Disease Induction Research Articles

Investigation of homocysteine, D-dimer and platelet count levels as potential predictors of thrombosis risk in COVID-19 patients.

Thrombosis plays an important role in induction of Coronavirus disease 19 (COVID-19) complications including heart attack and stroke. Reliable biomarkers are needed to predict thrombosis risk for better management and improve patient outcomes. This study aimed to investigate the relationship between homocysteine, a thrombosis-related biomarker, and other thrombosis-related parameters, such as D-dimer and platelet count with disease outcome in COVID-19 patients. This case-control study including 50 intensive care unit hospitalized patients with Covid-19 with a positive RT-PCR test for SARS-CoV-2 infection and 50 healthy individuals as a control group was conducted. Both groups were matched for age and body mass index (BMI) and had no history of underlying diseases such as cardiovascular, liver, kidney or smoking. Blood samples were collected from both groups to measure serum homocysteine, platelet count and D-dimer levels. Data were analyzed using GraphPad Prism version 8.3 software. The study found no statistically significant difference in homocysteine levels between COVID-19 patients and the control group. However, D-dimer levels were significantly higher in the patient group. Platelet count analysis revealed a significant difference between patients who died and those who were discharged from the hospital (P < 0.05). Despite previous studies suggesting a link between homocysteine and thrombosis, this study found no significant difference in homocysteine levels between COVID-19 patients and the control group. The significantly elevated D-dimer levels in the death group patient suggest that D-dimer and thrombocytopenia may be more reliable predictors of thrombosis and worse outcome in COVID-19 patients without underlying diseases.

Early detection of anthracycline-induced cardiotoxicity using [68Ga]Ga-FAPI-04 imaging.

Anthracycline-induced cardiotoxicity (AIC), whose major manifestation is diffuse myocardial fibrosis, is an important clinical problem in cancer therapy. Therefore, early identification and treatment are clinically important. This study aims to explore the feasibility of using 68Ga-labelled fibroblast activation protein (FAP) inhibitor ([68Ga]Ga-FAPI) positron emission tomography/computed tomography (PET/CT) for the early identification of the fibrotic process and guidance of antifibrosis therapy in AIC. An AIC rat model was induced by the intravascular administration of doxorubicin (DOX) once per week for 1, 2, 3 and 6weeks (2.5mg/kg/injection, groups 1-4), whereas intravascular saline was administered to control rats. Experimental and control groups (n = 4) underwent [68Ga]Ga-FAPI PET/CT following disease induction. Groups 5 and 6 received DOX injections for 3 and 6weeks, treated with angiotensin-converting enzyme (ACE) inhibitor starting at 3weeks, treated with enalapril (20mg/kg, gastric gavage) daily and underwent echocardiography and [68Ga]Ga-FAPI PET/CT at 3weeks after treatment. Rat hearts were subjected to haematoxylin and eosin staining, FAP immunohistochemistry, Sirius red staining and Masson's trichrome staining to investigate the pathological changes and deposition of collagen fibres. Rat blood was sampled weekly for the enzyme-linked immunosorbent assay of various markers of myocardial injury, such as plasma cardiac troponin I, B-type natriuretic peptide and angiotensin II. [68Ga]Ga-FAPI-04 uptake by the heart was significantly higher in the cardiotoxicity group than in the control group at weeks 3 (SUVmax: 1.21 ± 0.23 vs 0.67 ± 0.01, P < 0.05) and 6 (SUVmax: 1.48 ± 0.28 vs 0.67 ± 0.08, P < 0.001), whereas left ventricle ejection fraction (LVEF) did not significantly differ between normal and AIC rats at week 3. FAP+ expression began to increase starting at week 3, before irreversible fibrotic changes were detected, until week 6. After 3weeks of enalapril treatment, [68Ga]Ga-FAPI-04 accumulation decreased in groups 5 and 6 (SUVmax decreased from 1.21 ± 0.23 to 0.77 ± 0.08 and 1.48 ± 0.28 to 1.09 ± 1.06, P < 0.05). Cardiac function was preserved (LVEF was 75.7% ± 7.38% in group 3 vs 74.5% ± 2.45% in group 5, P > 0.05) and improved (LVEF increased from 51.6% ± 9.03% in group 4 to 65.2% ± 4.27% in group 6, P < 0.05), and myocardial fibrosis attenuated (from 6.5% ± 1.2% in group 4 to 4.31% ± 0.37% in group 6, P < 0.01). [68Ga]Ga-FAPI PET/CT can be used for the early detection of active myocardial fibrosis in AIC and the evaluation of the efficacy of therapeutic interventions. Early treatment guided by [68Ga]Ga-FAPI PET/CT may reduce anthracycline-induced myocardial injury and improve heart function.

The Janus-faced functions of Apolipoproteins L in membrane dynamics

The functions of human Apolipoproteins L (APOLs) are poorly understood, but involve diverse activities like lysis of bloodstream trypanosomes and intracellular bacteria, modulation of viral infection and induction of apoptosis, autophagy, and chronic kidney disease. Based on recent work, I propose that the basic function of APOLs is the control of membrane dynamics, at least in the Golgi and mitochondrion. Together with neuronal calcium sensor-1 (NCS1) and calneuron-1 (CALN1), APOL3 controls the activity of phosphatidylinositol-4-kinase-IIIB (PI4KB), involved in both Golgi and mitochondrion membrane fission. Whereas secreted APOL1 induces African trypanosome lysis through membrane permeabilization of the parasite mitochondrion, intracellular APOL1 conditions non-muscular myosin-2A (NM2A)-mediated transfer of PI4KB and APOL3 from the Golgi to the mitochondrion under conditions interfering with PI4KB-APOL3 interaction, such as APOL1 C-terminal variant expression or virus-induced inflammatory signalling. APOL3 controls mitophagy through complementary interactions with the membrane fission factor PI4KB and the membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). In mice, the basic APOL1 and APOL3 activities could be exerted by mAPOL9 and mAPOL8, respectively. Perspectives regarding the mechanism and treatment of APOL1-related kidney disease are discussed, as well as speculations on additional APOLs functions, such as APOL6 involvement in adipocyte membrane dynamics through interaction with myosin-10 (MYH10).

Effects of Aerobic Interval Training Along with Ginkgo biloba Supplementation on Passive Avoidance Memory and GDNF Gene Expression in Alzheimer Rats

Background: Alzheimer's disease (AD) represents the most prevalent form of dementia, characterized by memory loss, and is a complex, progressive neurodegenerative condition. Objectives: This study aimed to explore the impact of aerobic interval training (AIT) combined with Ginkgo biloba (GB) supplementation on passive avoidance memory function and the expression of the glial cell-derived neurotrophic factor (GDNF) gene in rats afflicted with AD. Methods: A total of forty-four male Wistar rats, each weighing approximately 250 ± 20 g, were maintained in a controlled environment at a specified temperature. Over 8 weeks (5 days per week), they underwent AIT and received GB supplements at a dosage of 100 mg/kg. The rats were randomly assigned into six groups: Healthy control (HC) with 7 rats, AD control (AC) with 8 rats, amyloid-β (Aβ) injection plus GB supplement (Aβ + GB) with 8 rats, Aβ injection plus GB supplement plus AIT (Aβ + GB + AIT) with 8 rats, Aβ injection plus AIT (Aβ + AIT) with 8 rats, and sham surgery (SS) with 5 rats. The shuttlebox apparatus was utilized to assess the effect of Aβ on passive avoidance memory and to confirm disease induction. GDNF gene expression was measured using the qRT-PCR method. Results: The study found significant improvements in passive avoidance memory in the Aβ + AIT and Aβ + GB + AIT groups compared to the AC group after 8 weeks of AIT and GB supplementation (P = 0.02 and P = 0.000, respectively). Long-term memory performance was notably enhanced in the Aβ + GB + AIT group (P = 0.000). Additionally, GDNF expression significantly increased in the Aβ + GB + AIT and Aβ + GB groups in comparison to the AC group (P = 0.000 and P = 0.01, respectively). Conclusions: A synergistic effect of AIT and GB supplementation was observed, leading to an increase in GDNF gene expression and improvements in both passive avoidance memory and long-term memory in male rats with AD.

Protective effects of flaxseed oil against dexamethasone induced skeletal muscle atrophy on rats

The production of omega-3 fatty acids in the lipids of muscle tissue was boosted by flaxseed oil (Linum usitatissimum), which is well-described in the Ayurvedic system of medicine. In skeletal muscle disorders, atrophy is a major problem which arises due to cachexia, sarcopenia and immobilization. Nevertheless, despite significant efforts, few FDA-approved medications are available in the market to treat skeletal muscle atrophy. The current project was conceptualized to investigate the protective effects of flaxseed oil against dexamethasone-induced muscular atrophy in adult Sprague Dawley Rats. Marketed preparation of dexamethasone was used to induce muscle atrophy and flaxseed oil was administered orally after disease induction of 7 days till 28 days. Body weight and behavioural studies were carried out to assess muscle mass and glucose. Due to its high antioxidant and fatty acid Omega-3 content, flaxseed oil promotes significant improvements in diseased animals. Rats administered with flaxseed oil demonstrated great weight gain and a decreased blood sugar level. After three weeks-blood sugar levels, muscle mass, momentary changes in rats and HDL levels were all significantly higher in the dexamethasone alone treated control group animals. Flaxseed oil protects against the biochemical and histopathological changes caused due to dexamethasone toxicity. The findings of this study reveals that, flaxseed oil protects against dexamethasone induced skeletal muscle atrophy and protective effect may be due to flaxseed oil's antioxidant properties. However, further research is essential to prove the protective effects of flaxseed oil in some more studies mainly revealing its actions at cellular and molecular level.

Three- and Seven-month Prostate-specific Antigen Levels as Prognostic Markers for Overall Survival in Metastatic Hormone-sensitive Prostate Cancer: Results from SWOG S1216, a Phase 3 Randomized Trial of Androgen Deprivation Plus Orteronel or Bicalutamide

BackgroundA robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with metastatic hormone-sensitive prostate cancer (mHSPC) since 2006, but the treatment of mHSPC has since evolved to include intensified therapy. ObjectiveWe assessed the association of PSA levels at 3 (PSA-3mo) and 7 (PSA-7mo) mo with overall survival (OS) in patients with mHSPC treated with ADT combined with either bicalutamide or orteronel in the S1216 phase 3 clinical trial. Design, setting, and participantsPSA responses to treatment of patients in the S1216 trial were categorized as: complete response (CR) if PSA was ≤0.2 ng/ml, partial response if PSA was >0.2 and ≤4 ng/ml, and no response (NR) if PSA was >4 ng/ml. Outcome measurements and statistical analysisA Cox analysis (adjusted for treatment arm and three stratification factors: performance status, severity of disease, and early vs late induction) was used for OS association. While PSA-7mo association was a prespecified objective, PSA-3mo association was also evaluated. Results and limitationsA total of 1251 and 1231 patients from the S1216 study were evaluable for PSA-3mo and PSA-7mo, respectively. A PSA-7mo CR was associated with improved OS compared with NR (HR: 0.20; p < 0.0001). A PSA-3mo CR showed a similar association to NR (HR: 0.34; p < 0.0001). The association of a PSA response with survival did not differ by treatment arm at either time point. ConclusionsThe PSA-3mo and PSA-7mo responses were strongly associated with OS; taken with other emerging prognostic biomarkers, these markers may allow for early identification of patients at the highest risk of death, aid with counseling in clinical practice, and permit design of future clinical trials targeting these patients. Patient summaryA low prostate-specific antigen level at 3 or 7 mo after starting treatment for metastatic hormone-sensitive prostate cancer predicts longer survival regardless of the first treatment given with androgen deprivation therapy.

Супресивен ефект на почвата към ризоктонийно кореново гниене, индуциран чрез имитирана монокултура на пшеница

Disease decline and induction of soil suppressiveness by continuous (5-6 years) monoculture with susceptible plant-host have been reported for various crop-pathogen systems. The present study achieves the goal of inducing suppressive effect in soil towards Rhizoctonia root rot (Rhizoctonia solani AG 4) through monoculture of winter wheat (Triticum aestivum L.). Twenty four high-quality wheat (c. Exotic) seeds were planted in plastic containers, each containing 1.1 L Alluvial-Meadow (sandy-clay) soil (Eutric Fluvisols, according to FAO classification). According to the treatment applied, the resulting plants were grown for 0-4 successive short cropping cycles, each lasting three months. Disease suppressiveness was measured in a bioassay in which the experimental units were rectangular, plastic containers (26 x 6 x 8 cm), with drainage holes in the bottom and detachable trays allowing for manual irrigation from the bottom of the container, 7 cm height of the column of tested soil in each container and a two-row crop of wheat (c. Exotic, 2 rows x 12 plants, 2 x 3 cm plant spacing). The spread of the disease was measured from a focus (point) source of inoculum of the pathogen – 20 inoculum grains from a pure culture developed on autoclaved (30 min at 121 °C) barley, introduced into the soil at the beginning of both rows after emergence of the plants. Immediately after termination of the soil suppressiveness test, the abundance of the major groups of soil microorganisms were determined in rhizosphere soil in each treatment by using the method of decimal dilutions and subsequent culturing on agar media. Separately, bacteria of the genus Pseudomonas were isolated from the rhizosphere soil on King’s medium. The antagonistic activity of 10 Pseudomonas spp. isolates from each treatment was tested against R. solani AG 4 in vitro by the double culture method. The monoculture of wheat imitated under controlled conditions resulted in a significant (P&lt;0.05) reduction of the spread of Rhizoctonia root rot from the source of infection. Furthermore, statistically significant differences (P&lt;0.05) were also found between the individual treatments with pre-cultivation of wheat: with the increase in the number of cultivation cycles from one to four, there was a significant reduction in disease spread – by 19.5%, 31.0%, 40.5% and 54.8%, respectively, as compared to the untreated control. Simultaneously, no substantial alterations were observed in the population densities of the monitored groups of microorganisms in the rhizosphere of the experimental plants, including ammonifying and spore-forming bacteria, microscopic fungi, Actinomycetes and bacteria, utilizing mineral N. With the increase in soil suppressiveness from the first to the fifth growing cycle of the crop, a significant increase in the average antagonistic activity of the isolated Pseudomonas spp. against R. solani AG 4 was observed. The thesis is argued that shattering rachis of the ripe ear in wild forms conditioned a continuous “natural” monoculture in which bread wheat and its predecessors grew and evolve during the prehistoric era. We speculate that this condition, along with the lack of genes for resistance to necrotrophic pathogens, have given rise to evolutionary stable defence mechanism and the latter based on mutualistic relationships between the host-plant and bacteria that naturally inhabit rhizosphere and exhibiting high antagonistic (antibiotic) activity against soil-borne plant pathogens. A manifestation of this mechanism is the increasing suppressive response of the soil and the disease decline during or after continuous wheat monoculture. The results obtained in this study are discussed in the light of the microbial eco-evolutionary dynamics in the plant rhizosphere. The progressively increasing pathogen-antagonistic activity of Pseudomonas spp. isolates is discussed as an example of “rapid microbial evolution”, accomplished by possible horizontal gene transfer within one or more successive cultivation cycles of the wheat crop.

Rheumatoid arthritis: Appraisement of the new security warnings for JAK-inhibitors

Januskinase-Inhibitors (JAKI) are highly effective substances (JAKi) for the treatment of rheumatoid arthritis (RA). In terms of efficiency in reduction of disease activity and induction of remission they are partially prior to biologic (b) DMARDs. Presently the four substances tofacitinib, baricitinib, upadacitinib and filgotinib are approved for the treatment of RA. The prospective controlled ORAL-SURVEILLANCE-trial investigated the safety of tofacitinib in comparison to TNF-inhibitors. Current results now show that treatment with tofacitinib might be associated with an increased risk for cardiovascular events, thromboembolism and certain malignancies. Affected are patients >65y, current or former smoker and, regarding cardiovascular events, patients who already had such an event. On the basis of this trial the Committee for Medical Products for Human Use (CHMP) of the European Medicines Agency (EMA) formulated actual recommendations for prescription of JAKi in order to reduce the risk of severe undesirable effects. These apply not only for tofacitinib but as well for all other JAKI named above, as a class effect was supposed. The data and their consequences are discussed and evaluated in this work.

Evaluation of antisense oligonucleotide therapy targeting Hsd17b13 in a fibrosis mice model

Human genetic evidence suggests a protective role of loss-of-function variants in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) for liver fibrotic diseases. Although there is limited preclinical experimental data on Hsd17b13 antisense oligonucleotide (ASO) or siRNA in a fibrosis model, several ASO and siRNA approaches are being tested clinically as potential therapies for nonalcoholic steatohepatitis (NASH). The aim of this study was to assess the therapeutic potential of Hsd17b13 ASO in a preclinical advanced NASH-like hepatic fibrosis in vivo model. In vitro testing on primary hepatocytes demonstrated that Hsd17b13 ASO exhibited strong efficacy and specificity for knockdown of the Hsd17b13 gene. In choline-deficient, L-amino acid-defined, HFD (CDAHFD)-induced steatotic and fibrotic mice, therapeutic administration of Hsd17b13 ASO resulted in a significant and dose-dependent reduction of hepatic Hsd17b13 gene expression. The CDAHFD group exhibited considerably elevated liver enzyme levels, hepatic steatosis score, hepatic fibrosis, and increased fibrotic and inflammatory gene expression, indicating an advanced NASH-like hepatic fibrosis phenotype. Although Hsd17b13 ASO therapy significantly affected hepatic steatosis, it had no effect on hepatic fibrosis. Our findings demonstrate, for the first time, that Hsd17b13 ASO effectively suppressed Hsd17b13 gene expression both in vitro and in vivo, and had a modulatory effect on hepatic steatosis in mice, but did not affect fibrosis in the CDAHFD mouse model of NASH.

Beyond drug discovery: Exploring the physiological and methodological dimensions of zebrafish in diabetes research.

Diabetes mellitus is a chronic disease that is now considered a global epidemic. Chronic diabetes conditions include type 1 and type 2 diabetes, both of which are normally irreversible. As a result of long-term uncontrolled high levels of glucose, diabetes can progress to hyperglycaemic pathologies, such as cardiovascular diseases, retinopathy, nephropathy and neuropathy, among many other complications. The complete mechanism underlying diabetes remains unclear due to its complexity. In this scenario, zebrafish (Danio rerio) have arisen as a versatile and promising animal model due to their good reproducibility, simplicity, and time- and cost-effectiveness. The Zebrafish model allows us to make progress in the investigation and comprehension of the root cause of diabetes, which in turn would aid in the development of pharmacological and surgical approaches for its management. The current review provides valuable reference information on zebrafish models, from the first zebrafish diabetes models using genetic, disease induction and chemical approaches, to the newest ones that further allow for drug screening and testing. This review aims to update our knowledge related to diabetes mellitus by gathering the most authoritative studies on zebrafish as a chemical, dietary and insulin induction, and genetic model for diabetes research.

Potential of Solanum betaceum to improve cognition: A systematic review of animal studies

Context: Solanum betaceum is rich in bioactive compounds associated with various health applications, including plausible benefits on cognitive impairment caused by neurodegenerative diseases such as Alzheimer’s disease (AD). Aims: To investigate the potential benefit of consuming S. betaceum to alleviate cognitive and memory decline. Methods: The review was conducted as a systematic review of an in vivo animal study. A search was performed of five databases using the keywords: “solanum betaceum”, “S. betaceum”, “tamarillo”, “neurodegenerative diseases”, “memory loss”, “cognitive impairment”. SYRCLE tool was used to assess the risk of bias. Data on the underlying molecular mechanisms of behavioral efficacy was additionally collected. Results: A total of 66 journals were retrieved from the databases, resulting in 3 eligible studies. All included studies used albino rats as an AD animal model that were accustomed to laboratory conditions for about a week prior to the disease induction. In two studies, aluminum chloride (AlCl3) was utilized to induce memory deficit, while another study used cigarette smoke. The result indicated that S. betaceum contained compounds such as phenolic and anthocyanin, which were plausibly responsible for the positive cognitive outcomes through molecular interaction with intracellular signaling protein cascades associated with anti-inflammation, brain oxygenation, synaptic plasticity, and cell viability. Further preclinical studies are needed to confirm these potentials. Conclusions: This systematic review of the current evidence on the behavioral and biological influences of S. betaceum administration on AD animal models pointed out that the fruit might improve cognitive performance and prevent cognitive deterioration raised by several neurotoxins.

Single-cell resolution of human airway epithelial cells exposed to bronchiolitis obliterans-associated chemicals.

Bronchiolitis obliterans (BO) is a fibrotic lung disease characterized by progressive luminal narrowing and obliteration of the small airways. In the nontransplant population, inhalation exposure to certain chemicals is associated with BO; however, the mechanisms contributing to disease induction remain poorly understood. This study's objective was to use single-cell RNA sequencing for the identification of transcriptomic signatures common to primary human airway epithelial cells after chemical exposure to BO-associated chemicals-diacetyl or nitrogen mustard-to help explain BO induction. Primary airway epithelial cells were cultured at air-liquid interface and exposed to diacetyl, nitrogen mustard, or control vapors. Cultures were dissociated and sequenced for single-cell RNA. Differential gene expression and functional pathway analyses were compared across exposures. In total, 75,663 single cells were captured and sequenced from all exposure conditions. Unbiased clustering identified 11 discrete phenotypes, including 5 basal, 2 ciliated, and 2 secretory cell clusters. With chemical exposure, the proportion of cells assigned to keratin 5+ basal cells decreased, whereas the proportion of cells aligned to secretory cell clusters increased compared with control exposures. Functional pathway analysis identified interferon signaling and antigen processing/presentation as pathways commonly upregulated after diacetyl or nitrogen mustard exposure in a ciliated cell cluster. Conversely, the response of airway basal cells differed significantly with upregulation of the unfolded protein response in diacetyl-exposed basal cells, not seen in nitrogen mustard-exposed cultures. These new insights provide early identification of airway epithelial signatures common to BO-associated chemical exposures.NEW & NOTEWORTHY Bronchiolitis obliterans (BO) is a devastating fibrotic lung disease of the small airways, or bronchioles. This original manuscript uses single-cell RNA sequencing for identifying common signatures of chemically exposed airway epithelial cells in BO induction. Chemical exposure reduced the proportion of keratin 5+ basal cells while increasing the proportion of keratin 4+ suprabasal cells. Functional pathways contributory to these shifts differed significantly across exposures. These new results highlight similarities and differences in BO induction across exposures.

Active Induction of a Multiple Sclerosis-Like Disease in Common Laboratory Mouse Strains.

Experimental autoimmune encephalomyelitis (EAE) is a neuroinflammatory disease with facets in common with multiple sclerosis (MS). It is induced in susceptible mammalian species, with rodents as the preferred hosts, and has been used for decades as a model to investigate the immunopathogenesis of MS as well as for preclinical evaluation of candidate MS therapeutics. Most commonly, EAE is generated by active immunization with central nervous system (CNS) antigens, such as whole CNS homogenate, myelin proteins, or peptides derived from these proteins. However, EAE actually represents a spectrum of diseases in which specific combinations of host/CNS antigen exhibit defined clinical profiles, each associated with unique immunological and pathological features. Similar to MS, EAE is a complex disease where development and progression are also modulated by environmental factors; therefore, the establishment of any given EAE variant can be challenging and requires careful optimization. Here, we describe protocols for three EAE variants, successfully generated in our laboratory, and provide additional information as to how to maintain their unique features and reproducibility.

Practical application of the Crohn's disease exclusion diet as therapy in an adult Australian population.

There is demand from patients and clinicians to use the Crohn's disease exclusion diet (CDED) with or without partial enteral nutrition (PEN). However, the therapeutic efficacy and nutritional adequacy of this therapy are rudimentary in an adult population. This review examines the evidence for the CDED in adults with active luminal Crohn's disease and aims to provide practical guidance on the use of the CDED in Australian adults. A working group of nine inflammatory bowel disease (IBD) dietitians of DECCAN (Dietitians Crohn's and Colitis Australian Network) and an IBD gastroenterologist was established. A literature review was undertaken to examine (1) clinical indications, (2) monitoring, (3) dietary adequacy, (4) guidance for remission phase, and (5) diet reintroduction after therapy. Each diet phase was compared with Australian reference ranges for food groups and micronutrients. CDED with PEN is nutritionally adequate for adults containing sufficient energy and protein and meeting >80% of the recommended daily intake of key micronutrients. An optimal care pathway for the clinical use of the CDED in an adult population was developed with accompanying consensus statements, clinician toolkit, and patient education brochure. Recommendations for weaning from the CDED to the Australian dietary guidelines were developed. The CDED+PEN provides an alternate partial food-based therapy for remission induction of active luminal Crohn's disease in an adult population. The CDED+PEN should be prioritized over CDED alone and prescribed by a specialist IBD dietitian. DECCAN cautions against using the maintenance diet beyond 12weeks until further evidence becomes available.

Clinical Manifestations.

The accumulation of toxic amyloid-ß protein in brain is a hallmark of Alzheimer's disease. The accumulation of such toxicants is prevented by a cellular protein quality control system. Molecular chaperons, which further prevent proteins from misfolding and aggregating, are produced by this system, which is mostly activated in response to acute thermal stress. This study aims to determine the therapeutic effect of frequent thermal shock on the development of Alzheimer's disease METHOD: The induction of Alzheimer's disease was caused by the intracerebroventricular (ICV) injection of the Aß (1-42) peptide into the ventricular system of the mouse brain. The animals were divided into four groups: normal control (NC), disease control (DC), sham control (SC), water immersion/no heat group (NH), and hot water immersion/high heat group (HH). The ICV-Aß injection was given to the DC, NH, and HH groups to induce dementia and AD-like symptoms. The animals in the HH treatment group were given heat shock in the form of hot water immersion for a period of 4 weeks, where each session lasted for 20 minutes. The animals in the NH group were also exposed to water immersion for 20 minutes daily for a period of 4 weeks, but the water temperature was maintained at room temperature. After the completion of the treatment period, the behavioural and biochemical parameters of the animals were assessed for learning and memory defects. The enzyme-linked immunosorbent assay (ELISA) was carried out for the Aß estimation. Behavioural assessments in the Y-maze and morris water maze showed that the animals given daily heat exposure for a period of 4 weeks resisted the detrimental memory effects of the ICV-Aß injection and had better memory than the water immersion group with no heat treatment given. Increased levels of lipid peroxidation and decreased levels of glutathione were significantly (p<0.05) antagonised by hot water immersion treatment. ELISA showed the lower level of Aß in hot water immersion/high heat group animals when compared to the disease control animals. The study concluded that frequent heat exposure from hot baths and saunas may reduce the risk of developing dementia and Alzheimer's-like symptoms in old age.

Dysregulation of miRNA expression in patients with chronic myelogenous leukemia at diagnosis: a systematic review.

Aim: The present systematic review aimed to explore miRNAs as a potential biomarker for early diagnosis of chronic myeloid leukemia (CML). Materials & methods: A systematic search was conducted in three electronic databases, including Web of Science, Scopus and PubMed, to obtain relevant articles investigating the alteration of miRNA expression in patients with CML. Results: The authors found miRNAs whose expression changes are effective in the induction of CML disease. Among them, miR-21 and miR-155 were identified as the most common miRNAs with increased expression and miR-150 and miR-146 as the most common miRNAs with decreased expression. Conclusion: miRNAs can be used as an indicator for the early detection and treatment of CML phase.

Noninvasive PET Detection of CD69-Positive Immune Cells Before Signs of Clinical Disease in Inflammatory Arthritis.

Rheumatoid arthritis (RA) is the most common inflammatory joint disease, and early diagnosis is key for effective disease management. CD69 is one of the earliest cell surface markers seen at the surface of activated immune cells, and CD69 is upregulated in synovial tissue in patients with active RA. In this study, we evaluated the performance of a CD69-targeting PET agent, [68Ga]Ga-DOTA-ZCAM241, for early disease detection in a model of inflammatory arthritis. Methods: A model of inflammatory arthritis was induced by transferring splenocytes from KRN T-cell receptor transgenic B6 mice into T-cell-deficient I-Ag7 major histocompatibility complex class II-expressing recipient mice. The mice were examined longitudinally by [68Ga]Ga-DOTA-ZCAM241 PET/CT before and 3, 7, and 12 d after induction of arthritis. Disease progression was monitored by clinical parameters, including measuring body weight and scoring the swelling of the paws. The uptake of [68Ga]Ga-DOTA-ZCAM241 in the paws was analyzed and expressed as SUVmean Tissue biopsy samples were analyzed for CD69 expression by flow cytometry or immunostaining for a histologic correlate. A second group of mice was examined by a nonbinding, size-matched Affibody molecule as the control. Results: Clinical symptoms appeared 5-7 d after induction of arthritis. The uptake of [68Ga]Ga-DOTA-ZCAM241 in the joints was negligible at baseline but increased gradually after disease induction. An elevated PET signal was found on day 3, before the appearance of clinical symptoms. The uptake of [68Ga]Ga-DOTA-ZCAM241 correlated with the clinical score and disease severity. The presence of CD69-positive cells in the joints and lymph nodes was confirmed by flow cytometry and immunostaining. The uptake of the nonbinding tracer that was the negative control also increased gradually with disease progression, although to a lesser extent than with [68Ga]Ga-DOTA-ZCAM241 Conclusion: The uptake of [68Ga]Ga-DOTA-ZCAM241 in the inflamed joints preceded the clinical symptoms in the KRN T-cell transfer model of inflammatory arthritis, in accordance with immunostaining for CD69. [68Ga]Ga-DOTA-ZCAM241 is thus a promising PET imaging marker of activated immune cells in tissue during RA onset.

Lupus mice derived mesenchymal stromal cells: Beneficial or detrimental on SLE disease outcome

BackgroundSystemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies against nuclear genes, deposition of immune complexes, and autoimmune T cells, through which, tissue damage would ultimately occur. Furthermore, loss of immune tolerance and imbalance of Th1/Th2 cells in addition to Th17/Treg are contributed to the pathogenesis of SLE. Mesenchymal stromal cells (MSCs) infusion is a potential therapy for SLE disease. Despite a majority of SLE patients achieving clinical remission after allogeneic MSC infusion from healthy individuals, SLE patients have less benefited from autologous MSC infusion, justifying the probable compromised function of SLE patients-derived MSCs. In this study, we aim to further investigate the potential immunoregulatory mechanisms in which mesenchymal stromal cells derived from pristane-induced lupus mice, following injection into healthy and lupus mice, exert their possible effects on the lupus process. Method40 female Balb/c mice aged 3 weeks were purchased and randomly divided into six groups. First, lupus disease was induced into the lupus groups by intraperitoneal injection of pristane and then the mice were surveyed for 6 months. The body weight, anti-dsDNA autoantibody levels, serum creatinine, and Blood Urea Nitrogen (BUN) levels were measured in two-month intervals. After 6 months, the group of lupus mice was sacrificed, and lupus MSCs were isolated. Two months later, cultured lupus MSCs were intravenously injected into two groups of healthy and lupus mice. After two months, the mice were euthanized and the kidneys of each group were examined histologically by hematoxylin & eosin (H&E) staining and the immunofluorescence method was also performed to evaluate IgG and C3 deposition. The frequency of splenic Th1, Th2, Th17, and Treg cells was measured by flow cytometry. Moreover, the cytokine levels of IFN-γ, IL-4, IL-17, and TGF-β in sera were measured by ELISA method. ResultsOur results showed that the induction of lupus disease by pristane in Balb/c mice caused the formation of lipogranuloma, increased levels of anti-dsDNA autoantibodies, and impaired renal function in all pristane-induced lupus groups. In addition, the injection of lupus mesenchymal stromal cells (L-MSC) into healthy and lupus mice led to a further rise in anti-dsDNA serum levels, IgG and C3 deposition, and further dysfunction of mice renal tissue. Also, the flow cytometry results implicated that compared to the control groups, splenic Th1, Th2, and Th17 inflammatory cell subtypes and their secreted cytokines (IFN-γ, IL-4, and IL-17) in the sera of healthy and lupus mice were increased after the intake of L-MSC. Additionally, the splenic Treg cells were also significantly increased in the lupus mice receiving L-MSC. However, a decrease in serum levels of TGF-β cytokine was observed in healthy and lupus mice following L-MSC injection. In contrast, the lupus mice receiving healthy mesenchymal stem cells (H-MSC) manifested opposite results. ConclusionIn a nutshell, our results suggest that although allogeneic MSCs are encouraging candidates for SLE treatment, syngeneic MSCs may not be eligible for treating SLE patients due to their defects in regulating the immune system in addition to their capability in promoting inflammation which would consequently worsen the SLE disease status.

A small molecule chaperone rescues keratin-8 mediated trafficking of misfolded podocin to correct genetic Nephrotic Syndrome

Podocin is a key membrane scaffolding protein of the kidney podocyte essential for intact glomerular filtration. Mutations in NPHS2, the podocin-encoding gene, represent the commonest form of inherited nephrotic syndrome (NS), with early, intractable kidney failure. The most frequent podocin gene mutation in European children is R138Q, causing retention of the misfolded protein in the endoplasmic reticulum. Here, we provide evidence that podocin R138Q (but not wild-type podocin) complexes with the intermediate filament protein keratin 8 (K8) thereby preventing its correct trafficking to the plasma membrane. We have also identified a small molecule (c407), a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator protein defect, that interrupts this complex and rescues mutant protein mistrafficking. This results in both the correct localization of podocin at the plasma membrane and functional rescue in both human patient R138Q mutant podocyte cell lines, and in a mouse inducible knock-in model of the R138Q mutation. Importantly, complete rescue of proteinuria and histological changes was seen when c407 was administered both via osmotic minipumps or delivered orally prior to induction of disease or crucially via osmotic minipump two weeks after disease induction. Thus, our data constitute a therapeutic option for patients with NS bearing a podocin mutation, with implications for other misfolding protein disorders. Further studies are necessary to confirm our findings.

A pro-inflammatory gut mucosal cytokine response is associated with mild COVID-19 disease and superior induction of serum antibodies

The relationship between gastrointestinal tract infection, the host immune response, and the clinical outcome of disease is not well understood in COVID-19. We sought to understand the effect of intestinal immune responses to SARS-CoV-2 on patient outcomes including the magnitude of systemic antibody induction. Combining two prospective cohort studies, International Severe Acute Respiratory and emerging Infections Consortium Comprehensive Clinical Characterisations Collaboration (ISARIC4C) and Integrated Network for Surveillance, Trials and Investigations into COVID-19 Transmission (INSTINCT), we acquired samples from 88 COVID-19 cases representing the full spectrum of disease severity and analysed viral RNA and host gut cytokine responses in the context of clinical and virological outcome measures. There was no correlation between the upper respiratory tract and faecal viral loads. Using hierarchical clustering, we identified a group of fecal cytokines including Interleukin-17A, Granulocyte macrophage colony-stimulating factor, Tumor necrosis factorα, Interleukin-23, and S100A8, that were transiently elevated in mild cases and also correlated with the magnitude of systemic anti-Spike-receptor-binding domain antibody induction. Receiver operating characteristic curve analysis showed that expression of these gut cytokines at study enrolment in hospitalised COVID-19 cases was associated negatively with overall clinical severity implicating a protective role in COVID-19. This suggests that a productive intestinal immune response may be beneficial in the response to a respiratory pathogen and a biomarker of a successful barrier response.