Typhoid toxin hijacks Wnt5a to establish host senescence and Salmonella infection.

Damage to our genome causes acute senescence in mammalian cells, which undergo growth arrest and release a senescence-associated secretory phenotype (SASP) that propagates the stress response to bystander cells. Thus, acute senescence is a powerful tumor suppressor. Salmonella enterica hijacks senescence through its typhoid toxin, which usurps unidentified factors in the stress secretome of senescent cells to mediate intracellular infections. Here, transcriptomics of toxin-induced senescent cells (TxSCs) and proteomics of their secretome identify the factors as Wnt5a, INHBA, and GDF15. Wnt5a establishes a positive feedback loop, driving INHBA and GDF15 expression. In fibroblasts, Wnt5a and INHBA mediate autocrine senescence in TxSCs and paracrine senescence in naive cells. Wnt5a synergizes with GDF15 to increase Salmonella invasion. Intestinal TxSCs undergo apoptosis without Wnt5a, which is required for establishing intestinal TxSCs. The study reveals how an innate defense against cancer is co-opted by a bacterial pathogen to cause widespread damage and mediate infections.

Xenobiotics Result in Hormonal and Enzymatic Dysregulations in the Red Mussel Mytilus galloprovincialis (Lamarck, 1819) (Bivalvia, Mytilidae).

<b>Background and Objective:</b> The contaminants in a marine ecosystem like mercury and synthetic hormones can disrupt the regulation of natural endocrine and reproductive systems of most organisms. This study aims to study the effect of organic and inorganic mercury on the viscera of <i>Mytilus galloprovincialis</i> after intracoelomic injection of 17α-ethinylestradiol, 17ß-estradiol and Dichlorodiphenyltrichloroethane (DDT) and check the histological changes in the gonads. <b>Materials and Methods:</b> Mussels are collected during June-August, 2018 from Ras el tin beach of the Mediterranean Sea of Alexandria, Egypt. This study aims to: test the effect of 17α-ethinylestradiol, 17ß-estradiol and DDT on vitellogenin (VTG) synthesis, enzymes dysfunction through intracoelomic injection of methyl mercury in a 0.75 µg/0.1 mL and mercury chloride to a 75 µg/0.1 mL. Gonads are studied histologically in control and treated mussels. Water-administered E2 and EE2 at 120 µL dose induced VTG expression in males 14 days exposure. <b>Results:</b> The relative concentration of VTG in the induced groups increases significantly as compared to the control. Alterations in the gonadal tissues and the maturation stages of the mussels are observed. The imposex mussels are characterized by concomitant secondary male sexual characteristics and the female gonad shows testicular structure. Superoxide Dismutase (SOD) activity in mussel digestive glands differed significantly (p = 0.002) after 72 hrs of MeHg exposure. <b>Conclusion:</b> Significant correlation can be observed between the activities of Glutathione S-Transferases (GST) and Glutathione Reductase (GR) in the digestive glands of mussels treated with MeHg, the enzyme activities of digestive glands treated with HgCl₂ and between Superoxide Dismutase<i>-</i>Catalase (SOD-CAT), SOD-GR and GST-GR.

Therapeutic Role of Annona muricata Fruit and Bee Venom Against MNU-Induced Breast Cancer in Pregnant Rats and its Complications on the Ovaries.

AIM: To evaluate the potential therapeutic role of Annona muricata (graviola) fruit and bee venom (BV) against N-methylnitrosourea (MNU)-induced breast cancer in pregnant female rats and complications in the ovaries. METHODS: A total of 24 female rats were induced with a single dose of MNU (50 mg/kg body weight). After confirmation of positive tumor marker, female rats were placed with the males for mating. The pregnant rats were randomly divided into four groups (n=6): MNU-induced only (group 1), MNU-induced rats and supplemented with A. muricata 200 mg/kg diet (group 2), MNU-induced and treated with two doses of BV 75 µg/kg (group 3), and MNU-induced and treated with both A. muricata and BV (group 4). RESULTS: In group 1, the breast tissue of mothers revealed pronounced cellular hyperplasia and histopathological signs. Also, the ovarian tissue of mothers and their offspring displayed deleterious histological changes. In groups 2 and 4, histopathological signs and cellular hyperplasia markedly disappeared in breast tissue. However, the histopathological signs induced by MNU in the ovarian tissue reversed to normal in groups 2-4. Also in groups 2-4, levels of serum MMP1, NFκB, and TNFα significantly decreased, and serum caspase 3 significantly increased either in mother rats or their offspring compared to the MNU-alone group. Levels of serum MDA significantly decreased; however, levels of serum antioxidants (CAT and SOD) significantly increased in all groups 2-4 compared to MNU-alone group. CONCLUSION: A. muricata has a more powerful therapeutic role than BV against MNU-induced breast cancer in rats; however, both have a powerful ameliorative role against ovarian histopathological alterations induced by MNU. Such ameliorative effects of A. muricata and BV are mainly attributed to their antioxidant, anti-inflammatory, and antiproliferative constituents.

Senescence and Host-Pathogen Interactions.

Damage to our genomes triggers cellular senescence characterised by stable cell cycle arrest and a pro-inflammatory secretome that prevents the unrestricted growth of cells with pathological potential. In this way, senescence can be considered a powerful innate defence against cancer and viral infection. However, damage accumulated during ageing increases the number of senescent cells and this contributes to the chronic inflammation and deregulation of the immune function, which increases susceptibility to infectious disease in ageing organisms. Bacterial and viral pathogens are masters of exploiting weak points to establish infection and cause devastating diseases. This review considers the emerging importance of senescence in the host-pathogen interaction: we discuss the pathogen exploitation of ageing cells and senescence as a novel hijack target of bacterial pathogens that deploys senescence-inducing toxins to promote infection. The persistent induction of senescence by pathogens, mediated directly through virulence determinants or indirectly through inflammation and chronic infection, also contributes to age-related pathologies such as cancer. This review highlights the dichotomous role of senescence in infection: an innate defence that is exploited by pathogens to cause disease.

Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection.

Salmonella Typhi activates the host DNA damage response through the typhoid toxin, facilitating typhoid symptoms and chronic infections. Here we reveal a non-canonical DNA damage response, which we call RING (response induced by a genotoxin), characterized by accumulation of phosphorylated histone H2AX (γH2AX) at the nuclear periphery. RING is the result of persistent DNA damage mediated by toxin nuclease activity and is characterized by hyperphosphorylation of RPA, a sensor of single-stranded DNA (ssDNA) and DNA replication stress. The toxin overloads the RPA pathway with ssDNA substrate, causing RPA exhaustion and senescence. Senescence is also induced by canonical γΗ2ΑΧ foci revealing distinct mechanisms. Senescence is transmitted to non-intoxicated bystander cells by an unidentified senescence-associated secreted factor that enhances Salmonella infections. Thus, our work uncovers a mechanism by which genotoxic Salmonella exhausts the RPA response by inducing ssDNA formation, driving host cell senescence and facilitating infection.