ABSTRACT
Introduction: Alzheimer pathology (AD) is characterized by the deposition of amyloid beta (Aß) and chronic neuroinflammation, with the NLRP3 inflammasome playing a significant role. This study demonstrated that the OCD drug fluvoxamine maleate (FXN) can potently ameliorate AD pathology in 5XFAD mice by promoting autophagy-mediated clearance of Aß and inhibiting the NLRP3 inflammasome. Methods: We used mice primary astrocytes to establish the mechanism of action of FXN against NLRP3 inflammasome by using various techniques like ELISA, Western blotting, confocal microscopy, Immunofluorescence, etc. The anti-AD activity of FXN was validated in transgenic 5XFAD mice following two months of treatment. This was followed by behavior analysis, examination of inflammatory and autophagy proteins and immunohistochemistry analysis for Aß load in the hippocampi. Results: Our data showed that FXN, at a low concentration of 78 nM, induces autophagy to inhibit NF-κB and the NLRP3 inflammasome, apart from directly inhibiting NLRP3 inflammasome in primary astrocytes. FXN activated the PRKAA2 pathway through CAMKK2 signaling, leading to autophagy induction. It inhibited the ATP-mediated NLRP3 inflammasome activation by promoting the autophagic degradation of NF-κB, resulting in the downregulation of pro-IL-1ß and NLRP3. The anti-NLRP3 inflammasome effect of FXN was reversed when autophagy was inhibited by either genetic knockdown of the PRKAA2 pathway or pharmacological inhibition with bafilomycin A1. Furthermore, FXN treatment led to improved AD pathology in 5XFAD mice, resulting in significant improvements in various behavioral parameters such as working memory and neuromuscular coordination, making their behavior more similar to that of wild-type animals. FXN improved behavior in 5XFAD mice by clearing the Aß deposits from the hippocampi and significantly reducing multiple inflammatory proteins, including NF-κB, GFAP, IBA1, IL-1ß, TNF-α, and IL-6, which are associated with NF-κB and NLRP3 inflammasome in the brain. Moreover, these changes were accompanied by increased expression of autophagic proteins. Discussion: Our data suggest that FXN ameliorates AD pathology, by simultaneously targeting two key pathological features: Aß deposits and neuroinflammation. As an already approved drug, FXN holds potential as a candidate for human studies against AD.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Astrocytes , Autophagy , Disease Models, Animal , Fluvoxamine , Mice, Transgenic , NLR Family, Pyrin Domain-Containing 3 Protein , Neuroinflammatory Diseases , Animals , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Mice , Fluvoxamine/pharmacology , Fluvoxamine/therapeutic use , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Astrocytes/drug effects , Astrocytes/metabolism , Autophagy/drug effects , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/metabolism , Inflammasomes/metabolism , Inflammasomes/drug effectsABSTRACT
Here, we report a silver-mediated coupling of acetylenes with sulfoximines to synthesize N-α-ketoacyl sulfoximines and N-α,ß-unsaturated acyl sulfoximines. The reactions are performed under an open atmosphere using the oxidant K2S2O8 and the ligand 2,2-bipyridyl. However, the fate of the product formation is controlled by the type of substrate used. The coupling between aryl acetylenes and sulfoximines afforded the N-α-ketoacylsulfoximines, while the alkyl acetylenes provided the N-α,ß-unsaturated acyl sulfoximines. Controlled experiments reveal the differential reactivity patterns of substrates. The labeling 18O experiments showed that water is the source of the incoming oxygen atom for the keto group of N-α-ketoacyl sulfoximines and N-α,ß-unsaturated acyl sulfoximines.
ABSTRACT
Here, we report a s-trichlorotriazine (TCT, also known as cyanuric chloride) mediated one-pot general method for the conversion of carboxylic acids into ubiquitous functionalities such as carbamides, carbamates, carbamothioates, amides, and amines. The TCT-mediated activation of acids followed by azidation and heating led to the isocyanate formation via Curtius rearrangement which involves click chemistry in the presence of nucleophiles and provided the coupled product. The TCT was employed at ≤40 mol% with respect to the starting materials; however, its bulk availability and low cost provide a unique opportunity towards its applicability in the synthesis of functional molecules. The optimized conditions have also been successfully demonstrated for gram scale synthesis and late-stage functionalization of natural products and drugs such as podophyllotoxin, eugenol, diosgenin, geraniol and fluvoxamine.
Subject(s)
Amides , Amines , Amides/chemistry , Amines/chemistry , Carbamates/chemistry , Carboxylic Acids/chemistry , Click Chemistry , Nitrogen , UreaABSTRACT
The Maldives tuna fishery landings in 2018 were 148, 000 t and accounted for nearly a quarter of the global pole-and-line tuna catch. This fishery partially relies on a network of 55 anchored fish aggregating devices (AFADs) deployed around the archipelago. About one-third of the total pole-and-line tuna catch is harvested at AFADs. Although the AFAD fishery has existed for 35 years, knowledge on the behaviour of tuna in the AFAD array is still limited, precluding the development of science-based fishery management. In this study, local ecological knowledge (LEK) of fishers was used to improve our understanding of tuna behaviour, through personal interviews of 54 pole-and-line fishers from different parts of the archipelago. Interview results suggest that during the northeast monsoon tuna are more abundant on the eastern side of the Maldives, while during the southwest monsoon they are more abundant on the western side of the Maldives. Most fishers believed that tuna tend to stay at the AFADs for 3 to 6 days and remain within 2 miles from the AFADs when they are associated. Fishers believe that strong currents is the main factor for tuna departure from AFADs, though high sea surface temperatures and stormy conditions were also thought to contribute to departures. Moderate currents are believed to be a favourable condition to form aggregations at the AFADs while other factors such as suitable temperature, prey and attractants enhance this aggregation. Fishers also believe that there are multiple schools segregated according to size and species at AFADs and that catchability is higher at dawn and in the late afternoon when the tuna occur shallower in the water column. This study is an important step towards engaging the Maldivian tuna fishers into a science-based fishery management.
Subject(s)
Fisheries , Tuna , Animals , Conservation of Natural ResourcesABSTRACT
Many viruses utilize the host endo-lysosomal network for infection. Tracing the endocytic itinerary of SARS-CoV-2 can provide insights into viral trafficking and aid in designing new therapeutic strategies. Here, we demonstrate that the receptor binding domain (RBD) of SARS-CoV-2 spike protein is internalized via the pH-dependent CLIC/GEEC (CG) endocytic pathway in human gastric-adenocarcinoma (AGS) cells expressing undetectable levels of ACE2. Ectopic expression of ACE2 (AGS-ACE2) results in RBD traffic via both CG and clathrin-mediated endocytosis. Endosomal acidification inhibitors like BafilomycinA1 and NH4Cl, which inhibit the CG pathway, reduce the uptake of RBD and impede Spike-pseudoviral infection in both AGS and AGS-ACE2 cells. The inhibition by BafilomycinA1 was found to be distinct from Chloroquine which neither affects RBD uptake nor alters endosomal pH, yet attenuates Spike-pseudovirus entry. By screening a subset of FDA-approved inhibitors for functionality similar to BafilomycinA1, we identified Niclosamide as a SARS-CoV-2 entry inhibitor. Further validation using a clinical isolate of SARS-CoV-2 in AGS-ACE2 and Vero cells confirmed its antiviral effect. We propose that Niclosamide, and other drugs which neutralize endosomal pH as well as inhibit the endocytic uptake, could provide broader applicability in subverting infection of viruses entering host cells via a pH-dependent endocytic pathway.
Subject(s)
COVID-19 Drug Treatment , COVID-19/virology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Virus Internalization/drug effects , Ammonium Chloride/pharmacology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Cell Line , Chlorocebus aethiops , Chloroquine/pharmacology , Clathrin/metabolism , Drug Synergism , Endocytosis/drug effects , Endocytosis/physiology , Endosomes/drug effects , Endosomes/metabolism , Humans , Hydrogen-Ion Concentration/drug effects , Hydroxychloroquine/administration & dosage , Macrolides/pharmacology , Niclosamide/administration & dosage , Niclosamide/pharmacology , Protein Binding/drug effects , Protein Domains , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/physiology , Vero CellsABSTRACT
Zootherapy is accepted all around the globe not only in ancient cultures but different animal derived medicines are also part of the practice in the modern health care systems. The present study assessed the traditional ethnozoological usage of wild animals by local inhabitants in Ladakh region, India, and the reference data for scientific approaches for protection of faunal diversity in trans-Himalayas. The ethnozoological documentation of the animals in Ladakh was carried out through semistructured and close-ended questionnaire surveys and interviews. Multivariate ecological community analysis was used to elucidate the relationship between ethnozoological usage and animal species. Our results showed three animal usage clusters with 32% similarity. Moreover, the similarity in animal usage between digging tools, trophy, handle of tools, decoration, and matting, showed less than 32% of similarity. The highest priority of local people was for food followed by decoration and medicinal usage. The most frequently used animal parts were meat followed by fur and horn. Medicinal uses of 48% of the reported species, i.e., Alectoris chukar (chukar), Cuon alpinus (Asiatic wild dog), Lepus oiostolus (hares), Marmota himalayana (marmots), Ovis aries vignei (Ladakh urial), Pantholops hodgsonii (Tibetan antelope), Procapra picticaudata (Tibetan gazelle), Pseudois nayaur (blue sheep), Tetraogallus himalayensis (Himalayan snow), Tetraogallus tibetanus (Tibetan snow cock), and Lutra lutra (common otter) were reported for the first time from this region. Our study provides innovative information regarding the ethnozoological knowledge in the Ladakh region and reference data for policymakers, researchers, land managers, common public, and the other stakeholders to develop logical and scientific approaches for sustainable use of faunal diversity in hotspot regions like trans-Himalayas and other similar biodiversity-rich sites.
ABSTRACT
Here, we are reporting a multicomponent cascade reaction approach for the synthesis of ß-keto sulfones by exploiting differential reactivity pattern of substrates under open-atmosphere and metal-free conditions. The coupling partners are aryldiazonium salts, unsaturated compounds, and DABSO. The optimized conditions worked well with both alkenes and alkynes. Moreover, the reaction also works with metabisulfite for the source of sulfone. The controlled liquid chromatography-mass spectrometry and 18O-labelled experiments suggested that air is a source of the incoming oxygen atom of the keto group of ß-keto sulfones.
ABSTRACT
Japanese encephalitis (JE) virus (JEV) is an important cause of encephalitis in children of South and Southeast Asia. However, the majority of individuals exposed to JEV only develop mild symptoms associated with long-lasting adaptive immunity. The related flavivirus dengue virus (DENV) cocirculates in many JEV-endemic areas, and clinical data suggest cross-protection between DENV and JEV. To address the role of T cell responses in protection against JEV, we conducted the first full-breadth analysis of the human memory T cell response using a synthetic peptide library. Ex vivo interferon-γ (IFN-γ) responses to JEV in healthy JEV-exposed donors were mostly CD8(+) and targeted nonstructural (NS) proteins, whereas IFN-γ responses in recovered JE patients were mostly CD4(+) and targeted structural proteins and the secreted protein NS1. Among patients, a high quality, polyfunctional CD4(+) T cell response was associated with complete recovery from JE. T cell responses from healthy donors showed a high degree of cross-reactivity to DENV that was less apparent in recovered JE patients despite equal exposure. These data reveal divergent functional CD4(+) and CD8(+) T cell responses linked to different clinical outcomes of JEV infection, associated with distinct targeting and broad flavivirus cross-reactivity including epitopes from DENV, West Nile, and Zika virus.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Encephalitis Virus, Japanese/immunology , Encephalitis, Japanese/immunology , Immunologic Memory , Viral Nonstructural Proteins/immunology , Adolescent , Adult , Child , Cross Reactions/immunology , Dengue Virus/immunology , Female , Humans , Interferon-gamma/immunology , MaleABSTRACT
A 50-year-old Omani woman presented to the Outpatient Clinic, Royal Hospital, Oman with right upper abdominal pain and backache that had lasted 10 days. She had no palpitation, sweating, or hypertension (blood pressure 122/78mmHg). The patient's history revealed that she had a similar incidence of abdominal pain two months prior, which was a "dull ache" in nature and somewhat associated with headache. The pain was relieved using a mild analgesic drug. Abdominal ultrasonography showed a right adrenal mass, and both computed tomography and magnetic resonance imaging of the adrenal glands confirmed a right adrenal mass consistent with adrenal pheochromocytoma. However, clinical biochemistry tests revealed normal levels of plasma catecholamines (dopamine, norepinephrine, and epinephrine) and metanephrine, which are unusual findings in adrenal pheochromocytoma. Meanwhile, the patient had markedly raised plasma normetanephrine (10-fold) which, together with the normal metanephrine, constitutes a metabolic profile that is compatible with extra-adrenal pheochromocytoma. The patient also had markedly raised chromogranin A (16-fold), consistent with the presence of a neuroendocrine tumor. Laparoscopic right adrenalectomy was done and the adrenal tumor was excised and retrieved in total. Histopathology and immunohistochemistry confirmed the diagnosis of adrenal pheochromocytoma; the tumor cells being positive for chromogranin, synaptophysin, and S-100 protein. Following surgery, the patient did well and showed full recovery at follow-up after three months. Molecular genetic testing showed no pathogenic mutation in pheochromocytoma genes: MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, VHL, and PRKAR1A. A review of the literature was conducted to identify the pathophysiology and any previous reports of such case. To our knowledge, this is the first report in Oman of the extremely rare entity of pheochromocytoma with an unusual clinical and biochemical scenario.
ABSTRACT
Herbal toothpowders are available in market in a wide varieties, which consist of various ingredients. In rural areas of the developing countries, they are still used for cleansing teeth. Erythema multiforme (EM) is an acute mucocutaneous disorder that is believed to be a sequel of a cytotoxic immunologic attack on keratinocytes which express non-self-antigens. A 31-year-old male who used herbal toothpowder for oral-hygiene maintenance presented with ulcers in mouth, encrustation on lips and target lesions on both hands, suggesting Erythema multiforme. An oral biopsy confirmed the diagnosis. To the best of our knowledge, there is no report of an association of herbal extracts and EM in the English literature. With this report, we present a rare new triggering factor of Erythema mutiforme, thus adding it to the endless list of aetiologies.
ABSTRACT
AIM: This study aims to evaluate the relation of erythrocyte indices and serum iron level with clinical and histopathological progression of oral squamous cell carcinoma (OSCC). METHODS: Eighty newly diagnosed OSCC patients recruited for the study were divided according to tumor size int three groups. Erythrocyte indices (e.g., hemoglobin [Hb], red blood cell [RBC] count, packed cell volume [PCV]) and serum iron level (S.Fe) were evaluated with normal reference values, control subject, primary tumor size and histopathological grading. Correlation of Hb to S.Fe was also analyzed. RESULTS: We found that 56.36, 61.81, and 83.63% of males and 76, 32, and 88% of female patients were anemic in terms of Hb%, RBC count and PCV respectively, whereas the remainding indices and S.Fe were within normal range (P < 0.05). Percent Hb, RBC count and PCV gradually decreased with increasing tumor size and histopathological grading (P > 0.05). Moderate to weak correlation was observed between Hb and S.Fe (P < 0.05). CONCLUSIONS: Tumor-induced hemolysis appeared to be responsible for anemia in OSCC and its severity increased with the progression of tumor. Moderate to weak correlation exists between Hb and S.Fe probably owing to the dual requirement of iron for bone marrow and the tumor.
Subject(s)
Carcinoma, Squamous Cell/blood , Erythrocyte Indices , Iron/blood , Mouth Neoplasms/blood , Adult , Aged , Anemia/blood , Disease Progression , Erythrocyte Count , Female , Hematocrit , Hemoglobins/analysis , Hemolysis , Humans , India , Male , Middle Aged , Mouth Mucosa/pathology , Neoplasm Grading , Neoplasm Staging , Tongue Neoplasms/bloodABSTRACT
Research indicates that a small population of cancer cells is highly tumorigenic, endowed with the capacity for self-renewal, and has the ability to differentiate into cells that constitute the bulk of tumors. These cells are considered the "drivers" of the tumorigenic process in some tumor types, and have been named cancer stem cells (CSC). Epithelial-mesenchymal transition (EMT) appears to be involved in the process leading to the acquisition of stemness by epithelial tumor cells. Through this process, cells acquire an invasive phenotype that may contribute to tumor recurrence and metastasis. CSC have been identified in human head and neck squamous cell carcinomas (HNSCC) using markers such as CD133 and CD44 expression, and aldehyde dehydrogenase (ALDH) activity. Head and neck cancer stem cells reside primarily in perivascular niches in the invasive fronts where endothelial-cell initiated events contribute to their survival and function. Clinically, CSC enrichment has been shown to be enhanced in recurrent disease, treatment failure and metastasis. CSC represent a novel target of study given their slow growth and innate mechanisms conferring treatment resistance. Further understanding of their unique phenotype may reveal potential molecular targets to improve therapeutic and survival outcomes in patients with HNSCC. Here, we discuss the state-of-the-knowledge on the pathobiology of cancer stem cells, with a focus on the impact of these cells on head and neck tumor progression, metastasis and recurrence due to treatment failure.