AMPK Alchemy: Therapeutic Potentials in Allergy, Aging, and Cancer.

All cells are equipped with intricate signaling networks to meet the energy demands and respond to the nutrient availability in the body. AMP-activated protein kinase (AMPK) is among the most potent regulators of cellular energy balance. Under ATP -deprived conditions, AMPK phosphorylates substrates and affects various biological processes, such as lipid/glucose metabolism and protein synthesis. These actions further affect the cell growth, death, and functions, altering the cellular outcomes in energy-restricted environments. AMPK plays vital roles in maintaining good health. AMPK dysfunction is observed in various chronic diseases, making it a promising target for preventing and alleviating such diseases. Herein, we highlight the different AMPK functions, especially in allergy, aging, and cancer, to facilitate the development of new therapeutic approaches in the future.

Anti-Citrullinated Protein Antibodies With Multiple Specificities Ameliorate Collagen Antibody-Induced Arthritis in a Time-Dependent Manner.

OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and have long been regarded as pathogenic. Despite substantial in vitro evidence supporting this claim, reports investigating the proinflammatory effects of ACPAs in animal models of arthritis are rare and include mixed results. Here, we sequenced the plasmablast antibody repertoire of a patient with RA and functionally characterized the encoded ACPAs. METHODS: We expressed ACPAs from the antibody repertoire of a patient with RA and characterized their autoantigen specificities on antigen arrays and enzyme-linked immunosorbent assays. Binding affinities were estimated by bio-layer interferometry. Select ACPAs (n = 9) were tested in the collagen antibody-induced arthritis (CAIA) mouse model to evaluate their effects on joint inflammation. RESULTS: Recombinant ACPAs bound preferentially and with high affinity (nanomolar range) to citrullinated (cit) autoantigens (primarily histones and fibrinogen) and to auto-cit peptidylarginine deiminase 4 (PAD4). ACPAs were grouped for in vivo testing based on their predominant cit-antigen specificities. Unexpectedly, injections of recombinant ACPAs significantly reduced paw thickness and arthritis severity in CAIA mice as compared with isotype-matched control antibodies (P ≤ 0.001). Bone erosion, synovitis, and cartilage damage were also significantly reduced (P ≤ 0.01). This amelioration of CAIA was observed for all the ACPAs tested and was independent of cit-PAD4 and cit-fibrinogen specificities. Furthermore, disease amelioration was more prominent when ACPAs were injected at earlier stages of CAIA than at later phases of the model. CONCLUSION: Recombinant patient-derived ACPAs ameliorated CAIA. Their antiinflammatory effects were more preventive than therapeutic. This study highlights a potential protective role for ACPAs in arthritis.

Antimitochondrial antibody-negative primary biliary cirrhosis with secondary Sjogren syndrome: a case report.

Introduction and importance: Primary biliary cholangitis (PBC) is a rare immune-mediated liver disease characterized by the destruction of intrahepatic bile ducts and a positive antimitochondrial antibody (AMA), which is considered a serological hallmark for the diagnosis. Rarely, AMA can be absent/nondetectable in a few cases and is referred to as 'AMA-negative'. Case presentation: The authors present such an uncommon case of AMA-negative PBC in a 39-year-female with Sjogren's syndrome who presented with fatigue, pruritus, and dry eyes. Clinical discussion: Previously published studies state that approximately only about 5% of patients with PBC are 'AMA-negative'. For patients negative for AMA, the diagnosis has to be based on typical pathological features of this disease. Once a diagnosis of PBC is established, regardless of whether it is positive or negative for AMAs, ursodeoxycholic acid is a widely accepted treatment. Conclusion: The presence/absence of AMAs is associated with similar clinical, biochemical, and histopathological characteristics in PBC. The identification of AMAs alone should not impact the diagnosis or treatment of PBC.

High-Altitude Exposure and Cerebral Venous Thrombosis: An Updated Systematic Review.

Kharel, Sanjeev, Suraj Shrestha, Samriddha Raj Pant, Suman Acharya, Amit Sharma, Santosh Baniya, and Sanjeeb S. Bhandari. High-altitude exposure and cerebral venous thrombosis: an updated systematic review. High Alt Med Biol. 24:167-174, 2023. Background: High altitude (HA) may increase the risk of cerebral venous thrombosis (CVT). Differentiating it from other HA illnesses is crucial for prompt treatment and better outcomes. We aimed to summarize the clinical data, etiology, and risk factors of this poorly understood entity at an HA. Materials and Methods: A systematic literature search of various databases, including PubMed, Embase, and Google Scholar, was done using relevant keywords; cerebral venous thrombosis; HA, up to May 1, 2022. Results: A total of nine studies, including 75 cases of CVT at HA (3,000-8,848 m), with 66 males and 9 females, were included in this review. Headache and seizure were the most common clinical presentations. Smoking, drinking habits, and the use of oral contraceptive pills (OCP) were the most common risk factors for the development of CVT. Similarly, various underlying hypercoagulable states were also present among cases of CVT associated with HA exposure. Conclusion: Our review concludes that HA exposure can predispose individuals with risk factors such as preexisting hypercoagulable states, smoking, drinking habits, and use of OCP to an increased risk of CVT.

Diffuse large B-cell lymphoma in a patient treated with azathioprine for ulcerative colitis: a case report.

Azathioprine (AZA) used as an immunomodulator agent in the management of inflammatory bowel disease (IBD) increases the risk of the development of lymphoma. Case presentation: We present a case of a 45-year-old female receiving AZA for severe ulcerative colitis for 4 years. She presented with the chief complaints of bloody stool and abdominal pain for 1 month. Through a series of investigations including colonoscopy, contrast-enhanced computed tomography scan of the abdomen and pelvis, and biopsy with immunohistochemistry; she was diagnosed to have diffuse large B-cell lymphoma of the rectum. She is currently on a chemotherapeutic regimen and is planned for surgical resection after the completion of neoadjuvant therapy. Clinical discussion: AZA is classified as a carcinogen by the International Agency for Research on Cancer. Prolonged exposure to higher doses of AZA increases the risk of developing lymphoma in IBD. Previous meta-analysis and research indicate that the risk of development of lymphoma after the use of AZA in IBD increases by about four- to six-fold, especially in older age groups. Conclusions: AZA may increase the susceptibility to developing lymphoma in IBD, but the benefit far outweighs the risk. Precautions must be taken in prescribing AZA in older individuals which mandates periodic screening.

Organizing pneumonia as an initial presentation in a male lupus: A rare case report.

Organizing pneumonia (OP) is one of the rare pulmonary manifestations of systemic lupus erythematosus (SLE) which is infrequently reported as a presenting manifestation. Early diagnosis of lupus-related OP with the help of imaging, can drive to prompt initiation of immunosuppressive therapy leading to a better prognosis. We present a case of a 34-year-old young male who presented with fever, myalgia, and a dry cough for 1 month and was later diagnosed as SLE-related organizing pneumonia.

Relevance of tributary inflows for driving molecular composition of dissolved organic matter (DOM) in a regulated river system.

River regulation by dams can alter flow regimes and organic matter dynamics, but less is known about how unregulated tributaries regulate organic matter composition and processing in the regulated river below the confluence. This study reports on water chemistry, especially dissolved organic matter (DOM) concentration and composition (dissolved organic carbon (DOC), organic nitrogen (DON), organic phosphorus (DOP) and combined amino acids (DCAA)) along the regulated Tumut and unregulated Goobarragandra (tributary) rivers under different flow conditions (base flow vs storm event) in south-east Australia. The tributary was significantly different from regulated and downstream sites during base flow conditions with higher temperature, pH, buffering capacity, DOC and nutrient concentrations (DON, DOP, DCAA). DOM characterisation by spectrometry and size exclusion chromatography revealed that the tributary contained a higher proportion of terrestrially derived humic-like and fulvic-like DOM. In contrast, regulated and downstream sites contained higher proportion of microbially derived DOM such as low molecular weight neutrals and protein-like components. Storm pulses of tributary flows into the regulated system, influenced both concentration and composition of DOM at the downstream site, which more strongly resembled the tributary site than the regulated site during the storm event. Additionally, we found that the tributary supplied fresh DOM, including small organic molecules to the regulated system during storm events. The presence of these different types of labile DOM can increase primary productivity and ecological functioning within regulated river reaches downstream of tributary junctions. This has important implications for the protection of unregulated tributary inflows within regulated river basins.

Pontine and bilateral cerebellar lesion in osmotic demyelination syndrome associated with uncontrolled type II diabetes mellitus: a case report.

Osmotic demyelination syndrome (ODS) as a result of the hyperosmolar hyperglycemic state is rare and can present with variable neurological manifestation due to lysis of myelin sheath. Case presentation: A 44-year diabetic male presented with complaints of sudden onset, progressive bilateral weakness in lower limbs, and slurring of speech for the past 1.5 months. Cerebellar examination showed a bilaterally impaired finger nose test, dysdiadochokinesia, impaired heel shin test, and an impaired tandem gait. MRI brain (T2 and fluid-attenuated inversion recovery sequences) showed high signal intensity in the central pons and bilateral cerebellum. With a diagnosis of ODS with poorly controlled diabetes, he was treated with insulin, metformin, and supportive measures following which his symptoms subsided gradually. Clinical discussion: A rapid correction of hyponatremia is considered the most common cause of ODS. Variations in plasma glucose levels, a rare cause of ODS, can cause an abrupt osmolality change causing pontine and extrapontine myelinolysis. Prevention of rapid correction of hyponatremia and rapid changes in plasma osmolality in vulnerable patients is the mainstay of treatment. Conclusions: Clinical features, imaging studies, and monitoring of serum osmolality, serum glucose, and electrolytes aid in diagnosis and favorable outcomes for the patient.

Advances in Catchment Science, Hydrochemistry, and Aquatic Ecology Enabled by High-Frequency Water Quality Measurements.

High-frequency water quality measurements in streams and rivers have expanded in scope and sophistication during the last two decades. Existing technology allows in situ automated measurements of water quality constituents, including both solutes and particulates, at unprecedented frequencies from seconds to subdaily sampling intervals. This detailed chemical information can be combined with measurements of hydrological and biogeochemical processes, bringing new insights into the sources, transport pathways, and transformation processes of solutes and particulates in complex catchments and along the aquatic continuum. Here, we summarize established and emerging high-frequency water quality technologies, outline key high-frequency hydrochemical data sets, and review scientific advances in key focus areas enabled by the rapid development of high-frequency water quality measurements in streams and rivers. Finally, we discuss future directions and challenges for using high-frequency water quality measurements to bridge scientific and management gaps by promoting a holistic understanding of freshwater systems and catchment status, health, and function.

Bilateral central retinal vein occlusion as an initial presentation of Waldenström macroglobulinemia: a case report.

BACKGROUND: Waldenström macroglobulinemia is a rare hematological malignancy and is the most common diagnosis in patients with hyperviscosity syndrome. Bilateral central retinal vein occlusion as an initial presentation of hyperviscosity syndrome in Waldenström macroglobulinemia is rare. CASE PRESENTATION: A 42-year-old Nepalese male presented with sudden-onset bilateral painless blurring of vision. Fundus examination revealed bilateral, diffusely dilated, tortuous retinal veins and intraretinal deep blot hemorrhages in all four quadrants of the retina in both eyes; features of bilateral central retinal vein occlusion. Serum electrophoresis showed hypoalbuminemia with an immunoglobulin M kappa monoclonal spike. Bone marrow picture and immunohistochemistry analysis were suggestive of lymphoplasmacytic lymphoma. The patient received systemic therapy for Waldenström macroglobulinemia, along with intravitreal bevacizumab. CONCLUSION: Adequate hydration, plasmapheresis, and a combination of bortezomib, dexamethasone, and rituximab regimen as a systemic therapy may represent an ideal choice for patients with hyperviscosity in Waldenström macroglobulinemia.

AMPK suppresses Th2 cell responses by repressing mTORC2.

Allergic inflammation is a T helper 2 (Th2) cell-driven pathophysiological phenomenon, but the mechanism by which the metabolic cascade affects Th2 cell differentiation remains unclear. In this study, we investigated the roles of AMP-activated protein kinase (AMPK) and intracellular energy sensors in Th2 cell differentiation and the pathogenesis of allergic inflammation. Accordingly, T-cell-specific AMPK or Sirtuin 1 (Sirt1)-knockout mice were subjected to allergic inflammation, and their Th2 cell responses were investigated. The results demonstrated that inducing allergic inflammation in AMPK- and Sirt1-knockout mice increased Th2 cell responses and exacerbated allergic phenotypes. Furthermore, treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMPK, ameliorated allergic inflammation in mice. Mechanistically, our findings revealed that AMPK repressed mechanistic target of rapamycin complex 2 (mTORC2), which downregulated the expression of suppressor of cytokine signaling 5 (SOCS5) in CD4+ T cells. In addition, the loss of AMPK signaling reduced SOCS5 expression and increased interleukin-4-STAT6-GATA3 axis-mediated Th2 cell differentiation. Finally, the T-cell-specific deletion of Rictor, a member of mTORC2, in Sirt1T-KO mice led to the reversal of allergic exacerbation to the level in control mice. Overall, our findings suggest that AMPK in CD4+ T cells inhibits the differentiation of Th2 cells by repressing mTORC2 and thus serves as a potential target for Th2 cell-associated diseases.

Impact of climate on COVID-19 transmission: A study over Indian states.

Coronavirus Disease-2019 (COVID-19) started in Wuhan province of China in November 2019 and within a short time, it was declared as a worldwide pandemic by World Health Organisation due to the very fast worldwide spread of the virus. There are a few studies that look for the correlation with infected individuals and different environmental parameters using early data of COVID-19 but there is no study so far that deals with the variation of effective reproduction number and environmental factors. Effective reproduction number is the driving parameter of the spread of a pandemic and it is important to study the effect of various environmental factors on effective reproduction number to understand the effect of those factors on the spread of the virus. We have used time-dependent models to investigate the variation of different time-dependent driving parameters of COVID-19 like effective reproduction number and contact rate using data from India as a test case. India is a large population country that is highly affected due to the COVID-19 pandemic and has a wide span of different temperature and humidity regions and is ideal for such study. We have studied the impact of temperature and humidity on the spread of the virus of different Indian states using time-dependent epidemiological models SIRD, and SEIRD for a long time scale. We have used a linear regression method to look for any dependency between the effective reproduction number with the relative humidity, absolute humidity, and temperature. The effective reproduction number shows a negative correlation with both relative and absolute humidity for most of the Indian states, which are statistically significant. This implies that relative and absolute humidity may have an important role in the variation of effective reproduction number. Most of the states (six out of ten) show a positive correlation while two (out of ten) show a negative correlation between effective reproduction number and average air temperature for both SIRD and SEIRD models.

Pseudohypoparathyroidism type 1 B mimicking Fahr's disease in a 28-year-old female: A case report.

In virtue of precise clinical history, physical examinations, and biochemical/radiological investigations, pseudohypoparathyroidism can be effectively diagnosed, and its types can be differentiated even without exorbitant tests.

Barraquer-Simons syndrome in systemic lupus erythematosus: A case report.

Barraquer-Simons syndrome is a rare entity characterized by progressive loss of subcutaneous tissue in the face and/or upper half of the body and can be associated with autoimmune conditions such as systemic lupus erythematosus. Close long-term follow-up is required to identify metabolic disturbances, potentially life-threatening renal problems, and other associated diseases.

Cryptococcal meningitis in an immunocompetent individual: A case report.

Cryptococcal meningitis (CM) is mostly seen in immune-compromised patients and rarely occurs in immune-competent individuals. Immunocompetent individuals with CM present with indolent neurological disease and have better clinical outcomes after treatment. However, misdiagnosis is common and these patients may suffer from serious complications with high mortality.

AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway.

BACKGROUND: AMP-activated protein kinase (AMPK) is a metabolic sensor that maintains energy homeostasis. AMPK functions as a tumor suppressor in different cancers; however, its role in regulating antitumor immunity, particularly the function of regulatory T cells (Tregs), is poorly defined. METHODS: AMPKα1fl/flFoxp3YFP-Cre, Foxp3YFP-Cre, Rag1-/-, and C57BL/6 J mice were used for our research. Flow cytometry and cell sorting, western blotting, immuno-precipitation, immuno-fluorescence, glycolysis assay, and qRT-PCR were used to investigate the role of AMPK in suppressing programmed cell death 1 (PD-1) expression and for mechanistic investigation. RESULTS: The deletion of the AMPKα1 subunit in Tregs accelerates tumor growth by increasing the expression of PD-1. Metabolically, loss of AMPK in Tregs promotes glycolysis and the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme of the mevalonate pathway. Mechanistically, AMPK activates the p38 mitogen-activated protein kinase (MAPK) that phosphorylates glycogen synthase kinase-3ß (GSK-3ß), inhibiting the expression of PD-1 in Tregs. CONCLUSION: Our study identified an AMPK regulatory mechanism of PD-1 expression via the HMGCR/p38 MAPK/GSK3ß signaling pathway. We propose that the AMPK activator can display synergic antitumor effect in murine tumor models, supporting their potential clinical use when combined with anti-PD-1 antibody, anti-CTLA-4 antibody, or a HMGCR inhibitor.

Heterospheroid formation improves therapeutic efficacy of mesenchymal stem cells in murine colitis through immunomodulation and epithelial regeneration.

Tissue repairing capacity and immunomodulatory effects of mesenchymal stem cells (MSCs) have been extensively utilized for treating various inflammatory disorders; however, inconsistent efficacy and therapeutic outcomes due to low survival rate after transplantation often restrain their clinical potential. To overcome these limitations, 3-dimensional culture (3D-culture) was established to augment stemness and paracrine functions of MSCs, although hypoxic stress at the core often leads to unexpected cell death. Thus, we designed a novel strategy to improve the microenvironment of MSCs by creating heterospheroids (HS) consisting of MSCs and quercetin (QUR)-loaded microspheres (MSCHS), to achieve local drug delivery to the cells. Notably, MSCHS exhibited resistance for senescence-associated phenotype and oxidative stress-induced apoptosis compared to 3D-cultured MSCs (MSC3D), as well as to 2D-cultured cells (MSC2D) in vitro. In a murine model of colitis, MSC3D and MSCHS exhibited enhanced anti-inflammatory impact than MSC2Dvia attenuating neutrophil infiltration and regulating helper T cell (Th) polarization into Th1 and Th17 cells. Interestingly, MSCHS provided better therapeutic outcomes compared to MSC3D, partially due to their enhanced survival capacity in vivo. Moreover, we found that MSC-derived paracrine factor, prostaglandin E2 (PGE2), can directly drive the epithelial regeneration process by inducing specialized tissue-repairing cell generation using the intestinal organoid culture. Importantly, MSC3D and MSCHS displayed an outstanding regeneration-inducing potency compared to MSC2D owing to their superior PGE2 secretion. Taken together, we suggest a convergent strategy of MSCHS formation with reactive oxygen species (ROS) scavenger, QUR, which can maximize the inflammation-attenuating and tissue-repairing capacity of MSCs, as well as the engraftment efficiency after transplantation.

Geranylgeranyl pyrophosphate amplifies Treg differentiation via increased IL-2 expression to ameliorate DSS-induced colitis.

Blocking the mevalonate pathway for cholesterol reduction by using statin may have adverse effects including statin-induced colitis. Moreover, one of the predisposing factors for colitis is an imbalanced CD4+ T cell, which can be observed on the complete deletion of HMG-CoA reductase (HMGCR), a target of statins. In this study, we inquired geranylgeranyl pyrophosphate (GGPP) is responsible for maintaining the T-cell homeostasis. Following dextran sulfate sodium (DSS)-induced colitis, simvastatin increased the severity of disease, while cotreatment with GGPP, but not with cholesterol, reversed the disease magnitude. GGPP ameliorated DSS-induced colitis by increasing Treg cells. GGPP amplified Treg differentiation through increased IL-2/STAT 5 signaling. GGPP prenylated Ras protein, a prerequisite for extracellular signal-regulated kinase (ERK) pathway activation, leading to increased IL-2 production. Higher simvastatin dose increased the severity of colitis. GGPP ameliorated simvastatin-increased colitis by increasing Treg cells. Treg cells, which have the capacity to suppress inflammatory T cells and were generated through IL-2/STAT5 signaling, increased IL-2 production through prenylation and activation of the Ras/ERK pathway.

Particulate-Based Single-Dose Local Immunosuppressive Regimen for Inducing Tolerogenic Dendritic Cells in Xenogeneic Islet Transplantation.

Recent studies emphasize on developing immune tolerance by an interim administration of various immunosuppressive drugs. In this study, a robust protocol is reported for local immunomodulation using a single-dose of FK506 microspheres and clodronate liposomes (mFK+CLO) in a xenogeneic model of islet transplantation. Surprisingly, the single-dose treatment with mFK+CLO induce tolerance to the islet xenograft. The recipient mice display tolerogenic dendritic cells (tDCs) with decreased antigen presenting ability and T cell activation capacity. Furthermore, a reduced percentage of CD4+ and CD8+ T cells and an impaired differentiation of naïve CD4+ T cells into interferon-γ producing Th1 and interleukin-17 producing Th17 cells are observed. In addition, the immunosuppressive protocol leads to the generation of Foxp3+ regulatory T cells (Tregs) which are required for the long-term graft survival. The enhanced generation of tDCs and Tregs by the single treatment of mFK+CLO cause xenograft tolerance, suggesting a possible clinical strategy which may pave the way towards improving therapeutic outcomes of clinical islet transplantation.

Spontaneous rupture of isolated splenic hydatid cyst without acute abdomen: A case report.

Isolated splenic hydatid cyst is a very rare manifestation of hydatid cyst. Rarely, patients present late after the cyst is ruptured. They might not present with usual presentations such as the acute abdomen, anaphylaxis, or urticarial rashes but only with a distended abdomen. Splenectomy is the emergency operative management.