The role of interleukin-10 receptor alpha (IL10Rα) in Mycobacterium avium subsp. paratuberculosis infection of a mammary epithelial cell line.

BACKGROUND: Johne's disease is a chronic wasting disease caused by the bacterium Mycobacterium avium subspecies paratuberculosis (MAP). Johne's disease is highly contagious and MAP infection in dairy cattle can eventually lead to death. With no available treatment for Johne's disease, genetic selection and improvements in management practices could help reduce its prevalence. In a previous study, the gene coding interleukin-10 receptor subunit alpha (IL10Rα) was associated with Johne's disease in dairy cattle. Our objective was to determine how IL10Rα affects the pathogenesis of MAP by examining the effect of a live MAP challenge on a mammary epithelial cell line (MAC-T) that had IL10Rα knocked out using CRISPR/cas9. The wild type and the IL10Rα knockout MAC-T cell lines were exposed to live MAP bacteria for 72 h. Thereafter, mRNA was extracted from infected and uninfected cells. Differentially expressed genes were compared between the wild type and the IL10Rα knockout cell lines. Gene ontology was performed based on the differentially expressed genes to determine which biological pathways were involved. RESULTS: Immune system processes pathways were targeted to determine the effect of IL10Rα on the response to MAP infection. There was a difference in immune response between the wild type and IL10Rα knockout MAC-T cell lines, and less difference in immune response between infected and not infected IL10Rα knockout MAC-T cells, indicating IL10Rα plays an important role in the progression of MAP infection. Additionally, these comparisons allowed us to identify other genes involved in inflammation-mediated chemokine and cytokine signalling, interleukin signalling and toll-like receptor pathways. CONCLUSIONS: Identifying differentially expressed genes in wild type and ILR10α knockout MAC-T cells infected with live MAP bacteria provided further evidence that IL10Rα contributes to mounting an immune response to MAP infection and allowed us to identify additional potential candidate genes involved in this process. We found there was a complex immune response during MAP infection that is controlled by many genes.

Alginate based biomaterials for hemostatic applications: Innovations and developments.

Development of the efficient hemostatic materials is an essential requirement for the management of hemorrhage caused by the emergency situations to avert most of the casualties. Such injuries require the use of external hemostats to facilitate the immediate blood clotting. A variety of commercially available hemostats are present in the market but most of them are associated with limitations such as exothermic reactions, low biocompatibility, and painful removal. Thus, fabrication of an ideal hemostatic composition for rapid blood clot formation, biocompatibility, and antimicrobial nature presents a real challenge to the bioengineers. Benefiting from their tunable fabrication properties, alginate-based hemostats are gaining importance due to their excellent biocompatibility, with >85 % cell viability, high absorption capacity exceeding 500 %, and cost-effectiveness. Furthermore, studies have estimated that wounds treated with sodium alginate exhibited a blood loss of 0.40 ± 0.05 mL, compared to the control group with 1.15 ± 0.13 mL, indicating its inherent hemostatic activity. This serves as a solid foundation for designing future hemostatic materials. Nevertheless, various combinations have been explored to further enhance the hemostatic potential of sodium alginate. In this review, we have discussed the possible role of alginate based composite hemostats incorporated with different hemostatic agents, such as inorganic materials, polymers, biological agents, herbal agents, and synthetic drugs. This article outlines the challenges which need to be addressed before the clinical trials and give an overview of the future research directions.

Chronic Nonhealing Wound Due To Iatrogenic Foreign Body- A Case Report.

A 5-year-old male child presented with nonhealing wound on the left scapular region. He had a history of multiple abscesses 8 months back. Incision and drainage were done for all abscesses in the same sitting at another hospital. All wounds healed except one of the scapular regions. The wound was explored and there was large cotton gauze inside the wound. The common causes of nonhealing of wound are tuberculosis, malignancy, and immunodeficiency. However, iatrogenic foreign body is also an important cause and should be considered in differential diagnosis. Careful history, wound examination, and radiological investigations are an important tool for diagnosis of retained foreign bodies. The scientific term for the retained foreign body is gossypiboma or textiloma.

A review of botany, traditional applications, phytochemistry, pharmacological applications, and toxicology of Rubus ellipticus Smith fruits.

Rubus ellipticus Smith. (Family Rosaceae), often known as the yellow Himalayan raspberry (Yellow Hissar), is one of the most widely used edible fruits in Indian folk medicinal systems. The current review aims to identify the gap between research and existing applications of this fruit to help scientists explore the current trends and opportunities for future development. Fruits of R. ellipticus are the source of several classes of compounds. Fruits of R. ellipticus are also rich in nutrients such as carbohydrates, vitamins, and minerals. It has been shown to have significant medical value in a variety of studies, including as an anti-diabetic, nephroprotective, anti-inflammatory, analgesic, antipyretic, antitumor, wound healing, antifertility, oviposition deterrent, antibacterial, and antioxidant. Fruits of R. ellipticus have been the subject of several in vitro and in vivo investigations, all of which have corroborated their wide range of biological activities and demonstrated their potential for the identification of new therapeutic candidates and the development of innovative herbal food supplements. Additional mechanism-based pharmacological evaluation and clinical research should provide an adequate scientific basis for the traditional usage of R. ellipticus fruits, which is currently not sufficiently supported by the available research on its active components and molecular mechanisms.

Chitosan/alginate nanogel potentiate berberine uptake and enhance oxidative stress mediated apoptotic cell death in HepG2 cells.

Biopolymer-based nanoscale drug delivery systems have become a promising approach to overcome the limitations associated with conventional chemotherapeutics used for cancer treatment. Herein, we reported to develop a hydrophilic nanogel (NG) composed of Chitosan (Chi) and sodium alginate (Alg) using the ion gelation method for delivering Berberine hydrochloride (BBR), an alkaloid obtained from Berberis aristata roots. The use of different nanocarriers for BBR delivery has been reported previously, but the bioavailability of these carriers was limited due to phagocytic uptake and poor systemic delivery. The developed NG showed enhanced stability and efficient entrapment of BBR ∼92 %, resulting in a significant increase in bioavailability. The pH-dependent release behavior demonstrated sustained and effective release of ∼86 %, ∼74 % and, ∼53 % BBR at pH 5.5, 6.6, and 7.4 respectively after 72h, indicating its potential as a drug carrier. Additionally, the cellular uptake of BBR was significantly higher ∼19 % in the BBR-NG (25 µM) than in bulk BBR (100 µM), leading to enhanced ROS generation, mitochondrial depolarisation, and inhibition of cell proliferation and colony formation in HepG2 cells. In summary, the results suggest that the Chi/Alg biopolymer-based nano-formulation could be an effective approach for delivering BBR and enhancing its cellular uptake, efficacy, and cytotoxicity.

Potential involvement of ferroptosis in BPA-induced neurotoxicity: An in vitro study.

BACKGROUND: Ferroptosis is a newly recognized cell death pathway having distinct characteristics compared to traditional cell death pathways such as apoptosis, necroptosis, or autophagy. However, the potential involvement of ferroptosis in bisphenol A (BPA)-induced neurotoxicity has not been well explored so far. In present study, we analyzed the relationship between ferroptosis and BPA-induced neurotoxicity. METHODS: In this study, a human neuroblastoma cell line, SH-SY5Y, was treated with BPA, ferrostatin-1 (FS-1, ferroptosis inhibitor) and RSL-3 (ferroptosis inducer). The cell viability was measured using MTT assay. Additionally, the levels of lipid peroxidation, total iron content, reactive oxygen species (ROS) generation, and nitrite content were measured to evaluate the key markers of ferroptosis. To further confirm the involvement of ferroptosis in BPA-induced neurotoxicity, other ferroptosis markers such as glutathione peroxidase (GPx) activity, total glutathione contents and antioxidant parameters were also evaluated. RESULTS: The cell viability of SH-SY5Y cells was down-regulated by BPA treatment in a concentration-dependent manner, the cell viability at 0.1 µM concentration was 97.63% whereas at highest BPA concentration i.e. 10 µM, the cell viability was 86.05% (p < 0.0001). Also the antioxidant parameters including catalase and superoxide dismutase activity of neuronal cells were down-regulated upon BPA exposure. However, the levels of lipid peroxidation, total iron, reactive oxygen species, and nitrite contents were increased in a concentration-dependent manner which could be rescued by FS-1 and exacerbated by RSL-3. The total iron in SH-SY5Y cells at 0.1 µM concentration was found to be 1.2 fold (p < 0.05) of control and at highest BPA concentration total iron was about 1.41 fold (p < 0.001) of control. CONCLUSIONS: The present study indicated that, ferroptosis plays an important role in the progression of BPA-induced neurotoxicity, and ferroptosis may become a novel target in the treatment of various neurological disorders.

Evaluation of Immunomodulatory Effects of Fusarium Mycotoxins Using Bacterial Endotoxin-Stimulated Bovine Epithelial Cells and Macrophages in Co-Culture.

Mycotoxins are secondary metabolites produced by a variety of fungi that contaminate animal food and feeds and are capable of inducing a wide range of toxicities. Predictive in vitro models represent valuable substitutes for animal experiments to assess the toxicity of mycotoxins. The complexities of the interactions between epithelial and innate immune cells, vital for upholding barrier integrity and averting infections, remain inadequately understood. In the current study, a co-culture model of bovine epithelial cells (MAC-T) and macrophages (BoMac) was used to investigate the impact of exposure to Fusarium mycotoxins, namely deoxynivalenol (DON), zearalenone (ZEN), enniatin B (ENB), and beauvericin (BEA), on the inflammatory response elicited by the bacterial lipopolysaccharide (LPS) endotoxin. The MAC-T cells and BoMac were seeded on the apical side of a Transwell membrane and in the lower chamber, respectively, and mycotoxin exposure on the apical side of the membrane was carried out with the different mycotoxins (LC20; concentrations that elicited 20% cytotoxicity) for 48 h followed by an LPS immunity challenge for 24 h. The culture supernatants were collected from the basolateral compartment and these samples were submitted for cytokine/chemokine multiplex analysis. RNA-Seq analysis was performed using total RNA extracted from the MAC-T cells to acquire a more detailed insight into their cellular functions. The multiplex analysis indicated that IFN-γ, IL-1α, IL-8, and MCP-1 were significantly induced post-DON treatment when compared to control cells, and levels of IL-1α and IL-8 were enhanced significantly in all mycotoxin-treated groups post-LPS challenge. Analysis of the sequencing results showed that there were 341, 357, and 318 differentially expressed MAC-T cell genes that were up-regulated in the DON, ENB, and BEA groups, respectively. Gene ontology and pathway analysis revealed that these DEGs were significantly enriched in various biological processes and pathways related to inflammation, apoptosis signaling, and Wnt signaling. These results provide a comprehensive analysis of the co-culture cytokine/chemokine production and MAC-T cells' gene expression profiles elicited by Fusarium mycotoxins, which further contributes to the understanding of early endotoxemia post-mycotoxin exposure.

Prognostic Nomogram for Lymph-Node Metastasis in Oral Squamous Cell Carcinoma (OSCC) Using Immunohistochemical Marker D2-40.

Introduction: Nomograms are proven in "individualized risk prediction" in sarcomas and breast and prostate cancers. Incorporating immunohistochemical markers and histopathological parameters can enhance accuracy of these graphical representations of statistical predictive models concerning metastasis. D2-40, a monoclonal antibody to podoplanin (regulator of motility expressed in malignant epithelial cells), dually predicts metastatic potential of tumour by estimating the motile tumour phenotype and by detecting lymphatic vessels/density, both essential to metastasis in OSCC. Thus, we propose a model that incorporates D2-40 immunostaining of individual tumour cells (ITC) too with other variables (seen in H+E staining) as a predictive nomogram. Methods: Sixty cases of OSCC were selected with equal number of cases (n=30) of pN0 and pN+ status. Bryne's grading of invasive front of tumour (ITF) was done on H+E-stained slides followed by D2-40 immunostaining for ITCs at ITF and lymphatic vessels. Multivariate regression analysis was used to generate the nomogram of LNM where the predictive contribution of each covariate, namely depth of invasion, D2-40-stained ITCs, gender, histological grade, and worst pattern of invasion (WPOI), was plotted on a scale of 1-100 points. Results: The nomogram showed that the strongest variable in OSCC was the WPOI in H+E-stained section followed by D2-40-positive ITCs and gender. Discussion: Our predictive nomogram for LNM in OSCC surprisingly showed that a tumour with lower score of WPOI (islands vs ITC) showed numerous D2-40-positive ITCs, drastically increasing the probability of metastasis. The concept of "individualized risk prediction" can be used to predict lymph node metastasis using a variety of histopathological criteria that can be visualized in routine and immunohistochemical staining in OSCC with the aid of a nomogram.

A systematic in silico report on iron and zinc proteome of Zea mays.

Zea mays is an essential staple food crop across the globe. Maize contains macro and micronutrients but is limited in essential mineral micronutrients such as Fe and Zn. Worldwide, serious health concerns have risen due to the deficiencies of essential nutrients in human diets, which rigorously jeopardizes economic development. In the present study, the systematic in silico approach has been used to predict Fe and Zn binding proteins from the whole proteome of maize. A total of 356 and 546 putative proteins have been predicted, which contain sequence and structural motifs for Fe and Zn ions, respectively. Furthermore, the functional annotation of these predicted proteins, based on their domains, subcellular localization, gene ontology, and literature support, showed their roles in distinct cellular and biological processes, such as metabolism, gene expression and regulation, transport, stress response, protein folding, and proteolysis. The versatile roles of these shortlisted putative Fe and Zn binding proteins of maize could be used to manipulate many facets of maize physiology. Moreover, in the future, the predicted Fe and Zn binding proteins may act as relevant, novel, and economical markers for various crop improvement programs.

Enhancing Functional Ability in Chronic Nonspecific Lower Back Pain: The Impact of EMG-Guided Trunk Stabilization Exercises.

BACKGROUND: Nonspecific lower back pain (NSLBP) is described as pain that is not caused by an identifiable, well-known disease, such as infection, tumor, osteoporosis, fracture, structural deformity, inflammatory condition, radicular syndrome, or cauda equina syndrome. AIM: The aim of this study was to determine the effect of EMG-guided trunk stabilization exercises on functional disability associated with LBP. MATERIALS AND METHODS: A single-blinded pre- and post-test experimental comparative design was used for this study. Fifty individuals with chronic NSLBP were screened for inclusion criteria. Of these, forty were randomly grouped into the EMG group receiving trunk-stability exercises with electromyography biofeedback and non-EMG group receiving trunk-stabilization exercises without EMG biofeedback. Participants performed five trunk-stability exercises 3 days a week for 4 weeks. The intensity of pain, range of motion, functional disability, and balance were measured at baseline and after 4 weeks. RESULTS: Both techniques indicated a significant effect on chronic NSLBP; however, trunk-stability exercises combined with EMG biofeedback produced better results in alleviating the intensity of pain, increasing the range of motion, and improving functional disabilities and static balance. CONCLUSION: The present study confirms that trunk-stability exercises with EMG biofeedback can be practiced safely, contributes to a greater boost in neuromuscular efficiency in the lumbar flexors and extensors, and is effective in modifying functional disability for patients with NSLBP.

AMP-activated protein kinase: An energy sensor and survival mechanism in the reinstatement of metabolic homeostasis.

Cells are programmed to favorably respond towards the nutrient availability by adapting their metabolism to meet energy demands. AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine energy-sensing kinase. It gets activated upon a decrease in the cellular energy status as reflected by an increased AMP/ATP ratio, ADP, and also during the conditions of glucose starvation without change in the adenine nucelotide ratio. AMPK functions as a centralized regulator of metabolism, acting at cellular and physiological levels to circumvent the metabolic stress by restoring energy balance. This review intricately highlights the integrated signaling pathways by which AMPK gets activated allosterically or by multiple non-canonical upstream kinases. AMPK activates the ATP generating processes (e.g., fatty acid oxidation) and inhibits the ATP consuming processes that are non-critical for survival (e.g., cell proliferation, protein and triglyceride synthesis). An integrated signaling network with AMPK as the central effector regulates all the aspects of enhanced stress resistance, qualified cellular housekeeping, and energy metabolic homeostasis. Importantly, the AMPK mediated amelioration of cellular stress and inflammatory responses are mediated by stimulation of transcription factors such as Nrf2, SIRT1, FoxO and inhibition of NF-κB serving as main downstream effectors. Moreover, many lines of evidence have demonstrated that AMPK controls autophagy through mTOR and ULK1 signaling to fine-tune the metabolic pathways in response to different cellular signals. This review also highlights the critical involvement of AMPK in promoting mitochondrial health, and homeostasis, including mitophagy. Loss of AMPK or ULK1 activity leads to aberrant accumulation of autophagy-related proteins and defective mitophagy thus, connecting cellular energy sensing to autophagy and mitophagy.

Editing of HSF-1 and Na/K-ATPase α1 subunit by CRISPR/Cas9 reduces thermal tolerance of bovine skin fibroblasts to heat shock in vitro.

A follow-up to our previous findings, the present study was planned to evaluate the role of Na/K-ATPase alpha1-subunit (ATP1A1) gene in heat shock tolerance. The primary fibroblast culture was established using ear pinna tissue samples of Sahiwal cattle (Bos indicus). The knockout cell lines of Na/K-ATP1A1 and HSF-1 (heat shock factor-1, as a positive control) genes were developed by CRISPR/Cas9 method and the gene-editing was confirmed by the genomic cleavage detection assay. The two knockout cell lines (ATP1A1 and HSF-1) and wild-type fibroblasts were exposed to heat shock at 42 °C in vitro and different cellular parameters viz., apoptosis, proliferation, mitochondrial membrane potential (ΔΨm), oxidative stress, along with expression pattern of heat-responsive genes were studied. The results showed that in vitro heat shock given to knockout fibroblast cells of both ATP1A1 and HSF-1 genes resulted in decreased cell viability, while increasing the apoptosis rate, membrane depolarization, and ROS levels. However, the overall impact was more in HSF-1 knockout cells as compared to ATP1A1 knockout cells. Taken together, these results indicated that the ATP1A1 gene plays a critical role as HSF-1 under heat stress and helps cells to cope with heat shock.

Understanding the mechanistic roles of environmental heavy metal stressors in regulating ferroptosis: adding new paradigms to the links with diseases.

Ferroptosis is a new type of iron-dependent cell death induced by a failure of the lipid repair protein GPX4 or the Xc- antiporter, which is essential for glutathione production. Some heavy metals such as arsenic (As), cobalt (Co), cadmium (Cd), iron (Fe), magnesium (Mg), manganese (Mn), nickel (Ni), mercury (Hg) as well as zinc (Zn) are shown to induce ferroptotic cell death involving the generation of oxidative stress, mitochondrial dysfunctioning, lipid peroxidation, and several other cellular etiologies. However, selenium (Se) treatment has been shown to enhance adaptive transcription responses to protect cells from ferroptosis. Heavy metals like Cadmium exposure activated ALK4/5 signaling via Smad3 and Akt signaling which leads to cell death mechanism. Continuous exposure to a small dose of mercury can damage tissues, and methylmercury bind to sulfhydryl proteins and GSH, this elevates oxidative stress, free radical accumulation, glutathione depletion, mitochondrial damage, and inhibited the nuclear factor-κB pathway which leads to ferroptotic cell death. Animals exposed to nickel and cobalt may have increased lipid peroxidation which can induce ferroptosis. Glutathione depletion is caused by Zn intoxication and exposure to manganese. These metals are systemic toxins that have been shown adverse effects on humans. Ferroptosis has recently been related to several pathological disorders, including, Alzheimer's disease, Parkinson's disease, Huntington's disease, as well as cardiovascular disease, and any type of cancer. For these disorders and some heavy metal toxicity, ferroptosis suppression needs to be looked upon as a promising therapeutic choice.

Silver nanoparticle-induced alteration of mitochondrial and ER homeostasis affects human breast cancer cell fate.

Breast cancer is one of the most frequent forms of cancer. Although different treatment modalities are available, none has proved to be a game-changer. In this context, nanomedicine is one of the hot research areas, with different nano-formulations being explored as a therapeutic strategy against breast cancer. Herein, silver nanoparticles (AgNPs) have shown prospects with their anti-tumor properties and are currently being explored aggressively; however, the underlying molecular mechanisms of AgNP action remain to be unearthed. As part of this study, human breast cancer cells- MCF7 were exposed to AgNPs (∼9 nm), and the effect of the same was explored on mitochondrial and endoplasmic reticulum (ER) dynamicity. We observed that the AgNPs co-localize with mitochondria and cause mitochondrial membrane depolarization, ROS generation, and destabilized mitochondrial homeostasis. Also, the NPs were found to enhance ER stress. We further found that increased ER stress is linked to the disruption of mitochondrial dynamics. Overall, our study shows that the AgNPs can effectively cause apoptosis of MCF-7 cells by regulating the mitochondrial-ER dynamicity. The results provide an insight into the mechanisms via which AgNPs act and can be used in developing a potential chemotherapeutic agent.

Rhinocerebral mucormycosis: a systematic review of case reports and case series from a global perspective.

OBJECTIVE: Rhinocerebral mucormycosis (RCM) is the most common variant and the presenting features in the head and neck region are seldom pathognomonic. The aim of this systematic review was to obtain a thorough insight into the predisposing factors, clinical features, disease course, management protocol, outcome, and prognosis. STUDY DESIGN: An electronic search was carried out using MEDLINE by PubMed, Scopus, Google Scholar, Web of Science, and EMBASE databases. Articles in which the clinical findings on the extra- and intraoral features of RCM were included for systematic review. Descriptive statistics was applied to obtain the results. RESULTS: A total of 124 case studies (90 case reports, 34 case series) which yielded 219 patients. Diabetes mellitus (57.40%) was the most common comorbid condition. Neurologic manifestations were noted in 23.3% of the individuals. Maxillary/hard palate involvement was a common occurrence (59.2%). Intra-oral necrotic lesions with eschar were noted in 75/219 patients. Amphotericin B was the commonly used drug for the management, and surgical debridement was performed in majority of the cases. The mortality rate was 18.4%. CONCLUSIONS: The clinical manifestations often mimic odontogenic symptoms, hence a sound knowledge about the pathogenesis and course of the disease will aid in the prompt diagnosis and management.

The effects of deoxynivalenol-contaminated corn in low-complexity diets supplemented with either an immune-modulating feed additive, or fish oil on nursery pig growth performance, immune response, small intestinal morphology, and component digestibility.

Three hundred twenty newly weaned pigs (21 days of age; 6.7 ± 0.3 kg BW) were used to determine the effects of supplementing low-complexity (LC) deoxynivalenol- (DON) contaminated nursery diets with a feed additive or fish oil on growth performance and immune response to an Escherichia coli lipopolysaccharide (LPS) challenge. Pens were randomly assigned to 1 of 5 dietary treatments (n = 8 pens per treatment): positive control (PC; contained multiple animal protein sources), or 1 of 4 LC diets (contained only plant-based protein sources) without (NC; negative control) or with ~ 3.5 ppm DON contamination, without (DON-) or with a feed additive containing a blend of immune-modulating components (DON+; 2 mg/kg, as-fed) or fish oil (DONω3; 2.5%, as-fed). Dietary treatments were fed during phases I and II (7 and 15 days, respectively) and a common phase III diet was fed for 20 days. On day 22, two pigs per pen were injected IM with 30 µg/kg BW LPS and 1 pig per pen with 1 mL saline. Rectal temperatures were recorded at 0, 1, 2, 3 h after injection. At 3 h, blood was collected for plasma cytokine analysis and small intestinal histomorphology was assessed. In phase I, pigs fed PC and NC did not differ for ADG, ADFI and G:F, but these outcomes were greater than for pigs fed DON+ and DONω (P < 0.05). In phase II, pigs fed NC had greater ADG and PC had greater ADFI but lower G:F than pigs fed DON- and DONω3 (P < 0.05). At the end of phase II, pigs fed DONω3 tended to have lower BW than PC and NC (P = 0.084 and 0.079, respectively). In phase III and overall, there were no differences among dietary treatments for ADG, ADFI, G:F, or final BW. The LPS injection increased rectal temperature and reduced jejunal and ileal villus height (versus saline; P < 0.05). Plasma interferon-γ concentration was only increased by LPS for pigs fed PC, NC, and DON+ compared to the saline-injected counterparts (P < 0.05). Regardless of LPS injection, jejunal villus height was greater for pigs fed DON+ than DONω3 (P < 0.05) and ileal villus height was greater for pigs fed DON+ and PC than DONω3 (P < 0.05). Therefore, nursery diet complexity did not affect growth performance or immune response to LPS. Regardless of DON contamination and feed additive inclusion in phases I and II, pigs were able to achieve nursery exit BW not different from those fed PC. The feed additive offered marginal benefits for small intestinal villus height and immune response for pigs fed DON-contaminated LC nursery diets.

An update on polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease affecting people older than 50 years and is 2-3 times more common in women. The most common symptoms are pain and morning stiffness in the shoulder and pelvic girdle and the onset may be acute or develop over a few days to weeks. General symptoms such as fatigue, fever and weight loss may occur, likely driven by systemic IL-6 signalling. The pathology includes synovial and periarticular inflammation and muscular vasculopathy. A new observation is that PMR may appear as a side effect of cancer treatment with checkpoint inhibitors. The diagnosis of PMR relies mainly on symptoms and signs combined with laboratory markers of inflammation. Imaging modalities including ultrasound, magnetic resonance imaging and positron emission tomography with computed tomography are promising new tools in the investigation of suspected PMR. However, they are still limited by availability, high cost and unclear performance in the diagnostic workup. Glucocorticoid (GC) therapy is effective in PMR, with most patients responding promptly to 15-25 mg prednisolone per day. There are challenges in the management of patients with PMR as relapses do occur and patients with PMR may need to stay on GC for extended periods. This is associated with high rates of GC-related comorbidities, such as diabetes and osteoporosis, and there are limited data on the use of disease-modifying antirheumatic drugs and biologics as GC sparing agents. Finally, PMR is associated with giant cell arteritis that may complicate the disease course and require more intense and prolonged treatment.

Antitumor Activity of Choerospondias axillaris Fruit Extract by Regulating the Expression of SNCAIP and SNCA on MDA-MB-231 Cells.

OBJECTIVE: Cancer is a huge problem of disease globally. Today, the percentage of people die from cancer is more than a combination of various diseases. In females, most common types of malignancies that occur are breast and cervical. The present focus has been shifted on medicinal plants as a form of therapy and there is a constant need to identify new therapeutic agents. Choerospondias axillaris (C. axillaris), an underutilized fruit, has been used in the remedy of various diseases. In the present communication, we evaluated the molecular mechanism of C. axillaris methanol extract in regulating cell death in human breast cancer cells (MDA-MB-231). METHODS: Methanol extract of C. axillaris was prepared and compounds were screened by Gas chromatography-mass spectrometry. The effect of fruit extract was determined on MDA-MB-231 cells by MTT ((3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay and to analyse the molecular mechanism of human breast cancer cells after treating with fruit extract, protein profiling study was performed by two-dimensional gel electrophoresis. RESULTS: A total 9 differentially expressed proteins were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS/MS) analysis. Among 9 identified proteins, synphilin-1 protein was found to be significantly downregulated, validated by western blot and RT-qPCR analysis. Possible interacting partners of synphilin-1 (SNCAIP) were analyzed for their possible role in cancer by the in-silico method. CONCLUSION: Our data implicate that the presence of bioactive compound(s) in C. axillaris fruits might play an important role in inhibiting the proliferation of breast carcinoma cells and Synphilin-1 protein may play a role of apoptotic function.

Phytochemicals in the Management of Arsenic Toxicity.

Arsenic toxicity is a major concern due to its deleterious consequences for human health. Rapid industrialization also has weakened the quality of the environment by introducing pollutants that may disrupt balanced ecosystems, adversely and irreversibly impacting humans, plants, and animals. Arsenic, an important toxicant among all environmental hazards, can lead to several detrimental effects on cells and organs, impacting the overall quality of life. Nevertheless, arsenic also has a rich history as a chemotherapeutic agent used in ancient days for the treatment of diseases such as malaria, cancer, plague, and syphilis when other chemotherapeutic agents were yet to be discovered. Arsenicosis-mediated disorders remain a serious problem due to the lack of effective therapeutic options. Initially, chelation therapy was used to metabolically eliminate arsenic by forming a complex, but adverse effects limited their pharmacological use. More recently, plant-based products have been found to provide significant relief from the toxic effects of arsenic poisoning. They act by different mechanisms affecting various cellular processes. Phytoconstituents such as curcumin, quercetin, diallyl trisulfide, thymoquinone, and others act via various molecular pathways, primarily by attenuating oxidative damage, membrane damage, DNA damage, and proteinopathies. Nonetheless, most of the phytochemicals reviewed here protect against the adverse effects of metal or metalloid exposure, supporting their consideration as alternatives to chelation therapy. These agents, if used prophylactically and in conjunction with other chemotherapeutic agents, may provide an effective approach for management of arsenic toxicity. In a few instances, such strategies like coadministration of phytochemicals with a known chelating agent have led to more pronounced elimination of arsenic from the body with lesser off-site adverse effects. This is possible because combination treatment ensures the use of a reduced dose of chelating agent with a phytochemical without compromising treatment. Thus, these therapies are more practical than conventional therapeutic agents in ameliorating arsenic-mediated toxicity. This review summarizes the potential of phytochemicals in alleviating arsenic toxicity on the basis of available experimental and clinical evidence.

Surface plasmon resonance: A promising approach for label-free early cancer diagnosis.

Cancer is the second leading cause of death worldwide after cardiovascular disease. The major cause of high mortality is delayed detection. Therefore, detection at an early stage followed by early treatment can mitigate morbidity as well as mortality. The utilization of biomarker-based detection tools helps in early-stage recognition. Fortunately, biomarkers indicating disease status are released in to the circulation. These include traditional marker proteins as well as exosomes, micro-RNA (miRNA) and circulating tumor DNA (ct-DNA). Biosensors are biological and chemical reaction devices that generate signals based on analyte concentration. Due to analyte binding, these devices demonstrate high sensitivity and specificity. This review examines the use of surface plasmon resonance (SPR)-based sensors in the diagnosis of various cancer including those of the breast, prostate, lung, ovary, cervix and pancreas. SPR is a label-free, real-time and non-invasive optical biosensing technology representing a novel diagnostic tool in cancer detection.