Advancing Vaccine Strategies against Candida Infections: Exploring New Frontiers.

Candida albicans, along with several non-albicans Candida species, comprise a prominent fungal pathogen in humans, leading to candidiasis in various organs. The global impact of candidiasis in terms of disease burden, suffering, and fatalities is alarmingly high, making it a pressing global healthcare concern. Current treatment options rely on antifungal drugs such as azoles, polyenes, and echinocandins but are delimited due to the emergence of drug-resistant strains and associated adverse effects. The current review highlights the striking absence of a licensed antifungal vaccine for human use and the urgent need to shift our focus toward developing an anti-Candida vaccine. A number of factors affect the development of vaccines against fungal infections, including the host, intraspecies and interspecies antigenic variations, and hence, a lack of commercial interest. In addition, individuals with a high risk of fungal infection tend to be immunocompromised, so they are less likely to respond to inactivated or subunit whole organisms. Therefore, it is pertinent to discover newer and novel alternative strategies to develop safe and effective vaccines against fungal infections. This review article provides an overview of current vaccination strategies (live attenuated, whole-cell killed, subunit, conjugate, and oral vaccine), including their preclinical and clinical data on efficacy and safety. We also discuss the mechanisms of immune protection against candidiasis, including the role of innate and adaptive immunity and potential biomarkers of protection. Challenges, solutions, and future directions in vaccine development, namely, exploring novel adjuvants, harnessing the trained immunity, and utilizing immunoinformatics approaches for vaccine design and development, are also discussed. This review concludes with a summary of key findings, their implications for clinical practice and public health, and a call to action for continued investment in candidiasis vaccine research.

Natural sources and encapsulating materials for probiotics delivery systems: Recent applications and challenges in functional food development.

Probiotics are known as the live microorganisms which upon adequate administration elicit a health beneficial response inside the host by decreasing the luminal pH, eliminating the pathogenic bacteria in the gut as well as producing short chain fatty acids (SCFA). With advancements in research; probiotics have been explored as potential ingredients in foods. However, their use and applications in food industry have been limited due to restrictions of maintaining the viability of probiotic cells and targeting the successful delivery to gut. Encapsulation techniques have significant influence on increasing the viability rates of probiotic cells with the successful delivery of cells to the target site. Moreover, encapsulating techniques also prevent the live cells from harsh physiological conditions of gut. This review discusses several encapsulating techniques as well as materials derived from natural sources and nutraceutical compounds. In addition to this, this paper also comprehensively discusses the factors affecting the probiotics viability and evaluation of successful release and survival of probiotics under simulated gastric, intestinal conditions as well as bile, acid tolerant conditions. Lastly applications and challenges of using encapsulated bacteria in food industry for the development of novel functional foods have also been discussed in detail too. Future studies must include investigating the use of encapsulated bacterial formulations in in-vivo models for effective health beneficial properties as well as exploring the mechanisms behind the successful release of these formulations in gut, hence helping us to understand the encapsulation of probiotic cells in a meticulous manner.

A comparative study of in-vitro and in-silico anti-candidal activity and GC-MS profiles of snow mountain garlic vs. normal garlic.

AIM: The study aimed to profile the volatile phytocomposition of snow mountain garlic (SMG) compared to normal garlic and investigate the anti-Candida efficacy against clinically relevant multi-drug resistant isolates of Candida species. METHODS AND RESULTS: Herein, SMG has shown significantly superior fungicidal power at 2x-MIC dose against C. albicans and C. glabrata in killing kinetic evaluation unlike the fungistatic effect of normal garlic. GC-MS headspace-based profiling of SMG showed 5 unique volatile compounds and a 5-fold higher content of saponins than normal garlic. In an in-silico analysis, cholesta-4,6-dien-3-ol,(3-beta) was uniquely identified in SMG as a potential inhibitor with high binding affinity to the active site of exo-1,3-betaglucan synthase, an established anti-candida drug target crucial for the biofilm matrix formation, thus suggesting a plausible anti-Candida mechanism. CONCLUSION: The in-vitro and in-silico studies have demonstrated the Candida-cidal and anti-biofilm activities of SMG, distinguishing it from the Candida-static efficacy of normal garlic. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report that identifies several phytochemical signatures of SMG along with a potential anti-Candida compound, that is cholesta-4,6-dien-3-ol,(3-beta)-, which appears worthy of detailed studies in the future to explore the utility of SMG as a fungal phytotherapy agent, especially against drug-resistant Candida sp.

Preventive preclinical efficacy of intravenously administered sphingosine-1-phosphate (S1P) in strengthening hypoxia adaptive responses to acute and sub-chronic hypobaric hypoxia.

Sphingosine-1-phosphate (S1P) is emerging as a hypoxia responsive bio-lipid; systemically raised levels of S1P are proposed to have potential hypoxia pre-conditioning effects. The study aims to evaluate the hypoxia pre-conditioning efficacy of exogenously administered S1P in rats exposed to acute (24-48 hs (h)) and sub-chronic (7 days) hypobaric hypoxia. Sprague-Dawley rats (200 ± 20 g) were preconditioned with 1 µg/kg body weight S1P intravenously for three consecutive days. On the third day, control and S1P preconditioned animals were exposed to hypobaric hypoxia equivalent to 7620 m for 24 h, 48 h and 7 days. Post exposure analysis included body weight quantitation, blood gas/chemistry analysis, vascular permeability assays, evaluation of oxidative stress/inflammation parameters, and estimation of hypoxia responsive molecules. S1P preconditioned rats exposed to acute HH display a significant reduction in body weight loss, as a culmination of improved oxygen carrying capacity, increased 2,3- diphosphoglycerate levels and recuperation from energy deficit. Pathological disturbances such as vascular leakage in the lungs and brain, oxidative stress, pro-inflammatory milieu and raised level of endothelin-1 were also reined. The adaptive and protective advantage conferred by S1P in the acute phase of hypobaric hypoxia exposure, is observed to precipitate into an improved sustenance even after sub-chronic (7d) hypobaric hypoxia exposure as indicated by decreased body weight loss, lower edema index and improvement in general pathology biomarkers. Conclusively, administration of 1 µg/kg body weight S1P, in the aforementioned schedule, confer hypoxia pre-conditioning benefits, sustained up to 7 days of hypobaric hypoxia exposure.

Enhancing Women's Well-Being: The Role of Psychological Capital and Perceived Gender Equity, With Social Support as a Moderator and Commitment as a Mediator.

The study aims to determine the role of psychological capital and perceived gender equity on employee well-being, particularly women, and assess if commitment mediates and social support moderates the relationships between psychological capital, perceived gender equity, and well-being. A personal survey method was employed for data collection using standardized measures from a representative sample of 433 managers (201 women and 233 men) from private sector companies in India. The findings revealed that perceived gender equity in the workplace positively impacts employee well-being for both men and women, with the greater impact being on women's well-being. To Facilitate employee well-being, organizations can leverage the strengths of psychological capital through training interventions and can promote perceived gender equity through appropriate policies and practices. This bridges the knowledge gap in developing and utilizing psychological capital to enhance employee well-being, especially for women, who are under pressure due to their demanding multiple roles at work and home.

Acute Hypobaric Hypoxia-Mediated Biochemical/Metabolic Shuffling and Differential Modulation of S1PR-SphK in Cardiac and Skeletal Muscles.

AIM: High altitude exposure alters biochemical, metabolic, and physiological features of heart and skeletal muscles, and hence has pathological consequences in these tissues. Central to these hypoxia-associated biochemical/metabolic shuffling are energy deficit accumulation of free radicals and ensuing oxidative damage in the tissue. Recent preclinical/clinical studies indicate sphingosine-1-phosphate (S1P) axis, comprising S1P G protein coupled receptors (S1PR1-5) and its synthesizing enzyme-sphingosine kinase (SphK) to have key regulatory roles in homeostatic cardiac and skeletal muscle biology. In view of this, the aim of the present study was to chart the initiation and progression of biochemical/metabolic shuffling and assess the coincident differential modulation of S1PR(1-5) expression and total SphK activity in cardiac and skeletal muscles from rats exposed to progressive hypobaric hypoxia (HH; 21,000 feet for 12, 24, and 48 hours). RESULTS: HH-associated responses were evident as raised damage markers in plasma, oxidative stress, decreased total tissue protein, imbalance of intermediate metabolites, and aerobic/anaerobic enzyme activities in cardiac and skeletal muscles (gastrocnemius and soleus) culminating as energy deficit. CONCLUSION: Cardiac and gastrocnemius muscles were more susceptible to hypoxic environment than soleus muscle. These differential responses were directly and indirectly coincident with temporal expression of S1PR(1-5) and SphK activity.

Sphingosine-1-phosphate pretreatment amends hypoxia-induced metabolic dysfunction and impairment of myogenic potential in differentiating C2C12 myoblasts by stimulating viability, calcium homeostasis and energy generation.

Sphingosine-1-phosphate (S1P) has a role in transpiration in patho-physiological signaling in skeletal muscles. The present study evaluated the pre-conditioning efficacy of S1P in facilitating differentiation of C2C12 myoblasts under a normoxic/hypoxic cell culture environment. Under normoxia, exogenous S1P significantly promoted C2C12 differentiation as evident from morphometric descriptors and differentiation markers of the mature myotubes, but it could facilitate only partial recovery from hypoxia-induced compromised differentiation. Pretreatment of S1P optimized the myokine secretion, intracellular calcium release and energy generation by boosting the aerobic/anaerobic metabolism and mitochondrial mass. In the hypoxia-exposed cells, there was derangement of the S1PR1-3 expression patterns, while the same could be largely restored with S1P pretreatment. This is being proposed as a plausible underlying mechanism for the observed pro-myogenic efficacy of exogenous S1P preconditioning. The present findings are an invaluable addition to the existing knowledge on the pro-myogenic potential of S1P and may prove beneficial in the field of hypoxia-related myo-pathologies.

S1P prophylaxis mitigates acute hypobaric hypoxia-induced molecular, biochemical, and metabolic disturbances: A preclinical report.

Sphingosine-1-phosphate (S1P) is emerging to have hypoxic preconditioning potential in various preclinical studies. The study aims to evaluate the preclinical preconditioning efficacy of exogenously administered S1P against acute hypobaric hypoxia (HH)-induced pathological disturbances. Male Sprague Dawley rats (200 ± 20 g) were preconditioned with 1, 10, and 100 µg/kg body weight (b.w.) S1P (i.v.) for three consecutive days. On the third day, S1P preconditioned animals, along with hypoxia control animals, were exposed to HH equivalent to 7,620 m (280 mm Hg) for 6 h. Postexposure status of cardiac energy production, circulatory vasoactive mediators, pulmonary and cerebral oxidative damage, and inflammation were assessed. HH exposure led to cardiac energy deficit indicated by low ATP levels and pronounced AMPK activation levels, raised circulatory levels of brain natriuretic peptide and endothelin-1 with respect to total nitrate (NOx), redox imbalance, inflammation, and alterations in NOx levels in the pulmonary and cerebral tissues. These pathological precursors have been routinely reported to be coincident with high-altitude diseases. Preconditioning with S1P, especially 1 µg/kg b.w. dose, was seen to reverse the manifestation of these pathological disturbances. The protective efficacy could be attributed, at least in part, to enhanced activity of cardioprotective protein kinase C and activation of small GTPase Rac1, which led to further induction of hypoxia-adaptive molecular mediators: hypoxia-inducible factor (HIF)-1α and Hsp70. This is a first such report, to the best of our knowledge, elucidating the mechanism of exogenous S1P-mediated HIF-1α/Hsp70 induction. Conclusively, systemic preconditioning with 1 µg/kg b.w. S1P in rats protects against acute HH-induced pathological disturbances. © 2016 IUBMB Life 68(5):365-375, 2016.

Differential modulation of S1PR(1-5) and specific activities of SphK and nSMase in pulmonary and cerebral tissues of rats exposed to hypobaric hypoxia.

Recent preclinical and clinical studies have unfolded the potential of pharmacological modulation of activities of sphingosine-1-phosphate (S1P) receptors and S1P metabolizing enzymes for the development of therapeutic interventions against a variety of pathologies. An understanding of differential and temporal effects of hypoxia exposure on the key components of S1P signalling would certainly aid in designing improved drug development strategies in this direction. In view of this, the aim of the present study was to assess the effect of progressive hypobaric hypoxia exposure on expression of S1P receptors (S1PR1-5) and specific activities of S1P synthesizing enzymes--neutral sphingomyelinase (nSMase) and sphingosine kinase (Sphk) in pulmonary and cerebral tissues of rats exposed to simulated altitude of 21,000 feet in an animal decompression chamber. Along with this, development of cerebral and pulmonary edema and markers of inflammation were studied at 12, 24, and 48 h to validate our study model of hypobaric hypoxia-induced stress. The protein expression of S1PR1-5 and activities of Sphk and nSMase enzymes were observed to be dramatically affected by simulated hypobaric hypoxia exposure, concurrent with deterioration of pathology, with 12 h of exposure appearing to be the most critical of the various time points studied.

Exogenous sphingosine-1-phosphate boosts acclimatization in rats exposed to acute hypobaric hypoxia: assessment of haematological and metabolic effects.

BACKGROUND: The physiological challenges posed by hypobaric hypoxia warrant exploration of pharmacological entities to improve acclimatization to hypoxia. The present study investigates the preclinical efficacy of sphingosine-1-phosphate (S1P) to improve acclimatization to simulated hypobaric hypoxia. EXPERIMENTAL APPROACH: Efficacy of intravenously administered S1P in improving haematological and metabolic acclimatization was evaluated in rats exposed to simulated acute hypobaric hypoxia (7620 m for 6 hours) following S1P pre-treatment for three days. MAJOR FINDINGS: Altitude exposure of the control rats caused systemic hypoxia, hypocapnia (plausible sign of hyperventilation) and respiratory alkalosis due to suboptimal renal compensation indicated by an overt alkaline pH of the mixed venous blood. This was associated with pronounced energy deficit in the hepatic tissue along with systemic oxidative stress and inflammation. S1P pre-treatment improved blood oxygen-carrying-capacity by increasing haemoglobin, haematocrit, and RBC count, probably as an outcome of hypoxia inducible factor-1α mediated erythropoiesis and renal S1P receptor 1 mediated haemoconcentation. The improved partial pressure of oxygen in the blood could further restore aerobic respiration and increase ATP content in the hepatic tissue of S1P treated animals. S1P could also protect the animals from hypoxia mediated oxidative stress and inflammation. CONCLUSION: The study findings highlight S1P's merits as a preconditioning agent for improving acclimatization to acute hypobaric hypoxia exposure. The results may have long term clinical application for improving physiological acclimatization of subjects venturing into high altitude for occupational or recreational purposes.

Exogenous sphingosine 1-phosphate protects murine splenocytes against hypoxia-induced injury.

Sphingosine-1-phosphate (S1P), a biologically active pleiotropic lipid, is involved in several physiological processes especially in the area of vascular biology and immunology encompassing cell survival, angiogenesis, vascular tone, immune response etc. by interacting with specific cell surface receptors. Hypoxia, a condition common to innumerable pathologies, is known to lethally affect cell survival by throwing off balance global gene expression, redox homeostasis, bioenergetics etc. Several molecular events of cellular adaptations to hypoxia have been closely linked to stabilization of hypoxia inducible factor-1α (HIF-1α). Signalling functions of S1P in physiological events central to hypoxia-induced pathologies led us to investigate efficacy of exogenous S1P in preconditioning murine splenocytes to sustain during cellular stress associated with sub-optimal oxygen. The present study recapitulated the pro-survival benefits of exogenous S1P under normobaric hypoxia. Results indicate a direct effect of S1P supplementation on boosting cellular adaptive responses via HIF-1α stabilization and, activation of pro-survival mediators ERK and Akt. Overwhelming anti-oxidative and anti-inflammatory benefits of S1P preconditioning could also be captured in the present study, as indicated by improved redox homeostasis, reduced oxidative damage, balanced anti/pro-inflammatory cytokine profiles and temporal regulation of nitric oxide secretion and intra-cellular calcium release. Hypoxia induced cell death and the associated stress in cellular milieu in terms of oxidative damage and inflammation could be alleviated with exogenous S1P preconditioning.