Phytol-Derived Novel Isoprenoid Immunostimulants

This review describes the adjuvanticity of novel diterpenoids (synthetic phytol derivatives) compared to some commercially available adjuvants. The efficacy of the phytol-derived immunostimulants was evaluated in terms of their ability to activate innate immunity, amplify various antigen-specific immune responses, and engender immunological memory with no discernible adverse effects in both competent and immune-deficient mice. The profile that emerges out of these studies reveals that the phytol derivatives are excellent immunostimulants, superior to a number of commercial adjuvants in terms of long-term memory induction and activation of both innate and acquired immunity. Additionally, the phytol-derived compounds have no cumulative inflammatory or toxic effects even in immuno-compromised mice

ROLE OF LIPOSOME IN NOVEL DRUG DELIVERY SYSTEM

Liposome was found by Alec Bangham of Babraham Institute in Cambridge, England in 1965.In 1990; drugs with liposome and Amphotericin B were approved by Ireland. In 1995 America F.D.A approved liposor doxodubicin. In 1965s, it was well recognized that microscopic lipid vesicles, known as liposomes, could be utilized to encapsulate drugs and dyes for the purpose of systemic administration and drug targeting.Considerable  progress was made in 1980s, in engeneering liposomes to circulate longer in blood and remain intact while doing so. The liposome a microscopic spherical particle formed by a lipid bilayer enclosing an aqueous compartment.An artificial microscopic vesicle consisting of an aqueous core enclosed in one or more phospholipid layers, used to convey vaccines, drugs, enzymes, or other substances to target cells or organs. Liposome was discovered about 40 years ago by Bangham and coworkersand was defined as microscopic spherical vesicles that form when phospholipids are hydrated or exposed to anaqueous environment.Liposomes are microscopic vesicles composed of a bilayer of phospholipids or any similar amphipathic lipids. They can encapsulate and effectively deliver both hydrophilic and lipophilic substances2â€3 and may be used as a nonâ€toxic vehicle for insoluble drugs. Liposomes are composed of small vesicles of phospholipids encapsulating an aqueous space ranging from about 0.03 to 10 µm in diameter. The membrane of liposome is made of phospholipids, which have phosphoric acid sides to form the liposome bilayers.Liposomes can be manufacturing in different lipid comopsitions or by different method show variation in par. Size , size distribution, surface electrical potential, no. of lamella, encapsulation efficacy,Surface modification showed great advantage to produce liposomes of different mechanisims, kinetic properties and biodistributio

Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells.

Huntington's disease is a neurodegenerative disorder caused by CAG expansion that results in expansion of a polyglutamine tract at the extreme N terminus of huntingtin (htt). htt with polyglutamine expansion is proapoptotic in different cell types. Here, we show that caspase inhibitors diminish the toxicity of htt. Additionally, we define htt itself as an important caspase substrate by generating a site-directed htt mutant that is resistant to caspase-3 cleavage at positions 513 and 530 and to caspase-6 cleavage at position 586. In contrast to cleavable htt, caspase-resistant htt with an expanded polyglutamine tract has reduced toxicity in apoptotically stressed neuronal and nonneuronal cells and forms aggregates at a much reduced frequency. These results suggest that inhibiting caspase cleavage of htt may therefore be of potential therapeutic benefit in Huntington's disease

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Effects of small intestinal submucosa (SIS) on the murine innate immune microenvironment induced by heat-killed Staphylococcus aureus.

The use of biological scaffold materials for wound healing and tissue remodeling has profoundly impacted regenerative medicine and tissue engineering. The porcine-derived small intestinal submucosa (SIS) is a licensed bioscaffold material regularly used in wound and tissue repair, often in contaminated surgical fields. Complications and failures due to infection of this biomaterial have therefore been a major concern and challenge. SIS can be colonized and infected by wound-associated bacteria, particularly Staphylococcus aureus. In order to address this concern and develop novel intervention strategies, the immune microenvironment orchestrated by the combined action of S. aureus and SIS should be critically evaluated. Since the outcome of tissue remodeling is largely controlled by the local immune microenvironment, we assessed the innate immune profile in terms of cytokine/chemokine microenvironment and inflammasome-responsive genes. BALB/c mice were injected intra-peritoneally with heat-killed S. aureus in the presence or absence of SIS. Analyses of cytokines, chemokines and microarray profiling of inflammasome-related genes were done using peritoneal lavages collected 24 hours after injection. Results showed that unlike SIS, the S. aureus-SIS interactome was characterized by a Th1-biased immune profile with increased expressions of IFN-γ, IL-12 and decreased expressions of IL-4, IL-13, IL-33 and IL-6. Such modulation of the Th1/Th2 axis can greatly facilitate graft rejections. The S. aureus-SIS exposure also augmented the expressions of pro-inflammatory cytokines like IL-1β, Tnf-α, CD30L, Eotaxin and Fractalkine. This heightened inflammatory response caused by S. aureus contamination could enormously affect the biocompatibility of SIS. However, the mRNA expressions of many inflammasome-related genes like Nlrp3, Aim2, Card6 and Pycard were down-regulated by heat-killed S. aureus with or without SIS. In summary, our study explored the innate immune microenvironment induced by the combined exposure of SIS and S. aureus. These results have practical implications in developing strategies to contain infection and promote successful tissue repair

Investigation of Energy Attenuation, Flow Resistance and Impending Motion of Downstream Bed Material in Rock Ramps

Block ramps are ecofriendly drop structures, which ensure stable downstream river bed, peculiar to flows over macro roughness elements. It uniquely serves an essential paradigm in riverine management, to encounter deliveries in an ecologically sound manner. It permits safe fish passage, stabilizes stream banks and bed profiles and creates habitat diversity. Study of flows over block ramps are quite extensive and are associated with many intricacies. In this paper, flume experiments were conducted in the hydraulic laboratory of National Institute of Technology Patna. The particle densimetric Froude number (F*) was calculated for the mobile bed and chosen to predict the hydraulic conditions for incipient sediment motion in the uniform beds and it is compared with the established literature formulations to estimate the stability of the beds under large-scale roughness conditions. Scour volumes from each experimental run is quantified and the intensity of sediment motion was determined. Experimental data analysis allowed describing the mechanism of incipient motion of the mobile bed in the stilling basin, energy dissipation, flow resistance and in the interstitial flow over rock ramps and intensity of block movement for various flow regimes. It was found that the dimensionless shields stress increases with ramp slope and the intensity of ramp motion decreases with the shear stress. The results indicated that friction resistance increases with relative submergence for the tested range of experiments. A comparison with previous literature with uniform sediment transport indicates that relative roughness of block is responsible for increasing the dimensionless Shields stress. The results of physical testing can be used to assess and predict the effective dissipation of energy and its impact on the stability of rock structures