Tularemia - a re-emerging disease with growing concern.

Tularemia caused by Gram-negative, coccobacillus bacterium, Francisella tularensis, is a highly infectious zoonotic disease. Human cases have been reported mainly from the United States, Nordic countries like Sweden and Finland, and some European and Asian countries. Naturally, the disease occurs in several vertebrates, particularly lagomorphs. Type A (subspecies tularensis) is more virulent and causes disease mainly in North America; type B (subspecies holarctica) is widespread, while subspecies mediasiatica is present in central Asia. F. tularensis is a possible bioweapon due to its lethality, low infectious dosage, and aerosol transmission. Small mammals like rabbits, hares, and muskrats are primary sources of human infections, but true reservoir of F. tularensis is unknown. Vector-borne tularemia primarily involves ticks and mosquitoes. The bacterial subspecies involved and mode of transmission determine the clinical picture. Early signs are flu-like illnesses that may evolve into different clinical forms of tularemia that may or may not include lymphadenopathy. Ulcero-glandular and glandular forms are acquired by arthropod bite or handling of infected animals, oculo-glandular form as a result of conjunctival infection, and oro-pharyngeal form by intake of contaminated food or water. Pulmonary form appears after inhalation of bacteria. Typhoidal form may occur after infection via different routes. Human-to-human transmission has not been known. Diagnosis can be achieved by serology, bacterial culture, and molecular methods. Treatment for tularemia typically entails use of quinolones, tetracyclines, or aminoglycosides. Preventive measures are necessary to avoid infection although difficult to implement. Research is underway for the development of effective live attenuated and subunit vaccines.

Clinical Strategies and Therapeutics for Human Monkeypox Virus: A Revised Perspective on Recent Outbreaks.

An enveloped double-stranded DNA monkeypox virus (MPXV) is a causative agent of the zoonotic viral disease, human monkeypox (HMPX). MPXV belongs to the genus Orthopoxviridae, a family of notorious smallpox viruses, and so it shares similar clinical pathophysiological features. The recent multicountry HMPX outbreak (May 2022 onwards) is recognized as an emerging global public health emergency by the World Health Organization, shunting its endemic status as opined over the past few decades. Re-emergence of HMPX raises concern to reassess the present clinical strategy and therapeutics as its outbreak evolves further. Keeping a check on these developments, here we provide insights into the HMPX epidemiology, pathophysiology, and clinical representation. Weighing on its early prevention, we reviewed the strategies that are being enrolled for HMPX diagnosis. In the line of expanded MPXV prevalence, we further reviewed its clinical management and the diverse employed preventive/therapeutic strategies, including vaccines (JYNNEOS, ACAM2000, VIGIV) and antiviral drugs/inhibitors (Tecovirimat, Cidofovir, Brincidofovir). Taken together, with a revised perspective of HMPX re-emergence, the present report summarizes new knowledge on its prevalence, pathology, and prevention strategies.

CRISPR-Cas9 in Alzheimer's disease: Therapeutic trends, modalities, and challenges.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no known cure, which has prompted the exploration of novel therapeutic approaches. The clustered regularly interspaced palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) tool has generated significant interest for its potential in AD therapeutics by correcting faulty genes. Our report comprehensively reviews emerging applications for CRISPR-Cas9 in developing in vitro and in vivo models for AD research and therapeutics. We further assess its ability to identify and validate genetic markers and potential therapeutic targets for AD. Moreover, we review the current challenges and delivery strategies for the in vivo application of CRISPR-Cas9 in AD therapeutics.

Shatavarin-IV saponin adjuvant elicits IgG and IgG2b responses against Staphylococcus aureus bacterin in a murine model.

Asparagus adscendens Roxb. also known as "safed musli" or "shatavari" is a medicinal plant commonly found in South Asian countries. Shatavari is effective for the treatment of gastric ulcers, renal stones, bronchitis, diabetes, diabetic neuropathy, irritable bowel syndrome, alcohol withdrawal and has reported immunostimulatory effects. In this study, the adjuvant potential of Shatavarin-IV saponin against Staphylococcus aureus bacterin in mice was investigated. Shatavarin-IV was evaluated for its toxicity and immunomodulatory potential against S. aureus bacterin in mice. Cellular and humoral immune responses were assessed. Shatavarin-IV was isolated from the fruit extract of Asparagus adscendens. The confirmation of the isolated molecule as Shatavarin-IV was done via TLC-based comparison with the standard molecule. Further, the structure was confirmed by using extensive spectroscopic analyses and comparing the observed data with literature reports. It was found safe up to the dose of 0.1 mg in the mice model. Shatavarin-IV adjuvant elicited IgG and IgG2b responses at the dose of 40 µg against S. aureus bacterin. However, the cell-mediated immune response was lesser as compared with the commercial Quil-A saponin . We demonstrated that Shatavarin-IV saponin adjuvant produced an optimum humoral immune response against S. aureus bacterin. These results highlight the potential of Shatavarin-IV as an adjuvant in a combination adjuvant in vaccine formulations for induction of potent immune response.

Evaluation of immunological adjuvant activities of saponin rich fraction from the fruits of Asparagus adscendens Roxb. with less adverse reactions.

The hemolytic activity, in vitro as well as in vivo toxicity, and immunomodulatory potential of saponins-rich fraction of Asparagus adscendens Roxb. fruit (AA-SRF) have been assessed in this study in order to explore AA-SRF as an alternative safer adjuvant to standard Quil-A saponin. The AA-SRF showed lower hemolytic activity (HD50 = 301.01 ± 1.63 µg/ml) than Quil-A (HD50 = 17.15 ± 2.12 µg/ml). The sulforhodamine B assay also revealed that AA-SRF was less toxic to VERO cells (IC50≥200 ± 4.32 µg/ml) than Quil-A (IC50 = 60 ± 2.78 µg/ml). The AA-SRF did not lead to mortality in mice up to 1.6 mg and was much safer than Quil-A for in vivo use. Conversely, mice were subcutaneously immunized with OVA 100 µg alone or along with Alum (200 µg) or Quil-A (10 µg) or AA-SRF (50 µg/100 µg/200 µg) on days 0 and 14. The AA-SRF at 100 µg dose best supported the LPS/Con A primed splenocyte proliferation activity, elevated the serum OVA-specific total IgG antibody, IL-12, CD4 titer and upsurged CD3/CD19 expression in spleen as well as lymph node sections which in turn advocated its adjuvant potential. Thus, AA-SRF can be further studied for use as a safe alternative adjuvant in vaccines.

Role of butyrogenic Firmicutes in type-2 diabetes.

Objective: The aim of this review is to speculate the pre-clinical and clinical evidences indicating the association between butyrate-synthesizing firmicutes and development and progression of type 2 diabetes mellitus. Methodology: Literature was searched using 'Google Scholar' and 'PubMed' to find out most relevant articles for the scope of this review. Information was also gathered from authentic sources such as the World Health Organisation and the International Diabetes Federation. Results: Evidences suggest that an abnormal perturbation in the gut microbiome characterized by subsided levels of butyrate-producing bacteria may gradually result in the progression of type-2 diabetes; however, the explicit mechanisms underlying and implicating the role of specific butyrate-producing microbes remain unclear. Conclusions: This review explicitly summarizes the role of butyrate-synthesizing firmicutes known to be reduced in the subjects with type-2 diabetes mellitus in host metabolic health and contemplates the putative and reported mechanisms underlying its implication in the pathophysiology of type-2 diabetes mellitus.

Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress.

Increasing evidence suggests that abnormal cerebral glucose metabolism is largely present in Alzheimer's disease (AD). The brain utilizes glucose as its main energy source and a decline in its metabolism directly reflects on brain function. Weighing on recent evidence, here we systematically assessed the aberrant glucose metabolism associated with amyloid beta and phosphorylated tau accumulation in AD brain. Interlink between insulin signaling and AD highlighted the involvement of the IRS/PI3K/Akt/AMPK signaling, and GLUTs in the disease progression. While shedding light on the mitochondrial dysfunction in the defective glucose metabolism, we further assessed functional consequences of AGEs (advanced glycation end products) accumulation, polyol activation, and other contributing factors including terminal respiration, ROS (reactive oxygen species), mitochondrial permeability, PINK1/parkin defects, lysosome-mitochondrial crosstalk, and autophagy/mitophagy. Combined with the classic plaque and tangle pathologies, glucose hypometabolism with acquired insulin resistance and mitochondrial dysfunction potentiate these factors to exacerbate AD pathology. To this end, we further reviewed AD and DM (diabetes mellitus) crosstalk in disease progression. Taken together, the present work discusses the emerging role of altered glucose metabolism, contributing impact of insulin signaling, and mitochondrial dysfunction in the defective cerebral glucose utilization in AD.

Corrigendum to "Cholesterol-Lowering Probiotics as Potential Biotherapeutics for Metabolic Diseases".

[This corrects the article DOI: 10.1155/2012/902917.].

Podophyllum hexandrum and its active constituents: Novel radioprotectants.

Human exposure to radiation has expanded considerably in recent years, due to a wide range of medical, agricultural, and industrial applications. Despite its beneficial utilities, radiation is also known to have a deleterious effect on cells and tissues, largely through the creation of free radicals, which cause severe damage to biological systems through processes such as DNA double/single-strand fragmentation, protein modification, and upregulation of lipid peroxidation pathways. In addition, radiation damages genetic material while inducing hereditary genotoxicity. Developing measures to counter radiation-induced damage is thus considered to be of significant importance. Considering the inherent capability of plants to survive radiative conditions, certain plants and natural compounds have been the subject of investigations to explore and harness their natural radioprotective abilities. Podophyllum hexandrum, an Indian medicinal plant with several known traditional phytotherapeutic uses, is considered in particular to be of immense therapeutic importance. Recent studies have been conducted to validate its radioprotective potential alongside discovering its protective mechanisms following γ-radiation-induced mortality and disorder in both mice and human cells. These findings show that Podophyllum and its constituents/natural compounds protect the lungs, gastrointestinal tissues, hemopoietic system, and testis by inducing DNA repair pathways, apoptosis inhibition, free radical scavenging, metal chelation, anti-oxidation and anti-inflammatory mechanisms. In this review, we have provided an updated, comprehensive summary of ionizing radiations and their impacts on biological systems, highlighting the mechanistic and radioprotective role of natural compounds from Podophyllum hexandrum.

Stem cells-derived in vitro meat: from petri dish to dinner plate.

Sustainable food supply to the world is possibly the greatest challenge that human civilization has ever faced. Among animal sourced foods, meat plays a starring role in human food chain. Traditional meat production necessitates high proportion of agricultural land, energy and clean water for rearing meat-producing animals; also massive emission of greenhouse gases from the unutilized nutrients of the digestive process into the environment is a major challenge to the world. Also, conventional meat production is associated with evolution and spread of superbugs and zoonotic infections. In vitro meat has the potential to provide a healthy alternative nutritious meal and to avoid the issues associated with animal slaughtering and environmental effects. Stem cell technology may provide a fascinating approach to produce meat in an animal-free environment. Theoretically, in vitro meat can supplement the meat produced by culling the animals and satisfy the global demand. This article highlights the necessity and potential of stem cell-derived in vitro meat as an alternative source of animal protein vis-a-vis the constraints of conventional approaches of meat production.

Non-alcoholic fatty liver disease: correlation with hyperuricemia in a European Mediterranean population.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are two pathologies that intersect each other. It was found that there is an association between MetS/NAFLD and hyperuricemia. The aim of our study was to demonstrate this association in a European Mediterranean population. METHODS: We compared 236 patients with NAFLD to 218 patients without NAFLD. We assessed laboratory metabolic parameters (serum uric acid - SUA, fasting glucose, triglycerides, total cholesterol, etc.) and the presence or absence of MetS in a retrospective, cross-sectional, case-control manner. RESULTS: Analysis of the two main variables in study showed a moderate direct correlation (p< 0.01; Pearson coefficient 0.443) between SUA and NAFLD. Evaluation for SUA quartiles showed a decreased risk of NAFLD for the first and second quartiles (OR Q1 = 0.20; OR Q2 = 0.59), but increased for the third and fourth quartiles (OR Q3 = 2.22; OR Q4 = 6.97). In females, the risk of NAFLD was less compared to males for the first three quartiles of SUA, but it was more than double for the fourth quartile (OR Q1 0.21 vs 0.16; OR Q2 0.82 vs 0.45; OR Q3 2.50 vs 2.26; OR Q4 4.50 vs 9.83). In the NAFLD group, hyperuricemia was significantly correlated with sex, obesity, hypertension, and with the number of components of the MetS. In the Control group, SUA directly correlated with age, diabetes, and ALT, but not with obesity. CONCLUSION: We have found a significant correlation between NAFLD and hyperuricemia. The higher SUA levels accompanied the risk of NAFLD.

Cell Transdifferentiation and Reprogramming in Disease Modeling: Insights into the Neuronal and Cardiac Disease Models and Current Translational Strategies.

Cell transdifferentiation and reprogramming approaches in recent times have enabled the manipulation of cell fate by enrolling exogenous/artificial controls. The chemical/small molecule and regulatory components of transcription machinery serve as potential tools to execute cell transdifferentiation and have thereby uncovered new avenues for disease modeling and drug discovery. At the advanced stage, one can believe these methods can pave the way to develop efficient and sensitive gene therapy and regenerative medicine approaches. As we are beginning to learn about the utility of cell transdifferentiation and reprogramming, speculations about its applications in translational therapeutics are being largely anticipated. Although clinicians and researchers are endeavoring to scale these processes, we lack a comprehensive understanding of their mechanism(s), and the promises these offer for targeted and personalized therapeutics are scarce. In the present report, we endeavored to provide a detailed review of the original concept, methods and modalities enrolled in the field of cellular transdifferentiation and reprogramming. A special focus is given to the neuronal and cardiac systems/diseases towards scaling their utility in disease modeling and drug discovery.

Mucormycosis in COVID-19 pandemic: Risk factors and linkages.

Mucormycosis is a serious and potentially fatal fungal infection caused by a type of rare but opportunistic fungal pathogen called mucormycetes. Recently, mucormycosis, also known as black fungus, made severe chaos in India during the second wave (between April and June 2021) of the tragical COVID-19 epidemic by its sudden and devastating surge with up to 50% mortality rate. While the exact cause of its sharp rise suddenly and specifically during the second wave still remains debatable, it has been noted that the people who are diabetic and have recovered from COVID-19 infection are more predisposed to mucormycosis. Nevertheless, the precise reason and mechanism(s) underlying the surge of this deadly infection needs to be investigated to comprehend its pathogenesis and pathological elements and discover rationale preventative/ therapeutic solutions. It is speculated that the indiscriminate use of steroids, antibiotics and zinc as a self-medication practice that increased during the COVID-19 epidemic may have promoted the dysbiosis of gut microbiota thereby inducing immune-suppression and making the risk group highly susceptible to this mycotic disease. In these contexts, this timely article attempts to contemplate and discuss some of the possible factors and potential mechanisms that can help to understand and explain the conundrum of sudden, steep and deadly upsurge of mucormycosis infections during the second wave of COVID-19 epidemic.

Pan-proteome profiling of emerging and re-emerging zoonotic pathogen Orientia tsutsugamushi for getting insight into microbial pathogenesis.

With the occurrence and evolution of antibiotic and multidrug resistance in bacteria most of the existing remedies are becoming ineffective. The pan-proteome exploration of the bacterial pathogens helps to identify the wide spectrum therapeutic targets which will be effective against all strains in a species. The current study is focused on the pan-proteome profiling of zoonotic pathogen Orientia tsutsugamushi (Ott) for the identification of potential therapeutic targets. The pan-proteome of Ott is estimated to be extensive in nature that has 1429 protein clusters, out of which 694 were core, 391 were accessory, and 344 were unique. It was revealed that 622 proteins were essential, 222 proteins were virulent factors, and 42 proteins were involved in antibiotic resistance. The potential therapeutic targets were further classified into eleven broad classes among which gene expression and regulation, transport, and metabolism were dominant. The biological interactome analysis of therapeutic targets revealed that an ample amount of interactions were present among the proteins involved in DNA replication, ribosome assembly, cellwall metabolism, cell division, and antimicrobial resistance. The predicted therapeutic targets from the pan-proteome of Ott are involved in various biological processes, virulence, and antibiotic resistance; hence envisioned as potential candidates for drug discovery to combat scrub typhus.

COVID-19, Neuropathology, and Aging: SARS-CoV-2 Neurological Infection, Mechanism, and Associated Complications.

The spectrum of health complications instigated by coronavirus disease 2019 (COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) pandemic has been diverse and complex. Besides the evident pulmonary and cardiovascular threats, accumulating clinical data points to several neurological complications, which are more common in elderly COVID-19 patients. Recent pieces of evidence have marked events of neuro infection and neuroinvasion, producing several neurological complications in COVID-19 patients; however, a systematic understanding of neuro-pathophysiology and manifested neurological complications, more specifically in elderly COVID-19 patients is largely elusive. Since the elderly population gradually develops neurological disorders with aging, COVID-19 inevitably poses a higher risk of neurological manifestations to the aged patients. In this report, we reviewed SARS-CoV-2 infection and its role in neurological manifestations with an emphasis on the elderly population. We reviewed neuropathological events including neuroinfection, neuroinvasion, and their underlying mechanisms affecting neuromuscular, central- and peripheral- nervous systems. We further assessed the imminent neurological challenges in the COVID-19 exposed population, post-SARS-CoV-2-infection. Given the present state of clinical preparedness, the emerging role of AI and machine learning was also discussed concerning COVID-19 diagnostics and its management. Taken together, the present review summarizes neurological outcomes of SARS-CoV-2 infection and associated complications, specifically in elderly patients, and underlines the need for their clinical management in advance.

Urine Cells-derived iPSCs: An Upcoming Frontier in Regenerative Medicine.

There is a momentous surge in the development of stem cell technology, such as therapeutic and diagnostic tools. Stem cell-derived cells are currently used in various clinical trials. However, key issues and challenges faced involve the low differentiation efficiency, integration and functioning of transplanted stem cells-derived cells. Extraction of bone marrow, adipose or other mesenchymal stem cells (MSCs) involves invasive methods, specialized skills and expensive technologies. Urine-derived cells, on the other hand, are obtained by non-invasive methods; samples can be obtained repeatedly from patients of any age. Urine-derived cells are used to generate reprogrammed or induced pluripotent stem cells (iPSCs) which can be cultured and differentiated into various types of cell lineages for biomedical investigations and drug testing in vitro or in vivo using model animals of human diseases. Urine cells-derived iPSCs (UiPSCs) have emerged as a major area of research having immense therapeutic significance. Given that preliminary preclinical studies are successful in terms of safety and as a regenerative tool, the UiPSCs will pave the way to the development of various types of autologous stem cell therapies.

Stem cell therapies and benefaction of somatic cell nuclear transfer cloning in COVID-19 era.

BACKGROUND: The global health emergency of COVID-19 has necessitated the development of multiple therapeutic modalities including vaccinations, antivirals, anti-inflammatory, and cytoimmunotherapies, etc. COVID-19 patients suffer from damage to various organs and vascular structures, so they present multiple health crises. Mesenchymal stem cells (MSCs) are of interest to treat acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 infection. MAIN BODY: Stem cell-based therapies have been verified for prospective benefits in copious preclinical and clinical studies. MSCs confer potential benefits to develop various cell types and organoids for studying virus-human interaction, drug testing, regenerative medicine, and immunomodulatory effects in COVID-19 patients. Apart from paving the ways to augment stem cell research and therapies, somatic cell nuclear transfer (SCNT) holds unique ability for a wide range of health applications such as patient-specific or isogenic cells for regenerative medicine and breeding transgenic animals for biomedical applications. Being a potent cell genome-reprogramming tool, the SCNT has increased prominence of recombinant therapeutics and cellular medicine in the current era of COVID-19. As SCNT is used to generate patient-specific stem cells, it avoids dependence on embryos to obtain stem cells. CONCLUSIONS: The nuclear transfer cloning, being an ideal tool to generate cloned embryos, and the embryonic stem cells will boost drug testing and cellular medicine in COVID-19.

Migratory Gaddi sheep and goats as potential carriers of Theileria infection: a molecular survey.

Theileriosis caused by parasites of the genus Theileria, is a vector-borne haemoprotozoan parasitic disease of critical concern in small ruminants. This study aimed to explore the infection status of migratory Gaddi sheep and goats with parasites from the Theileria genus in concurrence with ectoparasite infestations using molecular methods. Seventy three apparently healthy animals were randomly sampled from different flocks of migratory Gaddi sheep and goats and were systematically screened for ectoparasitic infestations. Molecular investigation for theileriosis was conducted using the genus wide polymerase chain reaction (PCR) technique. Out of 56 (76.71%) animals positive for the genus Theileria, 2 randomly selected amplicons were sequenced and subjected to BLAST analysis and were showing 99.71% identity with Theileria luwenshuni, a pathogenic Theileria species of small ruminants. To confirm the presence of T. luwenshuni, species-specific PCR was attempted to identify that 38 (52.05%) animals were infected by T. luwenshuni. On analysing the molecular prevalence data of Theileria to the ectoparasitism, it was evident that the infection existed in the animals irrespective of the type of ectoparasitic infestation and even T. luwenshuni was found in non-infested animals also. This is the first report of subclinical infections of T. luwenshuni in sheep and goats of Northern India and its potential carrier status. The asymptomatic carrier status of these nomadic animals is a matter possessing serious implications on the disease transmission rates and the production economics of small ruminant production in this region.

Futuristic Non-antibiotic Therapies to Combat Antibiotic Resistance: A Review.

The looming problem of resistance to antibiotics in microorganisms is a global health concern. The drug-resistant microorganisms originating from anthropogenic sources and commercial livestock farming have posed serious environmental and health challenges. Antibiotic-resistant genes constituting the environmental "resistome" get transferred to human and veterinary pathogens. Hence, deciphering the origin, mechanism and extreme of transfer of these genetic factors into pathogens is extremely important to develop not only the therapeutic interventions to curtail the infections, but also the strategies to avert the menace of microbial drug-resistance. Clinicians, researchers and policymakers should jointly come up to develop the strategies to prevent superfluous exposure of pathogens to antibiotics in non-clinical settings. This article highlights the present scenario of increasing antimicrobial-resistance in pathogenic bacteria and the clinical importance of unconventional or non-antibiotic therapies to thwart the infectious pathogenic microorganisms.

Irritable bowel syndrome and lactose intolerance: the importance of differential diagnosis. A monocentric study.

BACKGROUND: Nowadays irritable bowel syndrome (IBS) and lactose intolerance (LI) are two very frequent diseases. IBS is a functional disorder, while LI is caused by the inability to digest lactose. LI is often incorrectly diagnosed as IBS. The aim of our study is to identify LI patients among IBS patients, so as to set up a correct therapy. METHODS: We enrolled 259 patients with IBS and we compared them to a control group of 108 patients. All patients underwent H2 Breath-Test (HBT) and two questionnaires regarding the symptoms associated with IBS and LI were administered to the intolerant subjects and one questionnaire to IBS patients with no LI. RESULTS: At the HBT, 79.9% (N.=207) of patients with IBS were positive, while in the control group were positive 25.0% (N.=27) of subjects (P<0.001). The questionnaires showed, after a month of therapy, a marked improvement in LI symptoms subjects. In addition, there was also a prevalence of more severe symptoms among subjects with IBS and LI than those with IBS and no LI. CONCLUSIONS: We can affirm that most patients with initial diagnosis of IBS are, instead, lactose intolerant. This diagnosis allows us to undertake an adequate therapy so as to improve symptoms and quality of life. Therefore it is important to include LI in the pathologies with which IBS enters into differential diagnosis.