed significant upregulation vis-à-vis upregulation of TNF-α and MCP-1 genes, with an increase in the number of neutrophils following 72 h of injury that evidently cemented the conversion of superficial burn into partial-thickness burn. The molecular findings were profoundly supported by the histopathological changes. Thus, our foundational studies show distinct characteristic cutaneous changes correlated with the expression of key pro-inflammatory genes in three different types of burn injuries. Characterization of these cutaneous inflammatory responses provides a promising future for medical interventions involved with different degrees of burn injury, and it will also help in the pre-clinical testing of therapies for burn injury.

Artificial intelligence centric scientific research on COVID-19: an analysis based on scientometrics data.

With the spread of the deadly coronavirus disease throughout the geographies of the globe, expertise from every field has been sought to fight the impact of the virus. The use of Artificial Intelligence (AI), especially, has been the center of attention due to its capability to produce trustworthy results in a reasonable time. As a result, AI centric based research on coronavirus (or COVID-19) has been receiving growing attention from different domains ranging from medicine, virology, and psychiatry etc. We present this comprehensive study that closely monitors the impact of the pandemic on global research activities related exclusively to AI. In this article, we produce highly informative insights pertaining to publications, such as the best articles, research areas, most productive and influential journals, authors, and institutions. Studies are made on top 50 most cited articles to identify the most influential AI subcategories. We also study the outcome of research from different geographic areas while identifying the research collaborations that have had an impact. This study also compares the outcome of research from the different countries around the globe and produces insights on the same.

Sepsis modulates aortic AT1 and P2Y6 receptors to produce vascular hyporeactivity in mice.

PURPOSE: Hyporeactivity to vasopressors leading to multiple organ failure is a serious clinical implication in sepsis. Though the regulatory role of purinoceptors in inflammation is reported, their involvement in sepsis-induced vasoplegia is still unknown. Thus we investigated the effect of sepsis on vascular AT1 and P2Y6 receptors. MATERIALS AND METHODS: Polymicrobial sepsis was induced by cecal ligation and puncture in mice. Vascular reactivity was assessed by organ bath study and aortic mRNA expression of AT1 and P2Y6 was quantified by qRT-PCR. RESULTS: Both angiotensin-II and UDP produced higher contractions in the absence of endothelium as well as following inhibition of nitric oxide synthase. Angiotensin-II mediated aortic contraction was antagonized by losartan (AT1 antagonist), but not by PD123319 (AT2 antagonist) whereas UDP-induced aortic contraction was significantly inhibited by MRS2578 (P2Y6 antagonist). In addition, MRS2578 significantly inhibited the contractile response of Ang-II. Compared to SO mice, angiotensin-II and UDP-induced maximum contraction were found to be significantly attenuated in sepsis. Accordingly, aortic mRNA expression of AT1a receptors was significantly down-regulated while that of P2Y6 receptors was significantly increased in sepsis. 1400 W (a selective iNOS inhibitor) significantly reversed angiotensin-II-induced vascular hyporeactivity in sepsis without affecting UDP-induced hypo-reactivity. CONCLUSION: Sepsis-induced vascular hyporeactivity to angiotensin-II is mediated by enhanced expression of iNOS. Moreover, AT1R-P2Y6 cross talk/heterodimerization could be a novel target for regulating vascular dysfunction in sepsis.

Ascorbate formulation improves healing efficacy in excisional wound mice model through interplay between pro and anti-inflammatory cytokines and angiogenic markers.

BACKGROUND AND OBJECTIVE: Biomedical research in regenerative medicine prompts researchers to formulate cost-effective therapeutics for wound healing. The present study was conducted to characterize the ascorbate based formulation vis-a-vis investigating the molecular dynamics of the formulation. MATERIALS AND METHODS: To characterize the formulation, particle size, zeta potential, thermal stability, compatibility, anti-oxidant, and permeation prospective were measured using standard protocols. The in-vitro healing potential and safety formulae were evaluated using the L929 cell line. For molecular unravelling of the pharmacodynamics of formulation, an excision wound model was used, and 54 mice were randomly and equally divided into three groups, i.e., untreated, betadine-treated, and formulation-treated, to ascertain the interplay between cytokines and chemokines and their culminative role in the release of growth factors. RESULTS: The ascorbate formulae were found to be amorphous, biocompatible, safe, and long-lasting, with particle sizes and zeta potentials of 389.7 ± 0.69 nm and -38.1 ± 0.65 mV, respectively, and anti-oxidative potential. An in-vitro study revealed that the formulation has a significant (p<0.05) migration potential and is non-toxic. Expression profiling of TGF-ß, FGF-2, VEGF, and collagen III & I showed significant (p<0.05) up-regulation, whereas significant (p<0.05) down-regulation of pro-inflammatory genes like IL-1α, IL-1ß, TNF-α, IL-6, and temporal change in CCR-5 was observed in formulae-treated animals as compared to other groups. CONCLUSION: By up-regulating angiogenic and collagen-promoting growth factor gene expression while down-regulating pro-inflammatory gene expression, ascorbate formulation promotes wound healing via extracellular matrix and granulation tissue deposition with significant improvement in tensile strength.

Gigaelectronvolt emission from a compact binary merger.

An energetic γ-ray burst (GRB), GRB 211211A, was observed on 11 December 20211,2. Despite its long duration, typically associated with bursts produced by the collapse of massive stars, the observation of an optical-infrared kilonova points to a compact binary merger origin3. Here we report observations of a significant (more than five sigma) transient-like emission in the high-energy γ-rays of GRB 211211A (more than 0.1 gigaelectronvolts) starting 103 seconds after the burst. After an initial phase with a roughly constant flux (about 5 × 10-10 erg per second per square centimetre) lasting about 2 × 104 seconds, the flux started decreasing and soon went undetected. Our detailed modelling of public and dedicated multi-wavelength observations demonstrates that gigaelectronvolt emission from GRB 211211A is in excess with respect to the flux predicted by the state-of-the-art afterglow model at such late time. We explore the possibility that the gigaelectronvolt excess is inverse Compton emission owing to the interaction of a late-time, low-power jet with an external source of photons, and find that kilonova emission can provide the seed photons. Our results open perspectives for observing binary neutron star mergers.

Frailty is Associated With Poor Outcomes Following Emergency Laparotomy: What's Next?

Background and objective The Clinical Frailty Scale (CFS) is a rapid assessment tool to identify vulnerable and frail patients. We sought to evaluate the association between preoperative CFS scores and outcomes following emergency laparotomy in a dense, rural, and healthcare-deprived region of the UK inhabited by a multi-comorbid population. Methods We retrospectively reviewed regional National Emergency Laparotomy Audit (NELA) data across United Lincolnshire Hospitals NHS trust to identify all patients aged 65 years and above who underwent emergency laparotomy between December 2018 and March 2021. We also conducted a comprehensive multi-database literature search of Medline, Embase, and Cochrane to synthesise contemporaneous topical evidence. Results A total of 191 patients were assessed using the CFS before they underwent emergency laparotomy. Among 90 (47.1%) individuals categorised as vulnerable or frail (CFS score ≥4), there was no significant difference in age, gender, or length of stay related to the procedure compared with fit patients. However, vulnerable and frail patients were significantly more likely to die (84.8% vs. 39.2%, p<0.0001). Regression analysis identified a vulnerable or frail score to be a significant predictor of 30-day all-cause mortality (OR: 9.327; 95% CI: 3.101-28.054; p<0.0001). A total of six relevant papers were identified in the literature, all indicating a significant association between mortality as well as prolonged length and stay with clinical vulnerability and frailty. Conclusions The CFS is a practical and effective tool for assessing preoperative vulnerability and frailty among patients undergoing emergency laparotomy and can be used to predict mortality and morbidity after surgery.

IL1ß/ TNFα/COX-2/VEGF axis responsible for effective healing potential of C-glucoside xanthone (mangiferin) based ointment in immunocompromised rats.

Present study was conducted to undermine the wound healing potential of mangiferin vis a vis its molecular dynamics in immunocompromised excisional rat model. 120 rats were randomly and equally divided into five groups viz. group I (Healthy control), group II (Immunocompromised control), group III (Immunocompromised group treated with silver sulphadiazine), group IV (Immunocompromised group treated with 2.5 %Mangiferin) and group V (Immunocompromised group treated with 5 %Mangiferin). Immuno compromised state was achieved following intramuscular injection of Hydrocortisone @ 80 mg/kg body weight. Study was conducted for a period of 28 days. Six animals from each group were humanely sacrificed at weekly interval till day 28th of study. Planimetric analysis, biochemical studies viz. hydroxyproline assay, total protein and DNA content, antioxidative potential through LPO assay was done along with molecular studies involving expression profiling of IL1ß, TNFα and COX-2 and Immunohistochemistry of angiogenic marker i.e. VEGF was performed to undermine the pharmacodynamics of mangiferin. Histopathological studies including H&E and Masson's Trichome was also performed to study histoarchitectural changes in wound healing and reparative process following application of mangiferin ointment. Study revealed significant (P ≤ 0.05) reduction in wound area measurement and significant (P ≤ 0.05) increase in wound contraction (%) following mangiferin administration in immunocompromised rats. Hydroxyproline, DNA and total protein showed significant (P ≤ 0.05) increase in skin tissues of mangiferin treated immunocompromised rats. LPO assay revealed significant (P ≤ 0.05) reduction in mangiferin treated animals. Histopathological studies of skin tissues revealed complete restoration advocating grade III of healing in 2.5% mangiferin treated group. Higher expression and strong signal intensity of VEGF was noticed in 2.5% mangiferin treatment group along with significant (P ≤ 0.05) upregulation IL1ß and TNFα on day 7 in 2.5% mangiferin treatment group with significant (P ≤ 0.05) down regulation of COX-2 in mangiferin treatment group as compared to other groups i.e. group II and III. It is concluded from our study that mangiferin facilitates wound healing through improved wound closure, organized deposition of collagen deposition and granulation matrix formation.

Sepsis downregulates aortic Notch signaling to produce vascular hyporeactivity in mice.

Inhibition of Notch signaling in macrophages is known to reduce inflammation, however, its role in regulating vascular hyporeactivity in sepsis is unknown. Thus we aimed to evaluate the effect of sepsis on vascular Notch signaling. Polymicrobial sepsis was induced by caecal ligation and puncture (CLP) in mice. mRNA expressions of Notch receptors (Notch1,3) and ligands (Jag1, Dll4), and downstream effector genes (Hey1, MLCK, MYPT1) were assessed by RT-qPCR. Protein level of activated Notch (NICD) was assessed by Western blot and immuno-histochemistry. Isometric tension in isolated aortic rings was measured by wire myography.CLP down-regulated aortic expression of Notch3, Jag1 and Dll4 as compared to control mice. Additionally, the protein level of NICD was found to be lesser in aortic tissue sections from CLP mice. Expression of Hey1 and MLCK were attenuated whereas MYPT1 expression was increased in septic mouse aorta. DAPT pretreatment did not improve CLP-induced vascular hyporeactivity to NA, CaCl2 and high K+ (80 mM), rather significantly attenuated the aortic response to these vasoconstrictors in control mice. Treatment with 1400 W reversed attenuated Notch3 (but not Jag1 and MLCK) expression in septic mouse aorta. In conclusion, sepsis significantly attenuated the Notch (especially Notch3) signaling in mouse aorta along with reduction in contractile gene expression and vasoconstriction response. Further, iNOS/NO pathway was involved in sepsis-induced down-regulation of Notch3 receptor. Thus systemic inhibition of Notch signaling during sepsis may have serious impact on sepsis-induced vascular hyporeactivity.

An Atypical Presentation of Motor Aphasia: A Case Report and Review of Literature.

Broca's aphasia results due to lesions involving the anterior perisylvian speech area. Patients have intact comprehension and writing but have labored, nonfluent speech with decreased linguistic output. We hereby present a case of a 47-year-old female who was operated on for left ventricular trigonal meningioma by a modified middle temporal gyrus approach and developed motor aphasia as a complication. She had intact comprehension and writing but had decreased linguistic, labored output. It could not be labeled as subcortical aphasia as she had no repetition. Eventually, her aphasia improved completely. Our case is the first of its kind and hence we propose that the posterior middle temporal gyrus area has speech output function, the lesion of which could cause motor aphasia.

A Novel Smart City-Based Framework on Perspectives for Application of Machine Learning in Combating COVID-19.

The spread of COVID-19 worldwide continues despite multidimensional efforts to curtail its spread and provide treatment. Efforts to contain the COVID-19 pandemic have triggered partial or full lockdowns across the globe. This paper presents a novel framework that intelligently combines machine learning models and the Internet of Things (IoT) technology specifically to combat COVID-19 in smart cities. The purpose of the study is to promote the interoperability of machine learning algorithms with IoT technology by interacting with a population and its environment to curtail the COVID-19 pandemic. Furthermore, the study also investigates and discusses some solution frameworks, which can generate, capture, store, and analyze data using machine learning algorithms. These algorithms can detect, prevent, and trace the spread of COVID-19 and provide a better understanding of the disease in smart cities. Similarly, the study outlined case studies on the application of machine learning to help fight against COVID-19 in hospitals worldwide. The framework proposed in the study is a comprehensive presentation on the major components needed to integrate the machine learning approach with other AI-based solutions. Finally, the machine learning framework presented in this study has the potential to help national healthcare systems in curtailing the COVID-19 pandemic in smart cities. In addition, the proposed framework is poised as a pointer for generating research interests that would yield outcomes capable of been integrated to form an improved framework.

Molecular characterization of extended-spectrum ß-lactamase-producing Escherichia coli isolated from postpartum uterine infection in dairy cattle in India.

BACKGROUND AND AIM: Selection and dissemination of plasmid-encoded extended-spectrum ß-lactamase (ESBL) among Enterobacteriaceae confers resistance to beta-lactam antibiotics. The purpose of this study was to determine the prevalence and molecular characteristics of ESBL-producing organisms isolated from dairy cattle with a uterine infection. MATERIALS AND METHODS: Bacterial isolates (n=62) were characterized by biochemical test for genus and species determination. Antimicrobial susceptibility tests were performed by Kirby-Bauer disk diffusion method using panel of antibiotics for initial screening of ESBL organism. Phenotypic confirmation of ESBL-suspected strains was done by combination disk method and double-disk method. Multiplex polymerase chain reaction (PCR) was carried out for phylogrouping of Escherichia coli isolates as well as for genotyping ESBL genes. Enterobacterial repetitive intergenic consensus-PCR method was used for genotypic characterization of isolates. RESULTS: Antibiotic susceptibility profile of E. coli (n=40) isolates showed high rates of resistance for ampicillin (95.0%), cefpodoxime (97.5%), cefotaxime (87.5%), and ceftriaxone (70%). However, low rates of resistance were observed for cefoxitin (25%), amoxicillin/clavulanic acid (20%), ceftazidime (17.5%), gentamicin (10%), and ertapenem (7.5%). A total of 39/40 E. coli isolates were confirmed as ESBL with Epsilometer test as well as the genotypic method and 28 (70%) of them were multidrug-resistant. Genotype blaCTX-M was observed as a predominant beta-lactamase type with the preponderance of CTX-M Group 1. The following combinations were observed: blaTEM + blaCTX-M in 15 (36.2%) isolates, blaTEM /blaSHV in 8 (5.2%) isolates, and blaCTX-M /blaSHV in 6 (5.2%) isolates. The phylogenetic grouping of E. coli strains revealed the highest prevalence for B1 (22.0%) followed by A (20%). CONCLUSION: This report shows a high frequency of ESBL E. coli from cattle with postpartum uterine infections. These isolates showed reduced susceptibility to common antibiotics used for the treatment of uterine infections greater affecting the therapeutic outcome.

Chitosan and gelatin biopolymer supplemented with mesenchymal stem cells (Velgraft®) enhanced wound healing in goats (Capra hircus): Involvement of VEGF, TGF and CD31.

AIM: Cell-based therapy has emerged as promising strategy for chronic and impaired wounds treatment. Current research is focused on developing biomaterial systems that act as a niche for mesenchymal stem cells (MSCs) to promote wound healing through paracrine molecular cascading. This study was aimed to evaluate the wound healing potential of Velgraft, a ready-to-use biodegradable artificial skin substitute, on excision wound in goats. MATERIALS AND METHODS: Twelve male goats were randomized divided in to three groups of four animals each. After infliction of surgical wound, Velgraft and Soframycin were applied on wounds of the animals of Groups II and III while Group I (sham operated) served as control. Wound diameters were measured at pre-defined time-points for determination of progressive wound healing up to 28 days. Skin sections were stained using Hematoxylin and eosin (H&E) for examining the histoarchitectural changes, Masson trichome staining for ascertaining collagen synthesis and immunohistochemistry for expression of CD31, VEGF and TGF-ß1 proteins to determine post-treatment angiogenesis in the inflicted wounds. RESULTS: Velgraft application appreciably enhanced wound closure by day 21 which was confirmed through restoration of the normal skin architecture as evident based on histopathological examination and characterized by complete regeneration of epidermal layers, collagen fibers, blood capillaries and hair follicular formation. Stimulation of angiogenesis markers was also observed at different time-points post-Velgraft application; which is suggestive of the improved angiogenesis and vasculogenesis. CONCLUSION: Velgraft facilitates wound healing by augmenting early wound closure, enhancing collagen synthesis and deposition, trichosis development and promoting revascularization and epidermal layers restoration.

Soft Elastic Fibrous Scaffolds for Muscle Tissue Engineering by Touch Spinning.

This paper reports an approach for the fabrication of highly aligned soft elastic fibrous scaffolds using touch spinning of thermoplastic polycaprolactone-polyurethane elastomers and demonstrates their potential for the engineering of muscle tissue. A family of polyester-polyurethane soft copolymers based on polycaprolactone with different molecular weights and three different chain extenders such as 1,4-butanediol and polyethylene glycols with different molecular weight was synthesized. By varying the molar ratio and molecular weights between the segments of the copolymer, different physicochemical and mechanical properties were obtained. The polymers possess elastic modulus in the range of a few megapascals and good reversibility of deformation after stretching. The combination of the selected materials and fabrication methods allows several essential advantages such as biocompatibility, biodegradability, suitable mechanical properties (elasticity and softness of the fibers), high recovery ratio, and high resilience mimicking properties of the extracellular matrix of muscle tissue. Myoblasts demonstrate high viability in contact with aligned fibrous scaffolds, where they align along the fibers, allowing efficient cell patterning on top of the structures. Altogether, the importance of this approach is the fabrication of highly oriented fiber constructs that can support the proliferation and alignment of muscle cells for muscle tissue engineering applications.

Shape-Morphing Fibrous Hydrogel/Elastomer Bilayers Fabricated by a Combination of 3D Printing and Melt Electrowriting for Muscle Tissue Regeneration.

This paper reports an approach for the fabrication of shape-changing bilayered scaffolds, which allow the growth of aligned skeletal muscle cells, using a combination of 3D printing of hyaluronic acid hydrogel, melt electrowriting of thermoplastic polycaprolactone-polyurethane elastomer, and shape transformation. The combination of the selected materials and fabrication methods allows a number of important advantages such as biocompatibility, biodegradability, and suitable mechanical properties (elasticity and softness of the fibers) similar to those of important components of extracellular matrix (ECM), which allow proper cell alignment and shape transformation. Myoblasts demonstrate excellent viability on the surface of the shape-changing bilayer, where they occupy space between fibers and align along them, allowing efficient cell patterning inside folded structures. The bilayer scaffold is able to undergo a controlled shape transformation and form multilayer scroll-like structures with cells encapsulated inside. Overall, the importance of this approach is the fabrication of tubular constructs with a patterned interior that can support the proliferation and alignment of muscle cells for muscle tissue regeneration.

Myometrial Calcium and Potassium Channels Play a Pivotal Role in Chromium-Induced Relaxation in Rat Uterus: an In Vitro Study.

Hexavalent chromium, a well-known environmental toxicant, adversely affects female reproduction and results in abnormal implantation, fetal resorption, and reduction in litter size. Uterine myogenic activity is under control of number of receptors and ion channels, and it regulates fetal-implantation and feto-maternal communication. Despite several known adverse effects of chromium on female reproduction, direct action of chromium on myometrial activity is yet to be understood. In the present study, the effect of in vitro exposure of hexavalent chromium (Cr-VI) on the myogenic activity of isolated myometrial strips of rats was evaluated after mounting the tissue in thermostatically (37 ± 0.5 °C) controlled organ bath under a resting tension of 1 g. Chromium produced concentration-dependent (0.1 nM-0.1 mM) inhibitory effect on myometrial activity. Following pre-treatment of the myometrial strips with glibenclamide (a KATP channel blocker) and 4-aminopyridine (a Kv channel blocker), the concentration-response curve (CRC) of chromium was significantly (P < 0.05) shifted towards right with decrease in the maximum relaxant effect. Contractile effects of CaCl2 and BAY K-8644 (a selective opener of L-type Ca2+ channel) were significantly (P < 0.05) attenuated in the presence of chromium. Chromium-induced myometrial relaxation was also significantly (P < 0.05) reduced in the presence of ICI 118,551 (a selective ß2-antagonist) and SR 59230A (a selective ß3-antagonist). These findings evidently suggest that chromium produced relaxant effect on rat myometrium by interfering with Ca2+ entry through voltage-dependent Ca2+ channels, and by interacting with beta-adrenoceptors (ß2 and ß3) and potassium channels (especially KATP and Kv channels). Graphical Abstract Proposed signaling pathway(s) of chromium (VI)-induced myometrial relaxations in rats. KATP: ATP-sensitive K+ channel; KV: voltage-dependent K+ channel; VDCC: voltage-dependent Ca2+ channel; [Ca2+]i: intracellular calcium concentration, stimulatory mechanism, inhibitory mechanism.

Polyalthia longifolia leaves methanolic extract targets entry and budding of viruses-an in vitro experimental study against paramyxoviruses.

ETHNOPHARMACOLOGICAL RELEVANCE: Synthetic antiviral drugs have several limitations including high cost. Thus research on antiviral property of medicinal plants is continuously gaining importance. Polyalthia longifolia possesses several medicinal properties and has been used in traditional ayurvedic medicine for treatment of dermatological ailments as kushta, visarpa/herpes virus infection and also to treat pyrexia of unknown origin as mentioned in Visarpa Chikitsa. AIM OF THE STUDY: Keeping in view the cytotoxic, anti-cancer activity and antiviral efficacy of Polyalthia longifolia against herpes, present study was undertaken to evaluate the in vitro antiviral activity of methanolic extract of Polyalthia longifolia leaves, if any, and to unravel the possible target(s)/mechanism of action. MATERIAL AND METHODS: Antiviral activity of Polyalthia longifolia methanolic extract was studied using Vero cell lines against paramyxoviruses, namely-peste des petits ruminants virus (PPRV) and Newcastle disease virus (NDV). Cytotoxicity of the test extract was evaluated employing MTT assay. Virucidal activity, and viral-attachment, virus entry and release assays were determined in Vero cells using standard experimental protocols. The viral RNA in the virus-infected cells was quantified by qRT-PCR. RESULTS: At non-cytotoxic concentration, methanolic extract of Polyalthia longifolia leaves was found to inhibit the replication of PPRV and NDV at viral entry and budding level, whereas other steps of viral life cycle such as attachment and RNA synthesis remained unaffected. CONCLUSIONS: Polyalthia longifolia leaves extract possesses promising antiviral activity against paramyxoviruses and acts by inhibiting the entry and budding of viruses; and this plant extract evidently possesses excellent and promising potential for development of effective herbal antiviral drug.

Oleic Acid Prevents Isoprenaline-Induced Cardiac Injury: Effects on Cellular Oxidative Stress, Inflammation and Histopathological Alterations.

The present study was designed to assess the cardio-protective role of oleic acid in myocardial injury (MI) induced by intra-peritoneal injection of isoprenaline (ISO) in rats for 2 consecutive days. Oleic acid (OA) was administered orally (@ 5 mg/kg b.wt and 10 mg/kg b.wt) for 21 days before inducing MI. Pre-exposure to OA at higher dose significantly improved the HW/BW ratio, myocardial infarct size, lipid profiles (total cholesterol, HDL-C) and cardiac injury biomarkers (LDH, CK-MB, cardiac troponin-I, MMP-9), thus suggesting its cardio-protective role. The ameliorative potential of the higher dose of OA was further substantiated by its ability to reduce the cardiac oxidative stress as evidenced by significant decrease in lipid peroxidation coupled with increase in superoxide dismutase activity and reduced glutathione level. Significant decrease in heart rate as well as increase in RR and QT intervals in oleic acid pre-exposed rats were also observed. OA pre-treatment also reduced the histopathological alterations seen in myocardial injury group rats. The mRNA expression of cardiac UCP-2 gene, a regulator of reactive oxygen species (ROS) generation, was significantly increased in oleic acid pre-exposure group compared to the ISO-induced myocardial injury group. Thus increase in expression of UCP-2 gene in cardiac tissue seems to be one of the protective measures against myocardial injury. Based on the above findings, it may be inferred that oleic acid possesses promising cardio-protective potential against myocardial injury due to its anti-oxidative property and ability to modulate cardiac metabolic processes.

Investigations on Modulating Effect of Vanadium Supplementation on Growth and Metabolism Through Improved Immune Response, Antioxidative Profile and Endocrine Variables in Hariana heifers.

This study was conducted to investigate the effect of vanadium (V) supplementation on growth, metabolism, antioxidant, and immunological and endocrine variables in Hariana heifers. Eighteen indigenous Hariana heifers (body weight 130.0 ± 3.0 kg; age 10.0 ± 2.0 months) were randomly blocked into three groups, each comprising of six animals. All the animals were on same dietary plan except that the respective groups were additionally supplemented with 0.0, 2.5, and 5.0 mg of V/kg dry matter (DM), during the experimental period of 90 days. There was a linear increase (p < 0.05) in mean DMI and ADG in 5.0 mg of V/kg DM-supplemented group. However, the feed efficiency remained unaffected. Although no effects (p > 0.05) of V supplementation were observed on hemato-biochemical attributes, the mean plasma V concentration showed dose-dependent increase (p < 0.001) on V supplementation. The activity of SOD was significantly higher (p < 0.001), whereas mean values of LPO decreased linearly (p < 0.05) in V-supplemented groups. Plasma total antioxidant status (TAS) also increased linearly (p < 0.05) in V-supplemented groups. Plasma IgG levels increased linearly (p < 0.05). Plasma IGF-1 concentrations showed significant effect (p < 0.05) of V supplementation. Plasma T4 concentration increased linearly (p < 0.05). The results suggest that V supplementation may play a role in modulating the immunity and antioxidant status of growing Hariana heifers. Graphical Abstract.

Endocannabinoid-mediated modulation of Gq protein-coupled receptor mediates vascular hyporeactivity to nor-adrenaline during polymicrobial sepsis.

BACKGROUND: Endocannabinoids level are reported to increase in sepsis, however, the role of vascular cannabinoid receptor-1 (CB1R) in sepsis-induced vascular hyporeactivity is yet to be unravelled. METHODS: Polymicrobial sepsis was induced by caecal ligation and puncture in mice. Isometric tension in isolated aortic rings during early (6 h) and late (20 h) phases of sepsis was recorded and expression of mRNA of monoacylglycerol lipase (MAGL) and cannabinoid receptor-1 (CB1R) was investigated. RESULTS: Sepsis significantly (p < 0.001) reduced the mean survival time in mice along with increase in bacterial load in blood and peritoneal lavage. Compared to Sham-operated (SO) mice, vascular reactivity to nor-adrenaline (NA) was significantly (p < 0.05) attenuated in both early and late phases of sepsis. NA-induced vasoconstriction was significantly (p < 0.05) potentiated by inhibition of diacylglycerol lipase (DAGL) and attenuated by inhibition of MAGL in SO mice. Pre-incubation with KT 109, a DAGL inhibitor, significantly (p < 0.05) improved the vascular hypo-reactivity to NA during both the phases of sepsis. mRNA expression of MAGL in aorta was significantly (p < 0.05) attenuated during both the phases of sepsis. But in the presence of AM 251, specific antagonist of CB1R, vascular reactivity to NA was significantly (p < 0.05) restored along with significant (p < 0.05) increase in mRNA expression of CB1R in aortic rings from both early and late phases of septic mice. CONCLUSION: 2-AG regulates vascular response to NA and increased aortic expression of CB1R is responsible for vascular hyporeactivity to NA in sepsis, and in vitro inhibition of this receptor by AM 251 restored the vascular reactivity.