Histopathological Investigation of Varietal Responses to Cercospora beticola Infection Process on Sugar Beet Leaves.

Cercospora leaf spot (CLS) is the most destructive foliar disease in sugar beet (Beta vulgaris). It is caused by Cercospora beticola Sacc., a fungal pathogen that produces toxins and enzymes which affect membrane permeability and cause cell death during infection. In spite of its importance, little is known about the initial stages of leaf infection by C. beticola. Therefore, we investigated the progression of C. beticola on leaf tissues of susceptible and resistant sugar beet varieties at 12-h intervals during the first 5 days after inoculation using confocal microscopy. Inoculated leaf samples were collected and stored in DAB (3,3'-diaminobenzidine) solution until processed. Samples were stained with Alexa Fluor-488-WGA dye to visualize fungal structures. Fungal biomass accumulation, reactive oxygen species (ROS) production, and the area under the disease progress curve were evaluated and compared. ROS production was not detected on any variety before 36 h postinoculation (hpi). C. beticola biomass accumulation, percentage leaf cell death, and disease severity were all significantly greater in the susceptible variety compared with the resistant variety (P < 0.05). Conidia penetrated directly through stomata between 48 to 60 hpi and produced appressoria on stomatal guard cells at 60 to 72 hpi in susceptible and resistant varieties, respectively. Penetration of hyphae inside the parenchymatous tissues varied in accordance with time postinoculation and varietal genotypes. Overall, this study provides a detailed account to date of events leading to CLS disease development in two contrasting varieties.

Transcriptomic analysis reveals distinct adaptive molecular mechanism in the hippocampal CA3 from rats susceptible or not-susceptible to hyperthermia-induced seizures.

Febrile seizures during early childhood are a relevant risk factor for the development of mesial temporal lobe epilepsy. Nevertheless, the molecular mechanism induced by febrile seizures that render the brain susceptible or not-susceptible to epileptogenesis remain poorly understood. Because the temporal investigation of such mechanisms in human patients is impossible, rat models of hyperthermia-induced febrile seizures have been used for that purpose. Here we conducted a temporal analysis of the transcriptomic and microRNA changes in the ventral CA3 of rats that develop (HS group) or not-develop (HNS group) seizures after hyperthermic insult on the eleventh postnatal day. The selected time intervals corresponded to acute, latent, and chronic phases of the disease. We found that the transcriptional differences between the HS and the HNS groups are related to inflammatory pathways, immune response, neurogenesis, and dendritogenesis in the latent and chronic phases. Additionally, the HNS group expressed a greater number of miRNAs (some abundantly expressed) as compared to the HS group. These results indicate that HNS rats were able to modulate their inflammatory response after insult, thus presenting better tissue repair and re-adaptation. Potential therapeutic targets, including genes, miRNAs and signaling pathways involved in epileptogenesis were identified.

Increased risk of Parkinson's disease amongst patients with age-related macular degeneration and visual disability: A nationwide cohort study.

BACKGROUND AND PURPOSE: The association between Parkinson's disease (PD) and age-related macular degeneration (AMD) has been shown in previous reports. However, the association between the severity of AMD and PD development is unknown. The aim was to evaluate the association of AMD with/without visual disability (VD) with the risk of PD occurrence using the National Health Insurance data in South Korea. METHODS: A total of 4,205,520 individuals, 50 years or older and without a previous diagnosis of PD, participated in the Korean National Health Screening Program in 2009. AMD was verified using diagnostic codes, and participants with VD were defined as those with loss of vision or visual field defect as certified by the Korean Government. The participants were followed up until 31 December 2019, and incident cases of PD were identified using registered diagnostic codes. The hazard ratio was calculated for groups (control and AMD with/without VD) using multivariable adjusted Cox regression analysis. RESULTS: In total, 37,507 participants (0.89%) were diagnosed with PD. Amongst individuals with AMD, the risk of PD development was higher in individuals with VD (adjusted hazard ratio [aHR] 1.35, 95% confidence interval [CI] 1.09-1.67) than in those without (aHR 1.22, 95% CI 1.15-1.30) compared with controls. Additionally, an increased risk of PD was observed in individuals with AMD compared with controls, regardless of the presence of VD (aHR 1.23, 95% CI 1.16-1.31). CONCLUSIONS: Visual disability in AMD was associated with the development of PD. This suggests that neurodegeneration in PD and AMD may have common pathways.

Mediating a host cell signaling pathway linked to overwinter mortality offers a promising therapeutic approach for improving bee health.

INTRODUCTION: Honey bees provides valuable pollination services for world food crops and wild flowering plants which are habitats of many animal species and remove carbon dioxide from the atmosphere, a powerful tool in the fight against climate change. Nevertheless, the honey bee population has been declining and the majority of colony losses occur during the winter. OBJECTIVES: The goal of this study was to understand the mechanisms underlying overwinter colony losses and develop novel therapeutic strategies for improving bee health. METHODS: First, pathogen prevalence in overwintering bees were screened between 2015 and 2018. Second, RNA sequencing (RNA-Seq) for transcriptional profiling of overwintering honey bees was conducted and qRT-PCR was performed to confirm the results of the differential expression of selected genes. Lastly, laboratory bioassays were conducted to measure the effects of cold challenges on bee survivorship and stress responses and to assess the effect of a novel medication for alleviating cold stress in honey bees. RESULTS: We identified that sirtuin signaling pathway is the most significantly enriched pathway among the down-regulated differentially expressed genes (DEGs) in overwintering diseased bees. Moreover, we showed that the expression of SIRT1 gene, a major sirtuin that regulates energy and immune metabolism, was significantly downregulated in bees merely exposed to cold challenges, linking cold stress with altered gene expression of SIRT1. Furthermore, we demonstrated that activation of SIRT1 gene expression by SRT1720, an activator of SIRT1 expression, could improve the physiology and extend the lifespan of cold-stressed bees. CONCLUSION: Our study suggests that increased energy consumption of overwintering bees for maintaining hive temperature reduces the allocation of energy toward immune functions, thus making the overwintering bees more susceptible to disease infections and leading to high winter colony losses. The novel information gained from this study provides a promising avenue for the development of therapeutic strategies for mitigating colony losses, both overwinter and annually.

[Proteomics-based screening of differentially expressed protein in bronchial asthma(syndrome of excessive cold)].

Proteomic tools were used to identify the key proteins that might be associated with bronchial asthma(BA). Firstly, the serum samples from healthy adults and asthmatic patients were collected. Tandem Mass Tag~(TM)(TMT), which removes high-abundance structures and nonspecific proteins, was employed to identify the differentially expressed proteins between asthmatic patients and healthy adults. Gene Ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were carried out for the differentially expressed proteins. The core proteins in the asthma group were screened out by protein-protein interaction(PPI) analysis. Then the core proteins were verified by Western blot for 3 patients with bronchial asthma and 3 healthy adults. A total of 778 differentially expressed proteins were screened out, among which 32 proteins contained quantitative information, including 18 up-regulated proteins and 14 down-regulated proteins. The differentially expressed proteins were enriched in 28 KEGG signaling pathways. The PPI analysis showed that 10 proteins(GDN, 1433 Z, VWF, HEMO, CERU, A1 AT, TSP1, G3 P, IBP7, and KPYM) might be involved in the pathogenesis of bronchial asthma. Compared with those in healthy adults, the expression levels of SLC25 A4, SVEP1, and KRT25 in the sera of asthmatic patients were up-regulated(P<0.05). Therefore, it is hypothesized that a variety of immune signaling pathways and differentially expressed proteins play a role in the pathogenesis of BA, which provides potential target information for the treatment of BA.

The anti-aging effects of Renshen Guben on thyrotoxicosis mice: Improving immunosenescence, hypoproteinemia, lipotoxicity, and intestinal flora.

With the rapid aging of the population, the control of age-related disease susceptibility and prognosis faces greater challenges. There is an urgent need for a strategy to maintain the vitality of elderly people. In this study, the effect of Renshen Guben (RSGB) oral liquid was investigated on an accelerated aging mice model of thyrotoxicosis by conventional detection methods combined with multiomics technology. The results showed that RSGB increased the number of neutrophils and lymphocytes, enhanced the function of lymphocytes, and increased the levels of complement and antimicrobial peptides, which indicated that RSGB improved the immunity of thyrotoxicosis mice at the cellular and molecular levels. RSGB corrected malnutrition in thyrotoxicosis mice by improving anemia, hypoalbuminemia, ion transporters, and vitamin-binding proteins. RSGB significantly reduced the lipotoxicity by reducing the level of fatty acids, triglyceride, sphingolipids, and glucocorticoids, thus increasing the level of docosapentaenoic acid (DPA) and bile acids, which contributed to improve immunosenescence. The intestinal defense ability of thyrotoxicosis mice was enhanced with the increase of bile acids and lactic acid bacteria by the RSGB treatment. The plant metabolomics analysis showed that there were various active components in RSGB oral liquid and medicated serum, including terpenoids, phenolic acids, flavonoids, tannin, alkaloids, organic acids, phenolamines, amino acids, and others. They have antioxidant, immune regulation, and anti-aging effects, which was the material basis of RSGB. Totally, RSGB protected the thyrotoxicosis mice against aging by improving immunosenescence, hypoproteinemia, lipotoxicity, and the intestinal flora. It will be beneficial for improving the disease susceptibility and prognosis of the elderly.

Actividad antimicrobiana in vitro del extracto de hojas de Bixa orellana L. contra bacterias anaerobias asociadas a la vaginosis bacteriana y Lactobacillus spp / In vitro antimicrobial activity of Bixa orellana L. leaves extract against anaerobic bacteria associated to bacterial vaginosis and Lactobacillus spp.

Objetivos . Describir la actividad antimicrobiana in vitro del extracto metanólico de las hojas de Bixa orellana L. contra las bacterias anaerobias asociadas a la vaginosis bacteriana y Lactobacillus spp. Materiales y métodos . Se incluyeron en el estudio ocho cepas de referencia ATCC; Gardnerella vaginalis, Prevotella bivia, Peptococcus niger, Peptostreptococcus anaerobius, Mobiluncus curtisii, Atopobium vaginae, Veillonella parvula y Lactobacillus crispatus, y 22 aislamientos clínicos; once aislados de Gardnerella vaginalis y once aislados de Lactobacillus. La susceptibilidad antimicrobiana se determinó mediante el método de difusión en agar. La concentración mínima inhibitoria (CMI) y la concentración bactericida mínima (CBM) fueron determinadas utilizando el método de dilución en agar y un método de dilución modificado, respectivamente. Resultados . Todas las cepas de referencia ATCC tuvieron un alto nivel de susceptibilidad al extracto, con excepción de P. vibia, V. parvula y L. crispatus. Interesantemente, los aislamientos clínicos de G. vaginalis y la cepa ATCC de G. vaginalis fueron los más susceptibles al extracto dados los bajos valores de CMI (1,0 - 2,0 mg/mL) y CBM (1,0 - 4,0 mg/mL), mientras que, los aislamientos clínicos de Lactobacillus spp. y la cepa ATCC de L. crispatus fueron los menos susceptibles debido a los altos valores de CMI (32,0 mg/mL) y CBM (≥ 32,0 mg/mL). Conclusiones . Los experimentos in vitro sugieren que el extracto posee propiedades antibacterianas selectivas dada su alta actividad contra bacterias anaerobias asociadas a vaginosis bacteriana y baja actividad contra especies de Lactobacillus.

Objective. To describe the in vitro antimicrobial activity of the methanolic extract of Bixa orellana L. leaves against anaerobic bacteria associated to bacterial vaginosis and Lactobacillus spp. Materials and methods. Eight ATCC reference strains; Gardnerella vaginalis, Prevotella bivia, Peptococcus niger, Peptostreptococcus anaerobius, Mobiluncus curtisii, Atopobium vaginae, Veillonella parvula, and Lactobacillus crispatus, and twenty-two clinical isolates; eleven Gardnerella vaginalis and eleven Lactobacillus strains, were included in the study. The antimicrobial susceptibility was determined by the agar diffusion method. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined by using agar dilution and a modified dilution plating method, respectively. Results. All ATCC reference strains showed high levels of susceptibility to the extract, except P. vibia, V. parvula and L. crispatus. Interestingly, all G. vaginalis clinical isolates and the G. vaginalis ATTC strain were the most susceptible to the extract, given their low MIC (1.0 - 2.0 mg/mL) and MBC (1.0 - 4.0 mg/mL) values, whereas, the Lactobacillus spp. clinical isolates and the L. crispatus ATCC strain were the least susceptible bacteria given their high MIC (32.0 mg/mL) and MBC (≥ 32.0 mg/mL) values. Conclusions. In vitro experiments suggest that the extract possesses selective antimicrobial properties given its high activity against bacterial vaginosis-associated anaerobic bacteria and low activity against Lactobacillus species.

Sciatic-Vagal Nerve Stimulation by Electroacupuncture Alleviates Inflammatory Arthritis in Lyme Disease-Susceptible C3H Mice.

Lyme disease is caused by Borrelia burgdorferi, and the pathogenesis of the disease is complex with both bacterial and host factors contributing to inflammatory responses. Lyme disease affects different organs including joints and results in arthritis. Immune responses stimulated by B. burgdorferi through toll-like receptors cause infiltration of leukocytes, which produce inflammatory cytokines and facilitate spirochete clearance. However, arthritic manifestations and chronic fatigue syndrome-like symptoms persist long after completion of antibiotic treatment regimens in a significant number of patients. To counter the effects of inflammation, treatment by non-steroidal anti-inflammatory drugs, hydroxychloroquine, or synovectomy to eradicate inflammatory arthritis in the involved joint could be employed; however, they often have long-term consequences. Acupuncture has been used for a long time in Asian medicine to diminish pain during various ailments, but the effects and its mechanism are just beginning to be explored. Control of inflammation by neuronal stimulation has been exploited as a systemic therapeutic intervention to arrest inflammatory processes. Our objective was to determine whether activation of the sciatic-vagal network by electroacupuncture on ST36 acupoint, which is used to control systemic inflammation in experimental models of infectious disorders such as endotoxemia, can also alleviate Lyme arthritis symptoms in mice. This aim was further strengthened by the reports that sciatic-vagal neuronal network stimulation can lead to dopamine production in the adrenal medulla and moderate the production of inflammatory factors. We first assessed whether electroacupuncture affects spirochete colonization to attenuate Lyme arthritis. Interestingly, bioluminescent B. burgdorferi burden detected by live imaging and qPCR were similar in electroacupuncture- and mock-treated mice, while electroacupuncture induced a lasting anti-inflammatory effect on mice. Despite the discontinuation of treatment at 2 weeks, the simultaneous decrease in neutrophils in the joints and inflammatory cytokine levels throughout the body at 4 weeks suggests a systemic and persistent effect of electroacupuncture that attenuates Lyme arthritis. Our results suggest that electroacupuncture-mediated anti-inflammatory responses could offer promising healthcare benefits in patients suffering from long-term Lyme disease manifestations.

Vitamins C and D and COVID-19 Susceptibility, Severity and Progression: An Evidence Based Systematic Review.

Background and Objectives: Starting in early December 2019, the novel Coronavirus Disease (COVID-19) from infection with COVID-19 has caused a global pandemic. Many aspects of its pathogenesis and related clinical consequences are still unclear. Early diagnosis and dynamic monitoring of prognostic factors are essential to improve the ability to manage COVID-19 infection. This study aimed to provide an account of the role played by vitamins C and D on the onset, progression and severity of COVID-19. Clinical features and infection-related risk factors are also briefly discussed. Material and Methods: In March 2022, the main online databases were accessed. All the articles that investigate the possible role of vitamins C and D on COVID-19 susceptibility, severity and progression were considered. Results: The current evidence on vitamin C and D supplementation in patients with COVID-19 infection is inconsistent and controversial. In some studies, vitamins were used as coadjuvant of a formal experimental therapy, while in others as main treatment. Ethnicity and hospital setting (inpatient/outpatient) were also variable. Moreover, there was no consensus between studies in administration protocol: high heterogeneity in dosage, administration, and duration of the treatment were evident. Finally, some studies administered vitamins pre- and/or during COVID infection, in patients with different risk factors and infection severity. Conclusions: While waiting to develop a targeted, safe and effective therapy, it is important to investigate individual predisposition and proper disease management. Concluding, available data on the use of nutraceuticals in COVID-19 are inconsistent. However, there is a lack of evidence-based guidelines which recommend vitamin C and D supplementation in patients with COVID-19, and results from high quality randomised controlled trials (RCTs) are inconsistent. Current investigations so far are mostly observational, and include a relatively small sample size which can lead to biased results. Large-scale multicentre studies are therefore needed.

Leaf Bacteriome in Sugar Beet Shows Differential Response against Beet curly top virus during Resistant and Susceptible Interactions.

Beet curly top virus (BCTV) significantly reduces sugar beet yield in semi-arid production areas. Genetic resistance to BCTV is limited; therefore, identification of additional resistance-associated factors is highly desired. Using 16S rRNA sequencing and BCTV resistant (R) genotypes (KDH13, KDH4-9) along with a susceptible (S) genotype (KDH19-17), we investigated leaf bacteriome changes during BCTV post inoculation (pi). At day 6 (~6-week-old plants), Cyanobacteria were predominant (~90%); whereas, at week 4 (~10-week-old plants) Firmicutes (11-66%), Bacteroidetes (17-26%), and Verrucomicrobia (12-29%) were predominant phyla and genotype dependent. Both Bacteroidetes and Verrucomicrobia, increased post infection only in the R lines. The bacterial genera Brevibacillus increased at 6 dpi, and Akkermansia and Bacteroides at 4 wkpi in the R lines. Linear discriminant analysis effect size (LEfSe) identified potential biomarkers in the R vs. S lines. Functional profiling revealed bacterial enrichment associated with the TCA cycle, polyisoprenoid, and L-methionine biosynthesis pathways only in KDH4-9 at 6 dpi. At 4 wkpi, bacteria associated with tryptophan and palmitate biosynthesis in the R lines, and uridine monophosphate, phosphatidyl glycerol, and phospholipid biosynthesis in the S line, were enriched. Future characterization of bacterial genera with antiviral properties will help establish their use as biocontrol agents/biomarkers against BCTV.

Glutathione Modulation in PVYNTN Susceptible and Resistant Potato Plant Interactions.

Glutathione is a metabolite that plays an important role in plant response to biotic stress through its ability to remove reactive oxygen species, thereby limiting the degree of potential oxidative damage. It can couple changes in the intracellular redox state to the development, especially the defense responses, of plants. Several studies have focused on measuring glutathione levels in virus infected plants, but have not provided complete information. Therefore, we analyzed, for the first time, the content of glutathione as well as its ultrastructural distribution related to susceptible and hypersensitive potato-Potato virus Y NTN (PVYNTN) interaction, with an aim of providing new insight into interactive responses to PVYNTN stress. Our findings reported that the inoculation of PVYNTN caused a dynamic increase in the content of glutathione, not only in resistance but also in susceptible reaction, especially at the first steps of plant-virus interaction. Moreover, the increase in hypersensitive response was much more dynamic, and accompanied by a significant reduction in the content of PVYNTN. By contrast, in susceptible potato Irys, the content of glutathione decreased between 7 and 21 days after virus inoculation, which led to a significant increase in PVYNTN concentration. Additionally, our findings clearly indicated the steady induction of two selected potato glutathione S-transferase StGSTF1 and StGSTF2 genes after PVYNTN inoculation, regardless of the interaction type. However, the relative expression level of StGSTF1 did not significantly differ between resistant and susceptible plants, whereas the relative expression levels of StGSTF2 differed between susceptible and resistant reactions. Therefore, we proposed that StGSTF2 can act as a marker of the type of response to PVYNTN. Our observations indicated that glutathione is an important component of signaling as well as the regulatory network in the PVYNTN-potato pathosystem. In resistance responses to PVYNTN, this metabolite activates plant defenses by reducing potential damage to the host plant cell, causing a reduction in virus concentration, while it can also be involved in the development of PVYNTN elicited symptoms, as well as limiting oxidative stress, leading to systemic infection in susceptible potato plants.

Selenium deficiency is associated with disease severity, disrupted reward processing, and increased suicide risk in patients with Anorexia Nervosa.

BACKGROUND & AIMS: Patients with Anorexia Nervosa (AN) present many nutritional deficiencies (macro- and often also micro-nutrients), possibly explained by their inadequate food intake. Previous studies reported that selenium (Se) deficiency is common in the general population. As Se can be easily added as a supplement, the goal of this study was to evaluate the clinical impact of Se deficiency in patients with AN. METHODS: This cross-sectional study concerned 153 patients with AN (92.9% women) followed at the Eating Disorder Unit of Lapeyronie Academic Hospital, Montpellier, France. Patients underwent an extensive neuropsychological assessment, and completed validated questionnaires. Blood samples were collected for Se quantification. Results were compared with the t-test, Mann-Whitney U, and Chi square tests, and univariate linear and multivariate logistic regression models. RESULTS: Se plasma levels were below the cut-off of 80 µg/L in 53.6% (N = 82) of patients. AN onset was earlier in patients with Se deficiency, (p = .005), whereas disease duration was comparable between groups (p = .77). General eating disorder symptomatology in the past 28 days (Eating Disorder Examination Questionnaire) was more severe in patients with Se deficiency (p = .010). The suicide risk (MINI International Neuropsychiatric Evaluation) tended to be higher (p = .037), and suicide attempt history was more frequent (28.39% vs 9.85%, p = .004) in patients with low Se levels. Se plasma concentration was negatively correlated with the performance in the temporal delayed discounting task (p = .006). CONCLUSIONS: Our findings suggest that in patients with AN, Se plasma concentration might be implicated in disease severity and suicide risk. The finding that Se deficiency in patients with AN was associated only with reward-related processes, but not with other psychological functions suggests the selective involvement of dopamine-related pathways. Our results suggest that it might be useful to monitor the plasma micronutrient profile in patients with AN. Future studies should determine whether Se supplementation in AN might improve clinical outcomes.

Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives.

Voltage-gated calcium channels (VGCCs) are widely expressed in the brain, heart and vessels, smooth and skeletal muscle, as well as in endocrine cells. VGCCs mediate gene transcription, synaptic and neuronal structural plasticity, muscle contraction, the release of hormones and neurotransmitters, and membrane excitability. Therefore, it is not surprising that VGCC dysfunction results in severe pathologies, such as cardiovascular conditions, neurological and psychiatric disorders, altered glycemic levels, and abnormal smooth muscle tone. The latest research findings and clinical evidence increasingly show the critical role played by VGCCs in autism spectrum disorders, Parkinson's disease, drug addiction, pain, and epilepsy. These findings outline the importance of developing selective calcium channel inhibitors and modulators to treat such prevailing conditions of the central nervous system. Several small molecules inhibiting calcium channels are currently used in clinical practice to successfully treat pain and cardiovascular conditions. However, the limited palette of molecules available and the emerging extent of VGCC pathophysiology require the development of additional drugs targeting these channels. Here, we provide an overview of the role of calcium channels in neurological disorders and discuss possible strategies to generate novel therapeutics.

Berberine, a Herbal Metabolite in the Metabolic Syndrome: The Risk Factors, Course, and Consequences of the Disease.

In recent years, the health of patients exposed to the consequences of the metabolic syndrome still requires the search for new solutions, and plant nutraceuticals are currently being intensively investigated. Berberine is a plant alkaloid possessing scientifically determined mechanisms of the prevention of the development of atherosclerosis, type 2 diabetes, and obesity, as well as cardiovascular complications and cancer. It positively contributes to elevated levels of fasting, postprandial blood glucose, and glycosylated hemoglobin, while decreasing insulin resistance. It stimulates glycolysis, improving insulin secretion, and inhibits gluconeogenesis and adipogenesis in the liver; by reducing insulin resistance, berberine also improves ovulation. The anti-obesity action of berberine has been also well-documented. Berberine acts as an anti-sclerotic, lowering the LDL and testosterone levels. The alkaloid exhibits an anti-inflammatory property by stalling the expression of cyclooxygenase 2 (COX-2) and prostaglandin E2. Berberine is neuroprotective and acts as an antidepressive. However, the outcomes in psychiatric patients are nonspecific, as it has been shown that berberine improves metabolic parameters in schizophrenic patients, acting as an adjuvant during antipsychotic treatment. Berberine acts as an anticancer option by inducing apoptosis, the cell cycle arrest, influencing MAPK (mitogen-activated protein kinase), and influencing transcription regulation. The inhibition of carcinogenesis is also combined with lipid metabolism.

Gold (III) Derivatives in Colon Cancer Treatment.

Cancer is one of the leading causes of morbidity and mortality worldwide. Colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second in women. Standard patterns of antitumor therapy, including cisplatin, are ineffective due to their lack of specificity for tumor cells, development of drug resistance, and severe side effects. For this reason, new methods and strategies for CRC treatment are urgently needed. Current research includes novel platinum (Pt)- and other metal-based drugs such as gold (Au), silver (Ag), iridium (Ir), or ruthenium (Ru). Au(III) compounds are promising drug candidates for CRC treatment due to their structural similarity to Pt(II). Their advantage is their relatively good solubility in water, but their disadvantage is an unsatisfactory stability under physiological conditions. Due to these limitations, work is still underway to improve the formula of Au(III) complexes by combining with various types of ligands capable of stabilizing the Au(III) cation and preventing its reduction under physiological conditions. This review summarizes the achievements in the field of stable Au(III) complexes with potential cytotoxic activity restricted to cancer cells. Moreover, it has been shown that not nucleic acids but various protein structures such as thioredoxin reductase (TrxR) mediate the antitumor effects of Au derivatives. The state of the art of the in vivo studies so far conducted is also described.

Inflammatory Burden and Immunomodulative Therapeutics of Cardiovascular Diseases.

Phenotyping cardiovascular illness and recognising heterogeneities within are pivotal in the contemporary era. Besides traditional risk factors, accumulated evidence suggested that a high inflammatory burden has emerged as a key characteristic modulating both the pathogenesis and progression of cardiovascular diseases, inclusive of atherosclerosis and myocardial infarction. To mechanistically elucidate the correlation, signalling pathways downstream to Toll-like receptors, nucleotide oligomerisation domain-like receptors, interleukins, tumour necrosis factor, and corresponding cytokines were raised as central mechanisms exerting the effect of inflammation. Other remarkable adjuvant factors include oxidative stress and secondary ferroptosis. These molecular discoveries have propelled pharmaceutical advancements. Statin was suggested to confer cardiovascular benefits not only by lowering cholesterol levels but also by attenuating inflammation. Colchicine was repurposed as an immunomodulator co-administered with coronary intervention. Novel interleukin-1ß and -6 antagonists exhibited promising cardiac benefits in the recent trials as well. Moreover, manipulation of gut microbiota and associated metabolites was addressed to antagonise inflammation-related cardiovascular pathophysiology. The gut-cardio-renal axis was therein established to explain the mutual interrelationship. As for future perspectives, artificial intelligence in conjunction with machine learning could better elucidate the sequencing of the microbiome and data mining. Comprehensively understanding the interplay between the gut microbiome and its cardiovascular impact will help identify future therapeutic targets, affording holistic care for patients with cardiovascular diseases.

Editorial to Special Issue Molecular Biology of Selenium in Health and Disease.

The selenium field expanded at a rapid rate for about 45 years, from the mid-1970's until about 2015 (see [...].

Dual Blockade of TNF and IL-17A Inhibits Inflammation and Structural Damage in a Rat Model of Spondyloarthritis.

The tumor necrosis factor (TNF) and IL-23/IL-17 axes are the main therapeutic targets in spondyloarthritis. Despite the clinical efficacy of blocking either pathway, monotherapy does not induce remission in all patients and its effect on new bone formation remains unclear. We aimed to study the effect of TNF and IL-17A dual inhibition on clinical disease and structural damage using the HLA-B27/human ß2-microglobulin transgenic rat model of SpA. Immunized rats were randomized according to arthritis severity, 1 week after arthritis incidence reached 50%, to be treated twice weekly for a period of 5 weeks with either a dual blockade therapy of an anti-TNF antibody and an anti-IL-17A antibody, a single therapy of either antibody, or PBS as vehicle control. Treatment-blinded observers assessed inflammation and structural damage clinically, histologically and by micro-CT imaging. Both single therapies as well as TNF and IL-17A dual blockade therapy reduced clinical spondylitis and peripheral arthritis effectively and similarly. Clinical improvement was confirmed for all treatments by a reduction of histological inflammation and pannus formation (p < 0.05) at the caudal spine. All treatments showed an improvement of structural changes at the axial and peripheral joints on micro-CT imaging, with a significant decrease for roughness (p < 0.05), which reflects both erosion and new bone formation, at the level of the caudal spine. The effect of dual blockade therapy on new bone formation was more prominent at the axial than the peripheral level. Collectively, our study showed that dual blockade therapy significantly reduces inflammation and structural changes, including new bone formation. However, we could not confirm a more pronounced effect of dual inhibition compared to single inhibition.

Omega-3 fatty acids impair miR-1-3p-dependent Notch3 down-regulation and alleviate sepsis-induced intestinal injury.

BACKGROUND: Sepsis is a troublesome syndrome that can cause intestinal injury and even high mortality rates. Omega-3 fatty acids (FAs) are known to protect against intestinal damage. Accordingly, the current study set out to explore if omega-3 FAs could affect sepsis-induced intestinal injury with the involvement of the microRNA (miR)-1-3p/Notch3-Smad axis. METHODS: First, cecal ligation and perforation (CLP) was performed to establish septic mouse models in C57BL/6J mice, and mouse intestinal epithelial MODE-K cells were induced by lipopolysaccharide (LPS) to establish sepsis cell models. The CLP-induced septic mice or LPS-exposed cells were subjected to treatment with Omega-3 FAs and activin (Smad signaling activator), miR-1-3p inhibitor and over-expressed/short hairpin RNA (oe-/sh)-Notch3 to explore their roles in inflammation, intestinal oxidative stress and cell apoptosis. A dual-luciferase reporter gene assay was further performed to verify the regulatory relationship between miR-1-3p and Notch3. RESULTS: Omega-3 FAs inhibited CLP-induced intestinal injury and ameliorated LPS-induced intestinal epithelial cell injury by down-regulating miR-1-3p, as evidenced by decreased levels of tumor necrosis factor-α, interleukin-1ß (IL-1ß) and IL-6, in addition to diminished levels of reactive oxygen species, malondialdehyde levels and superoxide dismutase activity. Furthermore, miR-1-3p could down-regulate Notch3, which inactivated the Smad pathway. CONCLUSION: Collectively, our findings indicated that omega-3 FAs elevate the expression of Notch3 by down-regulating miR-1-3p, and then blocking the Smad pathway to alleviate intestinal epithelial inflammation and oxidative stress injury caused by sepsis.

Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation.

BACKGROUND: Alzheimer's disease (AD) is the most common type of neurodegenerative disease in the contemporary era, and it is still clinically incurable. Eriodictyol, a natural flavonoid compound that is mainly present in citrus fruits and some Chinese herbal medicines, has been reported to exert anti-inflammatory, antioxidant, anticancer and neuroprotective effects. However, few studies have examined the anti-AD effect and molecular mechanism of eriodictyol. METHODS: APP/PS1 mice were treated with eriodictyol and the cognitive function of mice was assessed using behavioral tests. The level of amyloid-ß (Aß) aggregation and hyperphosphorylation of Tau in the mouse brain were detected by preforming a histological analysis and Western blotting. HT-22 cells induced by amyloid-ß peptide (1-42) (Aß1-42) oligomers were treated with eriodictyol, after which cell viability was determined and the production of p-Tau was tested using Western blotting. Then, the characteristics of ferroptosis, including iron aggregation, lipid peroxidation and the expression of glutathione peroxidase type 4 (GPX4), were determined both in vivo and in vitro using Fe straining, Western blotting and qPCR assays. Additionally, the expression level of vitamin D receptor (VDR) and the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway were tested using Western blotting and qPCR assays. Afterward, HT-22 cells with VDR knockout were used to explore the potential mechanisms, and the relationship between VDR and Nrf2 was further assessed by performing a coimmunoprecipitation assay and bioinformatics analysis. RESULTS: Eriodictyol obviously ameliorated cognitive deficits in APP/PS1 mice, and suppressed Aß aggregation and Tau phosphorylation in the brains of APP/PS1 mice. Moreover, eriodictyol inhibited Tau hyperphosphorylation and neurotoxicity in HT-22 cells induced by Aß1-42 oligomer. Furthermore, eriodictyol exerted an antiferroptosis effect both in vivo and in vitro, and its mechanism may be associated with the activation of the Nrf2/HO-1 signaling pathway. Additionally, further experiments explained that the activation of Nrf2/HO-1 signaling pathway by eriodictyol treatment mediated by VDR. CONCLUSIONS: Eriodictyol alleviated memory impairment and AD-like pathological changes by activating the Nrf2/HO-1 signaling pathway through a mechanism mediated by VDR, which provides a new possibility for the treatment of AD.