The ageing suppressor α-klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion and vitamin D homeostasis. The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of α-klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, α-klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23–FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signalling. The structure of α-klotho is incompatible with its purported glycosidase activity. Thus, shed α-klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling
A few commonly used non-antibiotic drugs have recently been associated with changes in gut microbiome composition, but the extent of this phenomenon is unknown. Here, we screened more than 1,000 marketed drugs against 40 representative gut bacterial strains, and found that 24% of the drugs with human targets, including members of all therapeutic classes, inhibited the growth of at least one strain in vitro. Particular classes, such as the chemically diverse antipsychotics, were overrepresented in this group. The effects of human-targeted drugs on gut bacteria are reflected on their antibiotic-like side effects in humans and are concordant with existing human cohort studies. Susceptibility to antibiotics and human-targeted drugs correlates across bacterial species, suggesting common resistance mechanisms, which we verified for some drugs. The potential risk of non-antibiotics promoting antibiotic resistance warrants further exploration. Our results provide a resource for future research on drug–microbiome interactions, opening new paths for side effect control and drug repurposing, and broadening our view of antibiotic resistance.
ABSTRACT More than thirty years ago functions of vitamin D other than its beneficial effects on calcium homeostasis and bone metabolism have been identified, mainly in relation to its anti-proliferative effects on cancer cells. Notably, vitamin D deficiency has been associated with a number of pathological conditions, including infections, autoimmune and allergic diseases. Vitamin D, and its metabolites, are actively involved in the regulation of innate and adaptive immune responses. Vitamin D signals through the vitamin D receptor (VDR), a specific zinc-finger nuclear receptor. The functions of vitamin D are characterized as genomic, mediated through the VDR transcriptional effects inside the cell nucleus, and non-genomic, when the VDR induces rapid signaling, situated on the cell membrane and/or cytoplasm. Emerging evidence supports the notion that vitamin D enhances immunity, providing protection towards pathogens, while, concomitantly, it exerts immunosuppressive effects by preventing the detrimental effects of prolonged inflammatory responses to the host. Still, the precise molecular mechanisms involved in vitamin D’s genomic and non-genomic actions remain incompletely defined. Moreover, it is unclear whether vitamin D actions require the synergistic activation of other mediators, such as nuclear membrane receptors. Understanding the biology of vitamin D and the molecular pathways utilized will pave the way for the design of more effective therapeutic strategies. In this review, we present the recent genomic and non-genomic effects of vitamin D from an immunological perspective with a focus on immune-mediated diseases.
Abstract Introduction: At the turn of the twentieth century, ultraviolet light was successfully used to treat tuberculosis of the skin. Upper respiratory tract infections had been inversely associated with sun exposure. During the last decade, basic scientific research demonstrated that vitamin D has an important anti-infective role. Method: Review of the relevant literature on the influence of vitamin D on innate immunity and respiratory tract infection. Results: Vitamin D is involved in the production of defensins and cathelicidin – antimicrobial peptides that provide a natural defence against potential microbiological pathogens. Vitamin D supplementation increases cathelicidin production. Low vitamin D levels are associated with an increased incidence of upper respiratory tract infections. Conclusions: VitaminDappears to play an important role in the regulation of innate immunity in the upper respiratory tract. Optimal vitamin D levels and appropriate dosing schedules have yet to be determined.
Vitamin D is now known to be of physiological importance outside of bone health and calcium homeostasis, and there is mounting evidence that it plays a beneficial role in the prevention and/or treatment of a wide range of diseases. In this brief review the known effects of vitamin D on immune function are described in relation to respiratory health. Vitamin D appears capable of inhibiting pulmonary inflammatory responses while enhancing innate defence mechanisms against respiratory pathogens. Population-based studies showing an association between circulating vitamin D levels and lung function provide strong justification for randomized controlled clinical trials of vitamin D supplementation in patients with respiratory diseases to assess both efficacy and optimal dosage.
Available data suggest that vitamin D plays a role in controlling inflammation in the lungs. However, to date vitamin D-induced production of cathelicidin has not been shown to have an effect on the burden of either viruses or bacteria. Future work should continue to determine the effects of vitamin D-regulated mechanisms in the lung and the possible role of cathelicidin against different pulmonary pathogens in vivo.
Abstract: Vitamin D metabolizing enzymes and vitamin D receptors are present in many cell types including various immune cells such as antigen-presenting-cells, T cells, B cells and monocytes. In vitro data show that, in addition to modulating innate immune cells, vitamin D also promotes a more tolerogenic immunological status. In vivo data from animals and from human vitamin D supplementation studies have shown beneficial effects of vitamin D on immune function, in particular in the context of autoimmunity. In this review, currently available data are summarized to give an overview of the effects of vitamin D on the immune system in general and on the regulation of inflammatory responses, as well as regulatory mechanisms connected to autoimmune diseases particularly in type 1 diabetes mellitus.
Four types of observations have been used to illustrate the seasonal characteristics of epidemic influenza: (1) The experience of a small population during 28 consecutive years, 1946-74, (2) world influenza outbreaks 1964-75 reported to the World Health Organization, (3) the experience of two widely separated localities at about the same latitude, 1969-74, and (4) the experience of two places at latitudes 300 + on opposite sides of the Equator, 1968-74. The following tendencies are shown. (1) Outbreaks of influenza even in the small community came at approximately the same season almost every year. (2) Outbreaks are globally ubiquitous and epidemic loci move smoothly to and fro across the surface of the earth almost every year in a sinuous curve that runs parallel with the 'midsummer' curve of vertical solar radiation, but lags about six months behind it. Such findings exclude the mediation of seasonal control by any agencies of local distribution, and suggest a direct effect of variations in some component of solar radiation on virus or human host. (3) Antigenic variations in influenza A virus tended to have the same seasonal characteristics as epidemicity. This suggests that epidemicity and virus variation are two facets of one seasonally controlled process. None of these seasonal characteristics can be explained by the current concept of influenzal epidemiology. A new hypothesis recently proposed and recapitulated in the Appendix offers a possible explanation. The primary agency mediating seasonal control remains unidentified.