Cellular senescence is a cell fate that occurs in response to numerous types of stress and can promote tissue repair or drive inflammation and disruption of tissue homeostasis depending on the ...context. Aging and obesity lead to an increase in the senescent cell burden in multiple organs. Senescent cells release a myriad of senescence-associated secretory phenotype factors that directly mediate pancreatic β-cell dysfunction, adipose tissue dysfunction, and insulin resistance in peripheral tissues, which promote the onset of type II diabetes mellitus. In addition, hyperglycemia and metabolic changes seen in diabetes promote cellular senescence. Diabetes-induced cellular senescence contributes to various diabetic complications. Thus, type II diabetes is both a cause and consequence of cellular senescence. This review summarizes recent studies on the link between aging, obesity, and diabetes, focusing on the role of cellular senescence in disease processes.
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly
. To define the contribution of immune system ageing to organism ageing, here we ...selectively deleted Ercc1, which encodes a crucial DNA repair protein
, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence
in the immune system only. We show that Vav-iCre
;Ercc1
mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice
. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre
;Ercc1
or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre
;Ercc1
mice with rapamycin reduced markers of senescence in immune cells and improved immune function
. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
With aging, there is increased dysfunction of both innate and adaptive immune responses, which contributes to impaired immune responses to pathogens and greater mortality and morbidity. This ...age-related immune dysfunction is defined in general as immunosenescence and includes an increase in the number of memory T cells, loss of ability to respond to antigen and a lingering level of low-grade inflammation. However, certain features of immunosenescence are similar to cellular senescence, which is defined as the irreversible loss of proliferation in response to damage and stress. Importantly, senescence cells can develop an inflammatory senescence-associated secretory phenotype (SASP), that also drives non-autonomous cellular senescence and immune dysfunction. Interestingly, viral infection can increase the extent of immune senescence both directly and indirectly, leading to increased immune dysfunction and inflammation, especially in the elderly. This review focuses on age-related immune dysfunction, cellular senescence and the impaired immune response to pathogens.
Parasite infections in fish require constant surveillance and strategies for efficient treatments which guarantee the fish health, their sale value and the non‐propagation of pathogens in new ...environments. Fish treatments based on nanotechnology become of increasing interest since nanoparticles have been shown as efficient materials for optimizing administration of bioactives. In this study a chitosan derivative, alginate and praziquantel conjugated nanobioparticle of effective action for oral treatment of digenetic trematodes in highly infected Corydoras schwartzi was evaluated in terms of histological and hematological safety. The inherent absence of alterations in intestinal tissue and the reversible blood cells counting during a period up to 35 days showed the safety of the drug delivery nanobioparticles, which thus represent a promising strategy for effective applications in pathogens treatments by oral administration.
Summary
With aging, there is progressive loss of tissue homeostasis and functional reserve, leading to an impaired response to stress and an increased risk of morbidity and mortality. A key mediator ...of the cellular response to damage and stress is the transcription factor NF‐κB. We demonstrated previously that NF‐κB transcriptional activity is upregulated in tissues from both natural aged mice and in a mouse model of a human progeroid syndrome caused by defective repair of DNA damage (ERCC1‐deficient mice). We also demonstrated that genetic reduction in the level of the NF‐κB subunit p65(RelA) in the Ercc1−/∆ progeroid mouse model of accelerated aging delayed the onset of age‐related pathology including muscle wasting, osteoporosis, and intervertebral disk degeneration. Here, we report that the largest fraction of NF‐κB ‐expressing cells in the bone marrow (BM) of aged (>2 year old) mice (C57BL/6‐NF‐κBEGFP reporter mice) are Gr‐1+CD11b+myeloid‐derived suppressor cells (MDSCs). There was a significant increase in the overall percentage of MDSC present in the BM of aged animals compared with young, a trend also observed in the spleen. However, the function of these cells appears not to be compromised in aged mice. A similar increase of MDSC was observed in BM of progeroid Ercc1−/∆ and BubR1H/H mice. The increase in MDSC in Ercc1−/∆ mice was abrogated by heterozygosity in the p65/RelA subunit of NF‐κB. These results suggest that NF‐κB activation with aging, at least in part, drives an increase in the percentage of MDSCs, a cell type able to suppress immune cell responses.
The IL‐12 family of heterodimeric cytokines, consisting of IL‐12, IL‐23, IL‐27, and IL‐35, has important roles in regulating the immune response. IL‐12 family members are comprised of a heterodimer ...consisting of α and β chains: IL‐12 (p40 and p35), IL‐23 (p40 and p19), IL‐27 (Ebi3 and p28), and IL‐35 (Ebi3 and p35). Given the combinatorial nature of the IL‐12 family, we generated adenoviral vectors expressing two putative IL‐12 family members not yet found naturally, termed IL‐X (Ebi3 and p19) and IL‐Y (p40 and p28), as single‐chain molecules. Single chain IL‐Y (scIL‐Y), but not scIL‐X, was able to stimulate significantly a unique cytokine/chemokine expression profile as well as activate STAT3 in mice, in part, through a pathway involving IL‐27Rα in splenocytes. Adenoviral‐mediated, intratumoral delivery of scIL‐Y increased tumor growth in contrast to the anti‐tumor effects of scIL‐12 and scIL‐23. Similarly, treatment of prediabetic NOD mice by intravenous injection of Ad.scIL‐Y prevented the onset of hyperglycemia. Analysis of cells from Ad.scIL‐Y‐treated NOD mice demonstrated that scIL‐Y reduced expression of inflammatory mediators such as IFN‐γ. Our data demonstrate that a novel, synthetic member of the IL‐12 family, termed IL‐Y, confers unique immunosuppressive effects in two different disease models and thus could have therapeutic applications.
Shifting the bioprospecting targets toward underexplored bacterial groups combined with genome mining studies contributes to avoiding the rediscovery of known compounds by revealing novel, promising ...biosynthetic gene clusters (BGCs). With the aim of determining the biosynthetic potential of a novel marine bacterium, strain V10
T
, isolated from the Domitian littoral in Italy, a comparative phylogenomic mining study was performed across related photosynthetic bacterial groups from an evolutionary perspective. Studies on polyphasic and taxogenomics showed that this bacterium constitutes a new species, designated
Roseibaca domitiana
sp. nov. To date, this genus has only one other validly described species, which was isolated from a hypersaline Antarctic lake. The genomic evolutionary study linked to BGC diversity revealed that there is a close relationship between the phylogenetic distance of the members of the photosynthetic genera
Roseibaca, Roseinatronobacter
, and
Rhodobaca
and their BGC profiles, whose conservation pattern allows discriminating between these genera. On the contrary, the rest of the species related to
Roseibaca domitiana
exhibited an individual species pattern unrelated to genome size or source of isolation. This study showed that photosynthetic strains possess a streamlined content of BGCs, of which 94.34% of the clusters with biotechnological interest (NRPS, PKS, RRE, and RiPP) are completely new. Among these stand out T1PKS, exclusive of
R. domitiana
V10
T
, and RRE, highly conserved only in
R. domitiana
V10
T
and
R. ekhonensis
, both categories of BGCs involved in the synthesis of plant growth-promoting compounds and antitumoral compounds, respectively. In all cases, with very low homology with already patented molecules. Our findings reveal the high biosynthetic potential of infrequently cultured bacterial groups, suggesting the need to redirect attention to microbial minorities as a novel and vast source of bioactive compounds still to be exploited.
Purpose of Review
Obesity has increased worldwide recently and represents a major global health challenge. This review focuses on the obesity-associated cellular senescence in various organs and the ...role of these senescent cells (SnCs) in driving complications associated with obesity. Also, the ability to target SnCs pharmacologically with drugs termed senotherapeutics as a therapy for these complications is discussed.
Recent Findings
Several studies have shown a positive correlation between obesity and SnC burden in organs such as adipose tissue, liver, and pancreatic-β-cells. These SnCs produce several secretory factors which affect other cells and tissues in a paracrine manner resulting in organ dysfunction. The accumulation of SnCs in adipocytes affects their lipid storage and impairs adipogenesis. The inflammatory senescence-associated secretory phenotype (SASP) of SnCs downregulates the antioxidant capacity and mitochondrial function in tissues. Senescent hepatocytes cannot oxidize fatty acids, which leads to lipid deposition and senescence in β-cells decrease function. These and other adverse effects of SnCs contribute to insulin resistance and type-2 diabetes. The reduction in the SnC burden genetically or pharmacologically improves the complications associated with obesity.
Summary
The accumulation of SnCs with age and disease accelerates aging. Obesity is a key driver of SnC accumulation, and the complications associated with obesity can be controlled by reducing the SnC burden. Thus, senotherapeutic drugs have the potential to be an effective therapeutic option.
The fraction of low-abundance microbiota in the marine environment is a promising target for discovering new bioactive molecules with pharmaceutical applications. Phenomena in the ocean such as diel ...vertical migration (DVM) and seasonal dynamic events influence the pattern of diversity of marine bacteria, conditioning the probability of isolation of uncultured bacteria. In this study, we report a new marine bacterium belonging to the rare biosphere,
sp. nov. Mr9
, which was isolated employing seasonal and diel sampling approaches. Its complete characterization, ecology, biosynthetic gene profiling of the whole genus
, and bioactivity of its extract on human cells are reported. The phylogenomic and microbial diversity studies demonstrated that this bacterium is a new and rare species, barely representing 0.0029% of the bacterial community in Mediterranean Sea metagenomes. The biosynthetic profiling of species of the genus
showed nine functionally related gene cluster families (GCF), none were associated with pathways responsible to produce known compounds or registered patents, therefore revealing its potential to synthesize novel bioactive compounds.
screenings of
Mr9
showed that the total lipid content (lipidome) of the cell membrane reduces the prostatic and brain tumor cell viability with a lower effect on normal cells. The lipidome consisted of sulfobacin A, WB 3559A, WB 3559B, docosenamide, topostin B-567, and unknown compounds. Therefore, the bioactivity could be attributed to any of these individual compounds or due to their synergistic effect. Beyond the rarity and biosynthetic potential of this bacterium, the importance and novelty of this study is the employment of sampling strategies based on ecological factors to reach the hidden microbiota, as well as the use of bacterial membrane constituents as potential novel therapeutics. Our findings open new perspectives on cultivation and the relationship between bacterial biological membrane components and their bioactivity in eukaryotic cells, encouraging similar studies in other members of the rare biosphere.
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•Genotoxicity of NiO NPs was investigated in vivo and in vitro.•NiO NPs inhibited cell proliferation.•NiO NPs were mutagenic in the SMART test.•NiO NPs increased frequencies of ...micronucleus in V79 cells.•The DNA damage frequency was enhanced after exposure of V79 cells to NiO NPs.
Nickel-based nanoparticles (NPs) are new products with an increasing number of industrial applications that were developed in recent years. NiO NPs are present in several nanotechnological industrial products, and the characterization of their genotoxic potential is essential. The present study assessed the genotoxicity of NiO NPs in vivo and in vitro using the somatic mutation and recombination test in somatic cells of Drosophila melanogaster (SMART), the cytokinesis – block micronucleus assay (CBMN), and the comet assay in a V79 cell line. The NiO NPs used in this study were about 30 nm in mean size. Larvae of Drosophila melanogaster were exposed to 5 mL of five different concentrations (1.31, 2.62, 5.25, 10.5, and 21 mg/mL) of NiO NPs. In turn, V79 cells were treated with a concentration range of 15–2000 μg/mL NiO NPs. The SMART showed that all concentrations of NiO NPs are genotoxic to the standart (ST) cross when compared to the negative control. On the other hand, only the highest concentration (21 mg/mL) was genotoxic to the HB cross. Somatic recombination was the preferential mechanism lesions were induced in D. melanogaster. The results show that NiO NPs were mutagenic to V79 cells as assessed by the CBMN assay. Significant differences in the frequencies of micronuclei (MN) were observed using the highest NiO NP concentrations (250 and 500 μg/mL) in the 4- and 24-h treatments, but when 125 μg/mL NiO NPs was used, such difference was observed only in the 4-h exposure time. The comet assay revealed that 62, 125, 250 and 500 μg/mL NiO NPs induced a significant increase in DNA damage. The results observed in this study indicate that NiO NPs are genotoxic and mutagenic in vitro and in vivo.
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