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Caspase-1 As a Therapeutic Target in Intravascular Hemolysis-Induced Microvascular Inflammation and Occlusive Processes

Hemolytic anemias, such as sickle cell disease (SCD), are a group of acute and acquired conditions characterized by the accelerated destruction of red blood cells (RBC). Intravascular hemolysis (IVH), or RBC lysis within the bloodstream, incurs the release of damage-associated molecular patterns (DAMPs), trigging cell activation and immune responses. Caspase-1 (Casp-1), a protease enzyme, plays a critical role during inflammatory processes by initiating programed cell death and promoting the cleavage of pro-interleukin (IL)-1β into its active form, IL-1β, through inflammasome assembly. Here, we aimed to elucidate the complex mechanisms involved in IVH-induced inflammation, leukocyte-endothelium interactions, and microvascular dynamics. Acute IVH was induced in C57BL/6 mice (HEM) by the injection of sterile water (i.v., 150 µl), and control mice received i.v. saline (CON) (n=3-8 per group). Intravital microscopy was performed at 15 min post IVH induction on the cremaster muscle of mice to quantify venular leukocyte (WBC) rolling and adhesion, and non-invasive laser Doppler flowmetry (LDF) measured blood perfusion in the murine pelvis microvasculature. Blood samples were collected at 1-hour post-IVH for ELISA and flow cytometry analyses. Immortalized human endothelial cells (HUVEC; n=7 per group) were stimulated with heme or S100A8 for 3 hours. HEM mice demonstrated significantly increased plasma heme (P<0.0001) and cell-free hemoglobin (P<0.001), in association with significantly decreased plasma haptoglobin (P<0.05), compared to CON mice, thereby confirming the occurrence of IVH. Furthermore, HEM mice exhibited significantly increased plasma concentrations of the S100A8 alarmin (P<0.001) and IL1-β (P<0.001), as well as augmentations (P<0.001) in plasma TNF-ɑ and IL-6 levels. Flow cytometry was used to measure active Casp-1 in neutrophils and monocytes of mice using the FAM-FLICA probe. FLICA staining was significantly higher in the neutrophils (P<0.05) and monocytes (P<0.05) of HEM mice, compared to CON mice, implying Casp-1 activation in these cell subsets. WBC-endothelium interactions are a hallmark of vaso-occlusion in SCD. HEM mice exhibited elevated venular WBC rolling and adhesion to the endothelium, compared to CON mice (P<0.001), as previously shown (Almeida et al., 2015; PMID: 26019278). In addition, IVH significantly reduced the velocity of microvascular blood flow in mice (P<0.001), and impaired perfusion (P<0.001). To address the role of IVH-induced Casp-1 activation in microvascular dynamics, mice received i.p. administrations of the Casp-1 inhibitor, YVAD, at 1 hour prior to induction of IVH, or not, and were subjected to intravital microscopy or LDF. Interestingly, the inhibition of Casp-1 significantly abrogated IVH-induced WBC rolling (P<0.01) and adhesion to vessel walls (P<0.05) in HEM mice and significantly improved microvascular blood perfusion and flow velocity (P<0.05), suggesting a role for Casp-1 activation in the WBC-endothelium and occlusive interactions observed (See Figure). We then evaluated how heme and S100A8 may induce endothelial cell activation, as these DAMPs were found elevated in the plasma of HEM mice. As expected, compared to unstimulated HUVEC, heme induced endothelial cell activation in vitro, as shown by higher expressions of ICAM-1 (P<0.05), VCAM-1 (P<0.01) and E-selectin (P<0.01), and increased Casp-1 activity (P<0.01). In turn, S100A8 alone significantly elevated ICAM-1 (P<0.05) and E-selectin (P<0.01) expressions on HUVEC, as well as IL-1β release (P<0.001), however no significant increase in Casp-1 activity was observed. HUVEC, when pre-treated with YVAD, displayed a significant reduction in S100A8-induced E-selectin expression (P<0.05), but neither ICAM-1 nor VCAM-1 expression were significantly decreased. In contrast, no changes in the expressions of these adhesion molecules were observed in heme-stimulated cells after YVAD treatment. Taken together, these findings suggest that targeting caspase-1 activation and its associated pathways may represent a potential therapeutic intervention to mitigate the adverse inflammatory and microvascular effects of IVH, a disease mechanism that occurs in severe hemolytic anemias such as SCD.

S-nitrosylation switches the Arabidopsis redox sensor protein, QSOX1, from an oxidoreductase to a molecular chaperone under heat stress

The Arabidopsis quiescin sulfhydryl oxidase 1 (QSOX1) thiol-based redox sensor has been identified as a negative regulator of plant immunity. Here, we have found that small molecular weight proteins of QSOX1 were converted to high molecular weight (HMW) complexes upon exposure to heat stress and that this was accompanied by a switch in QSOX1 function from a thiol-reductase to a molecular chaperone. Plant treatment with S-nitrosoglutathione (GSNO), which causes nitrosylation of cysteine residues (S-nitrosylation), but not with H2O2, induced HMW QSOX1 complexes. Thus, functional switching of QSOX1 is induced by GSNO treatment. Accordingly, simultaneous treatment of plants with heat shock and GSNO led to a significant increase in QSOX1 chaperone activity by increasing its oligomerization. Consequently, transgenic Arabidopsis overexpressing QSOX1 (QSOX1OE) showed strong resistance to heat shock, whereas qsox1 knockout plants exhibited high sensitivity to heat stress. Plant treatment with GSNO under heat stress conditions increased their resistance to heat shock. We conclude that S-nitrosylation allows the thiol-based redox sensor, QSOX1, to respond to various external stresses in multiple ways.

In vitro effects of a natural marine algae polysaccharide (λ-carrageenan) on seabream erythrocytes, tumour cell lines and marine bacterial pathogens

AbstractCarrageenan is a high molecular weight sulphated polysaccharide used to induce experimental inflammation in mammals. In addition, it possesses a wide variety of properties that have not yet been studied in fish. This study evaluated the hemagglutinating, hemolytic, cytotoxic, and antibacterial activities of λ-carrageenan. The results showed that λ-carrageenan has hemagglutinating and hemolytic activities on gilthead seabream erythrocytes, which were dose and time-dependent during the first 6 h of incubation. No significant effects on the haemolytic activity of erythrocytes were observed after incubation for 12 or 24 h with λ-carrageenan. The PLHC-1 cell line showed significant increases in cytotoxic activity after 6 or 12 h of incubation compared with control cells, and the highest doses of λ-carrageenan caused cytotoxicity in PLHC-1 cells after 24 h of incubation. The morphology of PLHC-1 cells incubated with the highest doses of λ-carrageenan for 12 or 24 h showed obvious cell death changes compared with control cells. Interestingly, no significant variations in cytotoxic activity were observed in SAF-1 cell line after incubation with λ-carrageenan. Furthermore, λ-carrageenan showed significant dose-dependent bactericidal activity against Photobacterium damselae but had no significant effect on the bactericidal activity of Vibrio harveyi, Vibrio anguillarum, and Tenacibaculum maritimum. The study suggests that λ-carrageenan has potential applications in aquaculture and aquatic pharmaceutical industries as a hemagglutinating, hemolytic, and antibacterial agent.

Metabolic Mechanisms Underlying Heat and Drought Tolerance in Lentil Accessions: Implications for Stress Tolerance Breeding

Climate change has significantly exacerbated the effects of abiotic stresses, particularly high temperatures and drought stresses. This study aims to uncover the mechanisms underlying heat and drought tolerance in lentil accessions. To achieve this objective, twelve accessions were subjected to high-temperature stress (32/20 °C), while seven accessions underwent assessment under drought stress conditions (50% of field capacity) during the reproductive stage. Our findings revealed a significant increase in catalase activity across all accessions under both stress conditions, with ILL7814 and ILL7835 recording the highest accumulations of 10.18 and 9.33 under drought stress, respectively, and 14 µmol H2O2 mg protein−1 min−1 under high temperature. Similarly, ascorbate peroxidase significantly increased in all tolerant accessions due to high temperatures, with ILL6359, ILL7835, and ILL8029 accumulating the highest values with up 50 µmol ascorbate mg protein−1 min−1. In contrast, no significant increase was obtained for all accessions subjected to water stress, although the drought-tolerant accessions accumulated more APX activity (16.59 t to 25.08 µmol ascorbate mg protein−1 min−1) than the sensitive accessions. The accessions ILL6075, ILL7814, and ILL8029 significantly had the highest superoxide dismutase activity under high temperature, while ILL6363, ILL7814, and ILL7835 accumulated the highest values under drought stress, each with 22 to 25 units mg protein−1. Under both stress conditions, ILL7814 and ILL7835 recorded the highest contents in proline (38 to 45 µmol proline/g FW), total flavonoids (0.22 to 0.77 mg QE g−1 FW), total phenolics (7.50 to 8.79 mg GAE g−1 FW), total tannins (5.07 to 20 µg CE g−1 FW), and total antioxidant activity (60 to 70%). Further, ILL7814 and ILL6338 significantly recorded the highest total soluble sugar content under high temperature (71.57 and 74.24 mg g−1, respectively), while ILL7835 achieved the maximum concentration (125 mg g−1) under drought stress. The accessions ILL8029, ILL6104, and ILL7814 had the highest values of reducing sugar under high temperature with 0.62 to 0.79 mg g−1, whereas ILL6075, ILL6363, and ILL6362 accumulated the highest levels of this component under drought stress with 0.54 to 0.66 mg g−1. Overall, our findings contribute to a deeper understanding of the metabolomic responses of lentil to drought and heat stresses, serving as a valuable reference for lentil stress tolerance breeding.

Long-term HIF-1α stabilization reduces respiration, promotes mitophagy, and results in retinal cell death

Ocular hypertension during glaucoma can lead to hypoxia, activation of the HIF transcription factors, and a metabolic shift toward glycolysis. This study aims to test whether chronic HIF activation and the attendant metabolic reprogramming can initiate glaucoma-associated pathology independently of ocular hypertension. HIF-1α stabilization was induced in mice for 2 and 4 weeks by inhibiting prolyl hydroxylases using the small molecule Roxadustat. HIF-1α stabilization and the expression of its downstream bioenergetic targets were investigated in the retina by immunofluorescence, capillary electrophoresis, and biochemical enzyme activity assays. Roxadustat dosing resulted in significant stabilization of HIF-1α in the retina by 4 weeks, and upregulation in glycolysis-associated proteins (GLUT3, PDK-1) and enzyme activity in both neurons and glia. Accordingly, succinate dehydrogenase, mitochondrial marker MTCO1, and citrate synthase activity were significantly decreased at 4 weeks, while mitophagy was significantly increased. TUNEL assay showed significant apoptosis of cells in the retina, and PERG amplitude was significantly decreased with 4 weeks of HIF-1α stabilization. A significant increase in AMPK activation and glial hypertrophy, concomitant with decreases in retinal ganglion cell function and inner retina cell death suggests that chronic HIF-1α stabilization alone is detrimental to retina metabolic homeostasis and cellular survival.

The puzzling etiologies of transient black discoloration in Nile Tilapia (Oreochromis niloticus) intensively cultured under RAS system

The aim of this study is to identify the hidden etiologies of the black chromo-shifting transient phenomenon affecting Nile tilapia, Oreochromis niloticus, farmed in RAS-controlled ponds together with the assessment of the immunological reaction against the chronic irritating effects of the invasive agent. A total of 100 Nile Tilapia were collected from a private farm at Kafrelsheikh Province, located on the northern side of the Egyptian Nile Delta. The clinical history of the affected fish farm showed an unknown chromo-shifting phenomenon where tilapias were exhibiting severe black skin coloration, which gradually disappeared after removal from the tank’s water. A comprehensive gross examination of the collected fish; including parasitological examination of skin and gill scraps, was performed. Blood biochemical testing was performed on the infested blackish O. niloticus and control non-infested fish. The current study showed that the monogenean parasite, Gyrodactylus cichlidarum, was the abundant parasite detected in the infested fish leading to abnormal black discoloration of skin and disruption of the immune system represented by significant increase of cortisol levels, lysozyme activity and different liver enzymes compared to the control. Treatment trials have been applied with moderate degrees of success, where the monogenean count was sharply decreased, and the normal skin color was remarkably restored, at the end of day 14 post-treatment. A triple treatment plan was initiated through 7 days’ application of 0.7 g/m3 copper sulfates pentahydrate preceded by 1.5 ml/m3 hydrogen peroxide 40% solution for the same period. One day after the end of the initial treatment, a maintenance dosage of 0.095 ml/m3 of glutaraldehyde (15%)/quaternary ammonium compounds (QACs) mixture was administered for 3 days. As a supportive/immune-stimulant regimen, a weekly dosage of vitamin C (0.45 g g/m3) and Saccharomyces cerevisiae (0.45 g/m3) was added into the tank’s water to improve the general fish health.

Searching for Evidence: A Systematic Review of the Pathology of Lipoedema

Lipoedema is a symmetrically localised, painful hypertrophy of subcutaneous adipose tissue in the extremities with marked disproportion to the trunk, and almost exclusively affects females. Despite being first described over 80 years ago, the aetiology and pathogenesis of the disease are largely unknown and are currently the subject of intensive research efforts. To summarise the current evidence-based literature on the cellular pathologies and aetiology of lipoedema, a PRISMA-based systematic review was conducted within the National Library of Medicine and Cochrane databases. A total of 53 studies were identified and included in this review. The results were classified and summarised into categories. Although there has been a significant increase in research activity and recent publication of extensive studies with a histological and molecular genetic focus, the fundamental aetiology and pathology of lipoedema remains largely unclear. The current data shows discrepancies across studies, particularly with regard to the "oedematous" component of lipoedema. The frequently present comorbidities "lymphoedema" and "obesity", primarily in advanced stages of lipoedema, complicate the diagnostic differentiation and clear definition of study cohorts in scientific research.

Alkaloid-rich extract of Buchholzia coriacea seed mitigate the effect of copper-induced toxicity in Drosophila melanogaster

AbstractBuchholzia coriacea is known for its anti-oxidative, anti-inflammatory, and anti-diabetic properties. This study evaluated the effect of alkaloid-rich extract of Buchholzia coriacea seed (ArEBCs) against copper-induced toxicity in Drosophila melanogaster. The flies were exposed to graded doses (25 to 200 mg/kg diet) of ArEBCs for 12 days and thereafter, a survival test was carried out to determine the safe and therapeutic doses used in the ameliorative study. For this, flies were exposed to CuSO4 (1 mM) alone or in combination with ArEBCs (25 and 50 mg/kg diet) for 5 days. Locomotor activity and biochemical assays such as glucose (GLU) level, acetylcholinesterase (AChE) activity, malonaldehyde (MDA) and antioxidant biomarkers (catalase and reduced glutathione) were performed to assess the effect of ArEBCs on the copper-induced flies. Copper-exposed flies showed reduced survival rates and disrupted locomotor activity when compared to the control flies. In addition, a significant (p < 0.05) increase in AChE activity, GLU and MDA levels and a decrease in the antioxidant biomarkers activities were observed in the copper-exposed flies. Treatment of flies with ArEBCs mitigated the negative effect of copper on the flies by increasing the survival rate of the flies, reducing the activities of AChE, GLU and MDA. The activities of the cellular antioxidant status were also significantly (p < 0.05) increased. This study suggests that ArEBCs could mitigate the effect of copper-induced oxidative damage in Drosophila melanogaster and could be considered a potential therapeutic agent against copper-induced oxidative damage.

Assembly of two trinuclear-cluster-based metal-organic frameworks: Structures and methanol electro-oxidation properties

The direct methanol fuel cell (DMFC) is an efficient and non-polluting green energy conversion device. However, the electrocatalysts for the anodic methanol oxidation reaction (MOR) in DMFC are often precious metal catalysts, which suffer from high cost, poor stability, and easy deactivation. In this work, two isostructural metal-organic frameworks (MOFs) [M3(μ3-OH)(TATB)(Nic)2(H2O)2(DMA)] (M = Co, Ni) were successfully synthesized under solvothermal conditions. Both frameworks possess a unique trinuclear cluster [M3(μ3-OH)(COO)5] secondary building unit (SBU) and a rare binodal (3,7)-connected network. Due to the high density of metal sites and prominent pore system within CTGU-36-Ni, it can serve as an effective molecular electrocatalyst for MOR, while CTGU-36-Co is an inert material. Further experimental results showed that the introduction of conductive substances could lead to a significant increase in the MOR area activity of CTGU-36-Ni. This work not only provides a non-noble metal molecular MOR electrocatalyst but also opens a new vision for the design and application of crystalline materials in various energy conversion processes.

Char and soot records of the Holocene fire history and its implications for climate-vegetation change and human activities within the Guanzhong Basin, southern Loess Plateau, China

Black carbon in sediments has been widely used as a proxy for biomass burning/fire activity to reconstruct fire history and its evolution. Wildfire studies have revealed that different types of black carbon (char and soot) are formed due to changes in combustion efficiency. In this study, we obtained black carbon and its two subtypes, char and soot, from a typical Holocene aeolian loess-paleosol section in the Chilanqiao Ruins within the Guanzhong Basin, southern Loess Plateau, China. Combined with environmental proxies such as magnetic susceptibility, loss on ignition, and geochemical elements, along with AMS14C and optically stimulated luminescence (OSL) dates, we reconstructed the Holocene fire history and its evolution on the southern Loess Plateau at local and regional scales. The findings indicate that the limited vegetation during the relatively dry and cold early Holocene may have inhibited the spread of fires. In the warmer and wetter middle Holocene, there was higher local smoldering fire activity, likely influenced by both wet climatic conditions and an increase in the proportion of woody plants. Additionally, the fire history in relation to human activities at Shang Dynasty (1600–1046 BCE) including land reclamation, house construction, and bronze casting has also been identified. There has been a significant increase in regional flaming fire activity in the late Holocene as a result of drier climate and increased human activity. Notably, the significant increase in regional flaming fire activity since ~1.00 ka can be primarily linked to human-set fires with the usage of gunpowder in frequent wars. This research holds great importance in enhancing our understanding of the long-term interactions among fire activities, climate change and human activities.

Butyl benzyl phthalate induced reproductive toxicity in the endoplasmic reticulum and oxidative stress in Brachionus plicatilis Müller, 1786

To study the adverse effects of butyl benzyl phthalate (BBP) on Brachionus plicatilis, rotifers were exposed to different BBP concentrations (0 [control], 0.001, 0.01, 0.1, and 1 mg/L). We measured the activities of the antioxidant enzymes superoxide dismutase, catalase, and reduced glutathione, which play a key role in detoxification, and the malondialdehyde content, which represents the level of lipid peroxidation. In addition, we investigated the effect of BBP on the submicroscopic structure and transcriptome of rotifer ovary cells. Our results showed that B. plicatilis exhibited a rapid oxidative stress response accompanied by a significant increase in superoxide dismutase enzyme activity. High BBP concentrations resulted in a significant decrease in malondialdehyde content, which indicated that BBP interferes with the lipid metabolism of rotifer cells. Our observations showed that the endoplasmic reticulum structure of rotifer ovary cells was severely damaged by BBP exposure. Transcriptomic data further demonstrated that oxidative stress and cellular sub-microstructural damage were associated with altered expression of functional genes related to rotifer redox regulation, biosynthetic processes, and cellular damage components. In conclusion, our study demonstrates that BBP triggers changes in antioxidant-related indicators in rotifers; this leads to activation of related genes and subsequent changes in intracellular signaling, which in turn triggers endoplasmic reticulum stress and ultimately leads to disruption of cell function and structure. These findings highlight the potential risks associated with BBP exposure and provide fundamental insights into its toxicological effects on marine invertebrates.

Effects of dietary vitamin E and C co-supplementation on growth performance, hemato-immunological indices, digestive enzymes activity, and intestinal histology of rainbow trout fed diet contained spoiled fish meal and oil

An eight-week feeding trial was conducted to elucidate the effects of diets containing oxidized fish oil (OFO) and/or spoiled fish meal (SFM) supplemented with various contents of vitamins E (VE: 100 and 200 mg/kg) and C (VC: 200 and 400 mg/kg) on some selected physiological parameters of juvenile rainbow trout, Oncorhynchus mykiss. The growth indices were affected by OFO and SFM-contained diets; the lowest values were observed in those fish raised on diet containing OFO and high levels of the vitamins. In all experimental groups, the hematological parameters (erythrocytes, leukocytes, hematocrit, and hemoglobin) were increased compared to the control group, and higher values were recorded in group fed OFO+VE (200 mg/kg) +VC (400 mg/kg)-supplemented diet (P < 0.05). A significant increase in serum lysozyme activity, immunoglobulin content, and complement pathway, was observed in fish fed OFO or SFM-contained feeds compared to the control group (P < 0.05). Digestive enzyme activities were mainly affected by dietary OFO contents, where the highest activities were detected in fish fed contained OFO and the vitamins (P < 0.05). According to the histological results, vitamin supplementation of OFO or SFM contained diets, especially at higher concentration, effectively reduced intestinal tissue damage (P < 0.05). In conclusion, VE and VC supplementation could mitigate the adverse effects of dietary OFO or SFM (e.g., decreased fish performance or health) by improving physiological responses of rainbow trout.

Prosurvival Pathway Protects From Clostridioides difficile Toxin-Mediated Cell Death.

There is an urgent need for new nonantibiotic-based treatment strategies for Clostridioides difficile infection. C. difficile toxin B (TcdB) is a virulent factor that is essential for causing disease. Here, we investigated whether a survival-signaling pathway could protect against TcdB. We found significant increase in caspase-3 apoptotic activity in intestinal epithelial cells of mice exposed to TcdB. Subsequently, activation of the MIF-CD74-Akt prosurvival signaling pathway blocked TcdB-induced caspase-3 activity and intestinal epithelial cell death. This brief report provides proof-of-concept that targeting prosurvival pathways may represent a unique antibiotic-independent strategy for protecting against C. difficile toxin-mediated cell death.

Effect of high cyclic hydrostatic pressure on osteogenesis of mesenchymal stem cells cultured in liquefied micro-compartments

Bone resident cells are constantly subjected to a range of distinct mechanical loadings, which generates a complex microenvironment. In particular, hydrostatic pressure (HP) has a key impact on modulation of cell function and fate determination. Although HP is a constant mechanical stimulus, its role in regulating the osteogenesis process within a defined 3D microenvironment has not been comprehensively elucidated. Perceiving how environmental factors regulate the differentiation of stem cells is essential for expanding their regenerative potential. Inspired by the mechanical environment of bone, this study attempted to investigate the influence of different ranges of cyclic HP on human adipose-derived mesenchymal stem cells (MSCs) encapsulated within a compartmentalized liquefied microenvironment. Taking advantage of the liquefied environment of microcapsules, MSCs were exposed to cyclic HP of 5 or 50 MPa, 3 times/week at 37 °C. Biological tests using fluorescence staining of F-actin filaments showed a noticeable improvement in cell-cell interactions and cellular network formation of MSCs. These observations were more pronounced in osteogenic (OST) condition, as confirmed by fluorescent staining of vinculin. More interestingly, there was a significant increase in alkaline phosphatase activity of MSCs exposed to 50 MPa magnitude of HP, even in the absence of osteoinductive factors. In addition, a greater staining area of both osteopontin and hydroxyapatite was detected in the 50 MPa/OST group. These findings highlight the benefit of hydrostatic pressure to regulate osteogenesis of MSCs as well as the importance of employing simultaneous biochemical and mechanical stimulation to accelerate the osteogenic potential of MSCs for biomedical purposes.

Assessment of Mastitis Patterns in Serbian Dairy Cows: Blood Serum Metabolic Profile and Milk Composition Parameters.

Mastitis is one of the most important diseases in dairy cows, leading to substantial economic losses associated with decreased milk production and quality. Early detection of changes in metabolic and milk parameters is crucial for maintaining animal welfare and milk quality. This study aimed to detect patterns in metabolic and milk composition parameters in Serbian dairy cows affected by mastitis. It also examined the relationship between these factors in cows with clinical and subclinical mastitis, as well as in healthy cows. This study included 60 Holstein-Friesian cows with the same body score condition that were in the same lactation phase. They were divided into three groups of 20: clinical and subclinical mastitis and a control group of healthy cows. The categorization was based on clinical udder health and the California mastitis test. Blood serum metabolic profiles were measured using a Rayto spectrophotometer (Shenzhen, China), and milk composition was determined using MilcoScanTM (Foss, Hilleroed, Denmark) and FossomaticTM (Foss, Hilleroed, Denmark) instruments. Significant increases in non-esterified fatty acids (NEFAs), beta-hydroxybutyrate (BHB), total protein, globulin, urea, total bilirubin, magnesium, and enzyme activity were noted in mastitis-affected cows compared to healthy ones. Additionally, mastitis-affected cows had higher total protein and globulin levels and increased somatic cell counts (SCCs), while albumin concentrations were decreased. Furthermore, a negative correlation between total protein and lactose suggested inflammation leading to reduced lactose levels due to cell damage, infection, and lactose use by mastitis pathogens. Hence, indicators of the energy and protein status of the metabolic profile, together with the chemical composition of milk, may be significant diagnostic tools for detecting, monitoring, and predicting the outcome of mastitis in cows.

Resveratrol prevents age-related heart impairment through inhibiting the Notch/NF-κB pathway.

Resveratrol (RSV) is a natural polyphenol compound found in various plants that has been shown to have potential benefits for preventing aging and supporting cardiovascular health. However, the specific signal pathway by which RSV protects the aging heart is not yet well understood. This study aimed to explore the protective effects of RSV against age-related heart injury and investigate the underlying mechanisms using a D-galactose-induced aging model. The results of the study indicated that RSV provided protection against age-related heart impairment in mice. This was evidenced by the reduction of cardiac histopathological changes as well as the attenuation of apoptosis. RSV-induced cardioprotection was linked to a significant increase in antioxidant activity and mitochondrial transmembrane potential, as well as a reduction in oxidative damage. Additionally, RSV inhibited the production of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Furthermore, the expression of toll-like receptor 4 (TLR4), nuclear factor kappa-B p65 (NF-κB p65), and notch 1 protein were inhibited by RSV, indicating that inhibiting the Notch/NF-κB pathway played a critical role in RSV-triggered heart protection in aging mice. Moreover, further data on intestinal function demonstrated that RSV significantly increased short-chain fatty acids (SCFAs) in intestinal contents and reduced the pH value in the feces of aging mice. RSV alleviated aging-induced cardiac dysfunction through the suppression of oxidative stress and inflammation via the Notch/NF-κB pathway in heart tissue. Furthermore, this therapeutic effect was found to be associated with its protective roles in the intestine.

Comparative analysis of physiological traits and gene expression patterns in nitrogen deficiency among barley cultivars

BackgroundNitrogen is one of the most important mineral nutrients for plants and is absorbed by the root system mainly in the inorganic form (NH+4 and NO−3). Plants absorb nitrogen as a food source for growth, biomass production, and development. Nitrogen is mainly absorbed as nitrate, which is the most common source of nitrogen available to higher plants. One of the unique features of nitrate transport is that NO−3 is both a substrate for transport and an inducer of NO−3 transport systems in genes and at physiological levels. MethodsIn the present study, morphological and physiological traits (chlorophyll a/b, total chlorophyll, and carotenoid, antioxidant enzymes, and protein content), correlation between traits and gene expression, and principle component analysis of traits among five barley cultivars were measured in response to nitrogen deficiency (ND). The starved plants were transferred to a nutrient solution containing 0.2 mM and 2 mM NO−3 up to 7 and 14 days after ND application and non-stressed conditions, respectively. ResultsGene expression analysis revealed that the 10 HvNRT2 genes were induced in the leaf and root tissues at 7 and 14 days after ND treatments in five barley cultivars. Expression of NRT2 genes by relative quantitative qRT-PCR analysis for 10 HvNRT2 genes were determined. Based on the gene expression, HvNRT2.1, HvNRT2.2, and HvNRT2.4 were strongly induced by NO−3, peaking at 7 and 14 days after ND treatment. In contrast, the HvNRT2.4 showed only moderate induction in both leaves and roots. From our results, the Reyhan cultivar showed a significant increase in root fresh weight (RFW), protein content, and antioxidant enzyme activity in roots at 7 and 14 days after ND treatment as compared to the non-stressed condition. A highly positive correlation was observed between root catalase (CATr) and HvNRT2.2/2.5/2.6 leaves. ConclusionThe expression of HvNRT2.4 is increased during long-term nitrogen starvation, while the expression of HvNRT2.1 and HvNRT2.2 are transiently increased by ND. Based on physiological and morphological traits and molecular mechanisms, the Reyhan is considered a tolerant cultivar under ND condition.

Alterations in intestinal microbiota and enzyme activities under cold-humid stress: implications for diarrhea in cold-dampness trapped spleen syndrome.

Cold and humid environments alter the intestinal microbiota, and the role of the intestinal microbiota in the development of diarrhea associated with cold-dampness trapped spleen syndrome in Chinese medicine is unclear. The 30 mice were randomly divided into normal and model groups, with the model group being exposed to cold and humid environmental stresses for 7 days. Then, mouse intestinal contents were collected and analyzed their intestinal microbiota and digestive enzymes. Our findings revealed significant increases in sucrase and lactase activities, as well as microbial activity, in the model group (p < 0.05). β-diversity analysis highlighted distinct intestinal microbiota compositions between the two groups. Specifically, the experimental group showed a unique dominance of the genera and strains Clostridium sensu stricto 1 and Clostridium sp. ND2. LEfSe analysis identified Helicobacter, Roseburia, and Eubacterium plexicaudatum ASF492 as differentially abundant species in them model group. Network analysis demonstrated that rare bacterial species mostly governed the microbial interactions, exhibiting increased mutual promotion. On the other hand, abundant species like Lactobacillus johnsonii and Lactobacillus reuteri showed mutual inhibitory relationships. In summary, exposure to cold and humid conditions led to increased intestinal enzyme activities and a shift in microbial composition, favoring the growth of rare bacterial species. These changes suggest that rare bacteria in the intestinal microbiota play a critical role in the pathology of diarrhea associated with cold-dampness trapped spleen syndrome, revealing unique survival strategies among bacterial populations under stressful conditions.

“Listen to your heart”: A novel interoceptive strategy for real-time fMRI neurofeedback training of anterior insula activity

Real-time fMRI (rt-fMRI) neurofeedback (NF) training is a novel non-invasive technique for volitional brain modulation. Given the important role of the anterior insula (AI) in human cognitive and affective processes, it has become one of the most investigated regions in rt-fMRI studies. Most rt-fMRI insula studies employed emotional recall/imagery as the regulation strategy, which may be less effective for psychiatric disorders characterized by altered emotional processing. The present study thus aimed to examine the feasibility of a novel interoceptive strategy based on heartbeat detection in rt-fMRI guided AI regulation and its associated behavioral changes using a randomized double-blind, sham feedback-controlled between-subject design. 66 participants were recruited and randomly assigned to receive either NF from the left AI (LAI) or sham feedback from a control region while using the interoceptive strategy. N = 57 participants were included in the final data analyses. Empathic and interoceptive pre-post training changes were collected as behavioral measures of NF training effects. Results showed that participants in the NF group exhibited stronger LAI activity than the control group with LAI activity being positively correlated with interoceptive accuracy following NF training, although there were no significant increases of LAI activity over training sessions. Importantly, ability of LAI regulation could be maintained in a transfer session without feedback. Successful LAI regulation was associated with strengthened functional connectivity of the LAI with cognitive control, memory and learning, and salience/interoceptive networks. The present study demonstrated for the first time the efficacy of a novel regulation strategy based on interoceptive processing in up-regulating LAI activity. Our findings also provide proof of concept for the translational potential of this strategy in rt-fMRI AI regulation of psychiatric disorders characterized by altered emotional processing.

Mannich-type modifications of (−)-cannabidiol and (−)-cannabigerol leading to new, bioactive derivatives

(−)-Cannabidiol (CBD) and (−)-cannabigerol (CBG) are two major non-psychotropic phytocannabinoids that have many beneficial biological properties. However, due to their low water solubility and prominent first-pass metabolism, their oral bioavailability is moderate, which is unfavorable for medicinal use. Therefore, there is a great need for appropriate chemical modifications to improve their physicochemical and biological properties. In this study, Mannich-type reaction was used for the synthetic modification of CBD and CBG for the first time, and thus fifteen new cannabinoid derivatives containing one or two tertiary amino groups were prepared. Thereafter the antiviral, antiproliferative and antibacterial properties of the derivatives and their effects on certain skin cells were investigated. Some modified CBD derivatives showed remarkable antiviral activity against SARS-CoV-2 without cytotoxic effect, while synthetic modifications on CBG resulted in a significant increase in antiproliferative activity in some cases compared to the parent compound.