Primary Target Organ Research Articles

TOXICOLOGICAL AND HYGIENIC CHARACTERISTICS OF MYCOTOXIN STERIGMATOCYSTIN AND METHODS FOR ITS DETERMINATION IN FOOD PRODUCTS

The present issue reviews literature and own research data and gives toxicological and hygienic characteristic of sterigmatocystin. This mycotoxin is produced by fungi of Aspergillus, Bipolaris, Chaetomium, Emiricella species, and is found in cereals, food products (bread, cheese, spices, coffee, dietary supplements) and feed. Sterigmatocystin being a biogenic precursor of aflatoxin B1, has similar chemical structure and exhibits the same toxicological properties, but its toxicity is ten times lower. However, these toxins are rarely detected together. A. versicolor and A. nidulans do not have enzymes necessary for the conversion of sterigmatocystin into aflatoxins, on the contrary, A. flavus and А. parasiticus transform almost all STC into aflatoxins. Sterigmatocystin has been recognized by International Agency for Research on Cancer (IARC) as a 2B carcinogen (possibly carcinogenic to humans). The primary target organ for both mycotoxins is liver. Sterigmatocystin shows mutagenic, toxic and teratogenic effects in animals. Up to date national and international data on sterigmatocystin occurrence in different products is summarized, analytical methods of the determination are reviewed, hygienic assessment of the STC as a priority pollutant is given in the present paper. Also information on STC exposure assessment with regard to different kinds of foodstuff in different countries is being reported, available data on maximum levels of STC in food and feed is discussed. However, data on toxin’s occurrence in food is insufficient for elaboration of hygienic regulations on allowable mycotoxin’s concentration in priority products. Databases Web of Science, PubMed, E-library, CyberLeninka were used when searching the literature.

The neuroprotective properties of carnosine in a mouse model of manganism is mediated via mitochondria regulating and antioxidative mechanisms

ABSTRACT Objective(s): Manganese (Mn) is an essential trace element physiologically incorporated in the structure of several vital enzymes. Despite its essentiality, excessive Mn exposure is toxic with brain tissue as the primary target organ. There is no specific and clinically available therapeutic/preventive option against Mn neurotoxicity. Carnosine is a neuropeptide with several physiological roles. The neuroprotective properties of this peptide have been evaluated in different experimental models. The current study was designed to investigate the effect of carnosine supplementation and its potential mechanisms of action in an animal model of Mn-induced neurotoxicity. Materials and Methods: Male C57BL/6 mice received Mn (100 mg/kg, s.c) alone and/or in combination with carnosine (10, 50, and 100 mg/kg, i.p). Several locomotor activity indices were monitored. Moreover, biomarkers of oxidative stress and mitochondrial function were assessed in the brain tissue of Mn-exposed animals. Results: Significant locomotor dysfunction was revealed in Mn-exposed animals. Furthermore, brain tissue biomarkers of oxidative stress were significantly increased, and mitochondrial indices of functionality were impaired in Mn-treated animals. It was found that carnosine supplementation (10, 50, and 100 mg/kg, i.p) alleviated the Mn-induced locomotor deficit. Moreover, this peptide mitigated oxidative stress biomarkers and preserved brain tissue mitochondrial functionality in the animal model of manganism. Conclusion: These data indicate that carnosine is a potential neuroprotective agent against Mn neurotoxicity. Antioxidative and mitochondria protecting effects of carnosine might play a fundamental role in its neuroprotective properties against Mn toxicity.

Changes in hepato-renal gene expression in microminipigs following a single exposure to a mixture of perfluoroalkyl acids.

It is evident that some perfluoroalkyl acids (PFAAs), a group of globally dispersed pollutants, have long biological half-lives in humans and farm animals. However, the effects of PFAAs in domestic animals have not been fully elucidated. The present study investigated how exposure to a single dose of a mixture of 10 PFAAs influenced hepatic and renal gene expression and histopathology, as well as plasma clinical biochemistry, in microminipigs (MMPigs) over 21 days. In animals treated with PFAAs, the mRNA expression of twelve genes related to fatty acid metabolism was upregulated in the kidney, while only few of these genes were induced in the liver. The expression of several kidney injury-associated genes such as, IGFBP1, IGFBP6, GCLC X2, GCLC X3, MSGT1, OLR1 was upregulated in the kidney. Interestingly, the expression of IGFBP-genes was differentially altered in the liver and kidney. Our findings thus identified hepato-renal gene expression changes in MMPigs that were associated with various molecular pathways including peroxisome proliferation, lipid metabolism, kidney injury, and apoptosis. Furthermore, serum HDL levels were significantly decreased following exposure to PFAAs, whereas no significant histopathological changes were detected, as compared to the vehicle group. Taken together, the present study provided the first indication that a single exposure to a mixture of PFAAs can produce changes in MMPig renal gene expression that were observed three weeks post exposure, suggesting that more attention should be paid to the kidney as a primary target organ of PFAAs.

Naringenin Ameliorates Renovascular Hypertensive Renal Damage by Normalizing the Balance of Renin-Angiotensin System Components in Rats.

Background: Naringenin, a member of the dihydroflavone family, has been shown to have a protective function in multiple diseases. We previously demonstrated that naringenin played a protective role in hypertensive myocardial hypertrophy by decreasing angiotensin-converting enzyme (ACE) expression. The kidney is a primary target organ of hypertension. The present study tested the effect of naringenin on renovascular hypertensive kidney damage and explored the underlying mechanism.Methods and Results: An animal model of renovascular hypertension was established by performing 2-kidney, 1-clip (2K1C) surgery in Sprague Dawley rats. Naringenin (200 mg/kg/day) or vehicle was administered for 10 weeks. Blood pressure and urinary protein were continuously monitored. Plasma parameters, renal pathology and gene expression of nonclipped kidneys were evaluated by enzyme-linked immunosorbent assay, histology, immunohistochemistry, real-time polymerase chain reaction, and Western blot at the end of the study. Rats that underwent 2K1C surgery exhibited marked elevations of blood pressure and plasma Ang II levels and renal damage, including mesangial expansion, interstitial fibrosis, and arteriolar thickening in the nonclipped kidneys. Naringenin significantly ameliorated hypertensive nephropathy and retarded the rise of Ang II levels in peripheral blood but had no effect on blood pressure. 2K1C rats exhibited increases in the ACE/ACE2 protein ratio and AT1R/AT2R protein ratio in the nonclipped kidney compared with sham rats, and these increases were significantly suppressed by naringenin treatment.Conclusions: Naringenin attenuated renal damage in a rat model of renovascular hypertension by normalizing the imbalance of renin-angiotensin system activation. Our results suggest a potential treatment strategy for hypertensive nephropathy.

Ammonia-induced mitochondrial impairment is intensified by manganese co-exposure: relevance to the management of subclinical hepatic encephalopathy and cirrhosis-associated brain injury.

Aim of the studyHepatic encephalopathy (HE) is a neuropsychiatric syndrome ensuing from liver failure. The liver is the major site of ammonia detoxification in the human body. Hence, acute and chronic liver dysfunction can lead to hyperammonemia. Manganese (Mn) is a trace element incorporated in several physiological processes in the human body. Mn is excreted through bile. It has been found that cirrhosis is associated with hyperammonemia as well as body Mn accumulation. The brain is the primary target organ for both ammonia and Mn toxicity. On the other hand, brain mitochondria impairment is involved in the mechanism of Mn and ammonia neurotoxicity.Material and methodsThe current study was designed to evaluate the effect of Mn and ammonia and their combination on mitochondrial indices of functionality in isolated brain mitochondria. Isolated brain mitochondria were exposed to increasing concentrations of ammonia and Mn alone and/or in combination and several mitochondrial indices were assessed.ResultsThe collapse of mitochondrial membrane potential, increased mitochondrial permeabilization, reactive oxygen species formation, and a significant decrease in mitochondrial dehydrogenase activity and ATP content were evident in Mn-exposed (0.005-1 mM) brain mitochondria. On the other hand, ammonia (0.005-0.5 mM) caused no significant changes in brain mitochondrial function. It was found that co-exposure of the brain mitochondria to Mn and ammonia causes more evident mitochondrial impairment in comparison with Mn and/or ammonia alone.ConclusionsThese data indicate additive toxicity of ammonia and Mn in isolated brain mitochondria exposed to these neurotoxins.

2393. Evaluation of Antifungal Treatment in a Neutropenic Mouse Model of Scedosporiosis

BackgroundScedosporiosis is a rare fungal infection with high mortality rates. Because clinical trials are hard to conduct, we developed a murine model for evaluating the efficacy of currently used antifungals in treating scedosporiosis.MethodsMIC of isavuconazole (ISAV), posaconazole (POSA), voriconazole (VORI), and micafungin (MICA) were determined against 9 clinical isolates of Scedosporium apiospermum, S. boydii and Lomentospora prolificans using the CLSI M38 method. ICR mice were immunosuppressed with cyclophosphamide (200 mg/kg) and cortisone acetate (500 mg/kg) on days −2, +3, and +8 relative to intratracheal infection with 3.0 × 107 cells of S. apiospermum. For survival studies, treatment with placebo (vehicle control), ISAV (110 mg/kg, tid, po), POSA (30 mg/kg, tid, po), VORI (40 mg/kg, qd, po), MICA (3 or 10 mg/kg, qd, ip) or a combination of MICA (10 mg/kg) + ISAV (110 mg/kg) began 16 h post infection and continued for 7 days. For fungal burden studies, dosing began 8 h post infection and continued for 3 days. Mice were sacrificed on day +4. Survival and tissue fungal burden (by qPCR) served as efficacy endpoints.Results S. apiospermum was the most susceptible to all 4 antifungals with MICA MIC of 0.25 μg/mL and azole MICs of 1 μg/mL. S. boydii was also susceptible to MICA (0.125–0.5 μg/mL) but with variable susceptibility to azoles (1–16 μg/mL). In contrast, L. prolificans strains were resistant (MICA MIC 2–4 μg/mL and azole MIC >16 μg/mL). S. apiospermum DI16-478 was used to test in vivo efficacy. Only MICA (10 mg/kg) treatment prolonged survival of mice (n = 10) vs. placebo (median survival time = 8 days for MICA vs. 5 for placebo, P < 0.03 by log rank) and reduced fungal burden in lungs (primary target organ), brains and kidneys (P ≤ 0.02, by Wilcoxon rank sum). None of the azoles prolonged survival despite the significant reduction in the lung fungal burden (P < 0.002), possibly due to lack of reduction of fungal burden in kidneys and brains. MICA+ISAV did not enhance survival nor reduce tissue fungal burden vs. placebo.ConclusionDespite the in vitro activity of tested antifungals, only MICA demonstrated modest efficacy in mice infected with S. apiospermum. A combination of MICA+ISAV was ineffective in this model. Continued investigations of other drug combinations to treat scedosporiosis are needed.Disclosures T. Kitt, Astellas Pharma Inc.: Employee, Salary. A. S. Ibrahim, Astellas: Investigator and Research Contractor, Research grant.

Protective role of skeletal muscle mass against progression from metabolically healthy to unhealthy phenotype.

Metabolically healthy individuals are known to be resistant to cardiovascular disease development. However, a considerable fraction of those individuals shows deteriorated metabolic health over time. Although skeletal muscle is the primary insulin-responsive target organ, a longitudinal investigation of the skeletal muscle mass in relation to the development of metabolically unhealthy phenotype has not been performed. We aimed to evaluate whether greater skeletal muscle mass is an independent protective factor for the development of metabolically unhealthy phenotype. We conducted a retrospective cohort study with 9033 metabolically healthy volunteers who underwent routine health examinations in 2012 and a follow-up examination in 2016. Obesity was defined as Asian-Pacific body mass index criterion ≥25kg/m2 . Subjects with fewer than two risk factors (elevated blood pressure, triglyceride, glucose, high-sensitivity C-reactive protein, insulin resistance and decreased high-density lipoprotein cholesterol levels) were characterized as metabolically healthy using Wildman criteria. At the 4-year follow-up, approximately one-fourth of the nonobese participants and half of the participants with obesity showed metabolic deterioration. In nonobese men and women, higher appendicular skeletal muscle mass (ASM)/weight at baseline was significantly associated with decreased risk of metabolic deterioration. Compared to the lowest quartile of ASM/weight, the adjusted odds ratios (95% confidence intervals) of the highest quartile were 0.68 (0.52-0.89) in nonobese men and 0.64 (0.46-0.90) in nonobese women. However, this association was not observed in obese subjects. Greater skeletal muscle mass at baseline is significantly associated with maintenance of metabolically healthy status, especially in nonobese individuals.

Primary and secondary pyrrolic metabolites of pyrrolizidine alkaloids form DNA adducts in human A549 cells

Humans and animals can be exposed to carcinogenic pyrrolizidine alkaloids (PAs) through consumption of plants commonly found in many parts of the world. Although the liver is the primary target organ for carcinogenic PAs, they have also induced lung tumors in rodents. Hepatic cytochrome P450 activity converts PAs into dehydro-PAs that can be hydrolyzed to dehydropyrrolizidine (DHP); these reactive pyrrolic metabolites can produce four characteristic DNA adducts associated with PA-induced liver tumor initiation in laboratory animals. We reported recently that these four DNA adducts are also formed when 7-glutathione-DHP (7-GS-DHP) or 7-cysteine-DHP is incubated with calf thymus DNA. Here we showed that the four characteristic DNA adducts were formed when human A549 brochoalveolar carcinoma cells were treated with three dehydro-PAs (dehydroriddelliine, dehydromonocrotaline, or dehydroretronecine) or with 7-GS-DHP or 7-cysteine-DHP. For comparison, two parent PAs (riddelliine and monocrotaline) and 7,9-di-glutathionine-DHP were studied. No DHP-DNA adducts were detected with these incubations, confirming that A549 lung carcinoma cells do not express cytochrome P450 enzymes required for metabolic activation of PAs. Our results show that primary and secondary pyrrolic metabolites of carcinogenic PAs produce characteristic DHP-containing DNA adducts in A549 lung cancer cells, suggesting that they are DNA reactive metabolites.

Abstract P231: Circulatory Gene Regulation in Youth With Primary Hypertension and Target Organ Damage

Introduction: Primary hypertension (PH) is a multifactorial disease mainly influenced by genetic, epigenetic and environmental dynamics. Despite the occurrence of PH-associated cardiovascular (CV) events in youth, we have acquired only a limited understanding of epigenetic and gene regulation of blood pressure (BP)-related target organ damage (TOD) in adolescents. Aims and Objectives: To define circulatory gene and miRNA expression levels and allied signaling pathways in hypertensive adolescents (Hyp) with TOD. Methods and Results: Three hundred adolescents of both genders aged 11 to 18 years participated in the AHA-funded Study of Hypertension in Pediatrics - Adult Hypertension Onset in Youth (SHIP AHOY) Project. Mean clinic SBP was 104.3 ±8.1 and 133.0 ± 8.2 mmHg in normal vs Hyp ( p&lt;0.005 ) and mean daytime ambulatory SBP was 115.7 ±11.4 and 128.9 ±6.4 mmHg in normal vs Hyp ( p&lt;0.005 ), respectively. Youth with PH also had higher BMI (22.33 ±3.67 vs 31.56 ±9.42; p&lt; 0.05 ), elevated serum creatinine (0.73 ± 0.18 vs 0.92 ±0.12; p&lt; 0.05 ), and left ventricular hypertrophy (LVM/ht 2.7 ; 25.4 ±1.8 vs 41.7 ±1.8; p&lt; 0.05 ), and trend for increased arterial stiffness (PWV; 4.8 ±0.6 vs 5.8 ±2.0; p =0.18). mRNA and microRNA seq were performed using peripheral blood cells of 10 normal (mean 15.2 ±1.4 years; 50% male), and 10 Hyp patients (mean 15.5 ±1.5 years; 70% male). Seq data analysis revealed master genes (Fig. 1) and pathways that were differentially regulated in Hyp patients with TOD. Conclusions: PH in youth is associated with TOD that relates to a distinct gene expression profile. Knowledge of allied pathways may lead to new treatments in hypertensive youth to prevent future CV diseases.

MiRNA expression profiles of premalignant and malignant arsenic-induced skin lesions.

Arsenic, a naturally occurring element, contaminates the drinking water of over 200 million people globally. Chronic arsenic exposure causes multiple cancers including those originating from skin, lung and bladder, and is associated with liver, kidney, and prostate cancers. Skin is the primary target organ for arsenic toxicity; chronic toxicity initially manifests as non-malignant hyperkeratoses (HK) and subsequently advances to malignant lesions, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In this study, we evaluate the miRNA expression profiles of premalignant (3 HK) and malignant (3 BCC and 3 SCC) skin lesions from individuals chronically exposed to high levels of arsenic (59–172 ppb) in their drinking water in West Bengal, India. The lesions were histologically complex requiring histopathologic identification of keratinocytes to be isolated for RNA analyses. Keratinocytes were harvested using Laser Capture Microdissection and miRNA expression profiles were determined using TaqMan® Array Human MiRNA A Card v2.0. Thirty-five miRNAs were differentially expressed among the three lesion types analyzed. Two miRNAs (miR-425-5p and miR-433) were induced in both BCC and SCC relative to HK indicating their association with malignancy. Two other miRNAs (miR-184 and miR-576-3p) were induced in SCC relative to both BCC and HK suggesting selective induction in tumors capable of metastasis. Six miRNAs (miR-29c, miR-381, miR-452, miR-487b, miR-494 and miR-590-5p) were selectively suppressed in BCC relative to both SCC and HK. In conclusion, the differential miRNA expression was both phenotype- and stage-related. These miRNAs are potential biomarkers and may serve as therapy targets for arsenic-induced internal tumors.

Assessment of the effects of graphene exposure in Danio rerio: A molecular, biochemical and histological approach to investigating mechanisms of toxicity

Graphene has been shown to induce toxicity in mammals and marine crustaceans; however, information regarding oxidative stress in fish is scarce. The aim of this study was to evaluate the mechanism of graphene toxicity in different tissues of Danio rerio, considering different parameters of stress. Animals were injected intraperitoneally (i.p.) with 10 μL of suspensions containing different graphene concentrations (5 and 50 mg/L); the gills, intestine, muscle and brain were analysed 48 h later. There was no significant difference in the expression of the gclc (glutamate cysteine ligase catalytic subunit) and nrf2 (nuclear factor (erythroid-derived 2)-like 2) genes after exposure. In contrast, glutamate cysteine ligase (GCL) and glutathione-S-transferase (GST) activities were modulated and the glutathione (GSH) concentration was reduced in different tissues and at different concentrations. Lipid damage was observed in the gills. Histological analyses were performed to observe if the exposure could induce pathological damage in these tissues. The results showed pathological effects in all tissues, excluding the intestine, after exposure to both concentrations. Overall, these results indicate that graphene induces different grades of toxicological effects that are dependent on the analysed organ, with distinct pathological effects on some and oxidative effects on others. However, the brain and gills seem to be the primary target organs for graphene toxicity.

Protective role of curcumin in ameliorating AFB1-induced apoptosis via mitochondrial pathway in liver cells.

It is well documented that liver is the primary target organ of aflatoxin B1 (AFB1) and curcumin proved to be effective against AFB1-induced liver injury. In the present study, we investigated the preventive effects of curcumin against AFB1-induced apoptosis through the molecular regulation of p53, caspase-3, Bax, caspase-9, Bcl-2 and cytochrome-C associated with mitochondrial pathway. Liver antioxidant levels were measured. The hallmarks of apoptosis were analysed by methyl green-pyronin-Y staining, transmission electron microscopy, RT-PCR and western blot. Results revealed that dietary curcumin ameliorated AFB1-induced oxidative stress in a dose-dependent manner. Methyl green-pyronin-Y staining and transmission electron microscopy showed that AFB1 induced apoptosis and caused abnormal changes in liver cells morphology such as condensation of chromatin material, reduces cell volume and damaged mitochondria. Moreover, mRNA and protein expression results manifested that apoptosis associated genes showed up-regulation in AFB1 fed group. However, the supplementation of dietary curcumin (dose-dependently) alleviated the increased expression of the apoptosis associated genes at mRNA and protein level, and restored the hepatocytes normal morphology. The study provides an insight and a better understanding of the preventive mechanism of curcumin against AFB1-induced apoptosis in hepatocytes and provide scientific basis for the therapeutic uses of curcumin.

Cadmium-induced ultrastructural changes in primary target organs of developing chicken embryos (Gallus domesticus)

The aim of this study was to evaluate ultrastructural changes in kidney and liver tissue of chicken embryos exposed in ovo to cadmium. Embryonated eggs were injected on the 4th day of incubation with cadmium at the dose of 0, 2, 4 and 8 μg/egg (80 eggs/group). The samples of kidney and liver tissues were collected from embryos at the 14th and 18th day of incubation (E14 and E18) and at hatching day (D1). The tissue structure was evaluated by transmission electron microscopy (Tecnai G2 Spirit). The results indicate that hepatocytes responded to damage caused by toxic cadmium activity with a significant disturbance in the structure of mitochondria and a considerable expansion of the lysososmal system, while glomerular cells additionally reacted with an increased proliferation of peroxisomes. The range of changes observed on the subcellular level was dependent on the dose of cadmium, embryogenesis stage and cell type.

From the lung to the knee joint: Toxicity evaluation of carbon black nanoparticles on macrophages and chondrocytes

Carbon black (CB), a core elemental carbon component of airborne particles, has been used as a model material to study environmental safety and health impacts of airborne particles. Although potential adverse effects of CB have been reported, limited knowledge is available regarding CB-induced metabolic disorders and secondary effects distant from primary target organs, such as the effects on joints. The knee cavity is a relatively closed space along the peripheral circulation route with a slow rate of interchange of nutrition with blood. While epidemiologic studies have indicated that airborne particle exposure may affect the occurrence and severity of inflammatory knee diseases, no research has been performed to understand the potential hazardous direct/indirect interactions between particles and knee cells. Herein, we have scrutinized the toxicity of four commercial nano-sized CB samples in the lung and a distant site: knee joint. Our results indicated that CB triggered pulmonary and systemic inflammation upon inhalation exposure, and, more strikingly, CB also elicited injuries of the knee joint, as demonstrated by thickened synovial membrane, suggesting disordered cellular metabolism within the knee joint. Our data recognized the CB toxicity profiles to macrophages as characterized by pro-inflammatory reactions, and also defined an activated metabolic state of chondrocytes, as evidenced by metalloproteinase (MMP) induction. Of note, remarkable variations were also found for these changes induced by these four CB samples, due to their distinct physicochemical properties. Collectively, our results uncovered a significant toxicity of CB inhalation exposure to the knee joint, as reflected by metabolic activation of chondrocytes, and, more importantly, these findings unearthed CB-induced metabolic disorders and secondary effects owing to systemic pro-inflammatory conditions upon CB exposure, in addition to the likelihood of direct toxicity to knee cells.

Mesenchymal stem cell therapy for paraquat poisoning: A systematic review and meta-analysis of preclinical studies.

BackgroundParaquat (PQ) poisoning can cause multiple organ failure, in which the lung is the primary target organ. There is currently no treatment for PQ poisoning. Mesenchymal stem cells (MSCs), which differentiate into multiple cell types, have generated much enthusiasm regarding their use for the treatment of several diseases. The aim of this study was to systematically review and analyze published preclinical studies describing MSC administration for the treatment of PQ poisoning in animal models to provide a basis for cell therapy.MethodsThe electronic databases PubMed and CBMdisc were searched in this systematic review and meta-analysis. The MSC treatment characteristics of animal models of PQ poisoning were summarized. After quality assessment was performed, the effects of MSC transplantation were evaluated based on the survival rate, lung wet/dry weight, fibrosis scores, oxidative stress response, and inflammatory response. Publication bias was assessed.ResultsEleven controlled preclinical studies involving MSC transplantation in animal models of PQ poisoning were included in this review. MSC therapy improved the survival rate and reduced the lung wet/dry weight and histopathological fibrosis changes in most studies. MSCs decreased serum or plasma malondialdehyde levels in the acute phase after 7 and 14 d and increased serum or plasma superoxide dismutase and glutathione levels at the same time points. IL-1β, TNF-α and TGF-β1 levels in blood or lung tissues were decreased to different degrees by MSCs. Lung hydroxyproline was decreased by MSCs after 14 d. No obvious evidence of publication bias was found.ConclusionMSCs showed anti-fibrosis therapeutic effects in animal models of lung injury caused by PQ poisoning, which may be related to reduced oxidative stress and inflammatory cytokine levels. Our review indicates a potential therapeutic role for MSC therapy to treat PQ poisoning and serves to augment the rationale for clinical studies.

Myokine—Irisin—and Its Effects Linking Bone and Muscle Function

Irisin is a myokine secreted by the skeletal muscle during physical activity both in mice and humans. Its first identified role was to activate the browning response in white adipocytes, subsequently triggering non-shivering thermogenesis; therefore, Irisin has raised great expectations as a potential target in the treatment of obesity. In 2015, we demonstrated that Irisin plays a central role in the control of bone mass, driving positive effects on cortical mineral density and bone mechanical properties. This effect on the bone was triggered using an Irisin dosage 70 times lower than the one needed to induce the browning response, suggesting that the skeleton is the primary target organ of this myokine. Moreover, our studies also highlighted the autocrine effect of Irisin on the skeletal muscle, overall suggesting that Irisin plays a fundamental role in the physiology of the musculoskeletal system. More recently, we demonstrated the efficacy of Irisin in preventing and restoring bone and muscle losses in a mouse model affected by disuse-induced osteoporosis and muscular atrophy. Hopefully, if future investigations will be confirmed in humans, it may lead to develop an Irisin-based therapy for physically disable or bedridden patients and it might also represent a countermeasure for astronauts subjected to microgravity.

Silver effects on silkworm, Bombyx mori.

Silver nanoparticles (Ag-NPs) are known as a noble metal, and owing to their exclusive properties, their use is widespread in consumer products and they are mostly incorporated into food packaging and food contact products. The aim of this work was to evaluate the effects of direct ingestion of Ag-NPs through food to assess their toxicity effects on the growth and development of silkworms at different concentrations (1 mg·L-1 to 100 mg·L-1), in addition to the examination of the distribution of Ag-NPs in the silkworm body and midgut histopathological analysis. RNA sequencing was performed to investigate the transcriptomic responses to Ag-NPs exposure. Our results show that the highest Ag-NPs' concentrations induced a significant increase in the silkworm body weight with histopathological changes in the midgut compared to the control group. The gene ontology (GO) and pathway enrichment analysis for differentially expressed genes showed that Ag-NPs altered the gene expressions and that they were significantly involved in carbohydrate metabolism, digestive system, and energy metabolism. These findings indicate that the Ag-NPs may induce harmful effects on the primary target organs (alimentary system) with energy deregulation and nutrition digestion and absorption imbalance. This study is an important step in understanding the molecular mechanisms of Ag-NPs' toxicity in vivo.

Chicken galectin-1B inhibits Newcastle disease virus adsorption and replication through binding to hemagglutinin–neuraminidase (HN) glycoprotein

Galectin-1 is an important immunoregulatory factor and can mediate the host-pathogen interaction via binding glycans on the surface of various viruses. We previously reported that avian respiratory viruses, including lentogenic Newcastle disease virus (NDV), can induce up-regulation of chicken galectin (CG)-1B in the primary target organ. In this study, we investigated whether CG-1B participated in the infectious process of NDV in chickens. We demonstrated that velogenic NDV induced up-regulation of CG-1B in target organs. We also found that CG-1B directly bound to NDV virions and inhibited their hemagglutination activity in vitro We confirmed that CG-1B interacted with NDV hemagglutinin-neuraminidase (HN) glycoprotein, in which the specific G4 N-glycans significantly contributed to the interaction between CG-1B and HN glycoprotein. The presence of extracellular CG-1B, rather than the internalization process, inhibited adsorption of NDV. The interaction between intracellular CG-1B and NDV HN glycoproteins inhibited cell-surface expression of HN glycoprotein and reduced the titer of progeny virus in NDV-infected DF-1 cells. Significantly, the replication of parental and HN glycosylation mutant viruses in CG-1B knockdown and overexpression cells demonstrated that the replication of NDV was correlated with the expression of CG-1B in a specific glycan-dependent manner. Collectively, our results indicate that CG-1B has anti-NDV activity by binding to N-glycans on HN glycoprotein.

Vaccarin alleviates hypertension and nephropathy in renovascular hypertensive rats

The kidney is an important organ in the regulation of blood pressure, and it is also one of the primary target organs of hypertension. Kidney damage in response to hypertension eventually leads to renal insufficiency. The authors previously demonstrated that vaccarin exhibits a protective role in endothelial injury. However, the effects of vaccarin on the two-kidney, one clip (2K1C) renovascular hypertension model and subsequent kidney injury have yet to be fully elucidated. The present study was designed to investigate the roles and mechanisms of vaccarin in attenuating hypertension and whether vaccarin had beneficial effects on kidney injury. The 2K1C rats had greater fibrosis, apoptosis, reactive oxygen species production, inflammation, angiotensin II (Ang II) and angiotensin type 1 (AT1) receptors in the right kidney compared with normotensive rats, which were alleviated by a high dose of vaccarin and captopril. Vaccarin treatment attenuated hypertension, reduced fibrosis markers, NADPH oxidase (NOX)-2, NOX-4, 3-nitrotyrosine, tumor necrosis factor-α, interleukin 1β (IL-1β), and IL-6 protein levels and altered pro-apoptotic protein levels including caspase-3, anti-apoptosis protein B cell lymphoma (Bcl)-2 and Bcl-2 associated X, apoptosis regulator in the right kidney of 2K1C rats. These findings suggest that the protective effects of vaccarin on the right kidney in renovascular hypertension are possibly due to downregulation of fibrosis, inflammatory molecules, oxidative stress, Ang II, and AT1 receptor levels.

Cellular Architecture of Spinal Granulomas and the Immunological Response in Tuberculosis Patients Coinfected with HIV.

Mycobacterium tuberculosis (M.tb) and HIV are individually responsible for the most deaths worldwide among all infectious agents, and coinfection with M.tb and HIV is a significant public health challenge in the developing world. Although the lung is the primary target organ for tuberculosis (TB), M.tb can also cause extrapulmonary tuberculosis (EPTB) such as in the bones and joints. Treatment of EPTB is much more challenging than treatment of pulmonary TB. The hallmark of the host immune response against TB is the formation of organized structures called granulomas that are infiltrated with immune cells and are rich in cytokines and chemokines. Inside granulomas, the host confines the M.tb bacteria to a particular region of the organ and avoids dispersion. In this study, we analyzed immune cells in bone granulomas of patients with EPTB that are also coinfected with HIV. We found that HIV-infected TB patients have dispersed bone granulomas, with reduced T cell numbers and a concomitant increase in plasma cells. Additionally, HIV-infected patients exhibited dramatically increased serum levels of IgM and IgG1 antibodies, which is indicative of T-cell-independent B-cell activation and mucosal T-cell activation, respectively. Interestingly, we also observed that CD29+ stem cells are increased in HIV–TB coinfection, suggesting a link with HIV infection. Therefore, our work provides new insights into the architecture of spinal TB granulomas and the role of B-cells and humoral immunity against a highly infectious intracellular pathogen. We propose that our findings will inform biomarker identification for EPTB and possibly the development of related therapeutics and/or vaccines to protect HIV-infected patients against disseminated TB.