Although the gut microbiota has been reported to influence osteoporosis risk, the individual species involved, and underlying mechanisms, remain largely unknown. We performed integrative analyses in a Chinese cohort of peri-/post-menopausal women with metagenomics/targeted metabolomics/whole-genome sequencing to identify novel microbiome-related biomarkers for bone health. Bacteroides vulgatus was found to be negatively associated with bone mineral density (BMD), which was validated in US white people. Serum valeric acid (VA), a microbiota derived metabolite, was positively associated with BMD and causally downregulated by B. vulgatus. Ovariectomized mice fed B. vulgatus demonstrated increased bone resorption and poorer bone micro-structure, while those fed VA demonstrated reduced bone resorption and better bone micro-structure. VA suppressed RELA protein production (pro-inflammatory), and enhanced IL10 mRNA expression (anti-inflammatory), leading to suppressed maturation of osteoclast-like cells and enhanced maturation of osteoblasts in vitro. The findings suggest that B. vulgatus and VA may represent promising targets for osteoporosis prevention/treatment.

Background: Limited and inconclusive data exist concerning the associations between lipid-lowering drugs and serum micronutrient concentrations. Methods: We conducted Mendelian randomization (MR) analyses to explore the associations between lipid-lowering drug targets and serum micronutrients. Single-nucleotide polymorphisms in genes encoding molecular targets of LDL cholesterol-lowering therapies were selected as instrumental variables for 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR; target of statins), proprotein convertase subtilisin/kexin type 9 (PCSK9; target of PCSK9 inhibitors), and Niemann-Pick C1-Like 1 (NPC1L1; target of ezetimibe). Exposure data were extracted from a published genome-wide association study (GWAS) of lipids in 188,577 European individuals, with outcome data obtained from the Integrative Epidemiology Unit (IEU) GWAS database (). Overall, age and sex information were not calculable from the summary-level GWAS data. MR analyses were performed using the inverse-variance weighted method and MR sensitivity analysis methods. Results: We found genetically proxied inhibition of HMGCR to lower iron (effect, -0.16; 95% CI: -0.27, -0.06; P value = 0.003), zinc (effect, -0.83; 95% CI: -1.36, -0.31; P value = 0.002), magnesium (effect, -0.17; 95% CI: -0.27, -0.06; P value = 0.003), potassium (effect, -0.17; 95% CI: -0.27, -0.06; P value = 0.002), genetically proxied inhibition of NPC1L1 to increase calcium (effect, 0.28; 95% CI: 0.10, 0.46; P value = 0.003), retinol (effect, 0.25; 95% CI: 0.07, 0.44; P value = 0.01), and genetically proxied inhibition of PCSK9 to increase vitamin D (effect, 0.10; 95% CI: 0.07, 0.12; P value = 1.8 x 10(-19)). These associations were robust in MR sensitivity analyses. However, the associations between genetically proxied inhibition of HMGCR and NPC1L1 and the micronutrients were not consistent in multiple comparisons. Conclusions: Our results provide evidence that statin use may lower serum concentrations of iron, zinc, magnesium, and potassium, PCSK9 inhibitors may increase serum vitamin D, and ezetimibe may increase serum calcium and retinol concentrations.

ZF2001, a protein subunit vaccine against coronavirus disease 2019 (COVID-19), contains recombinant tandem repeat of dimeric receptor-binding domain (RBD) protein of the SARS-CoV-2 spike protein with an aluminium-based adjuvant. During the development of this vaccine, two nonclinical studies were conducted to evaluate female fertility, embryo-fetal development, and postnatal developmental toxicity in Sprague‒Dawley rats according to the ICH S5 (R3) guideline. In Study 1 (embryo-fetal developmental toxicity, EFD), 144 virgin female rats were randomly assigned into four groups and received three doses of vaccine (25 μg or 50 μg RBD protein/dose, containing the aluminium-based adjuvant), the aluminium-based adjuvant or a sodium chloride injection administered intramuscularly on days 21 and 7 prior to mating and on gestation day (GD) 6. In Study 2 (pre- and postnatal developmental toxicity, PPND), ZF2001 at a dose of 25 μg RBD protein/dose or sodium chloride injection was administered intramuscularly to female rats (n = 28 per group) 7 days prior to mating and on GD 6, GD 20 and postnatal day (PND) 10. There were no obvious adverse effects in dams, except for local injection site reactions related to the aluminium-based adjuvant (yellow nodular deposits in the interstitial muscle fibres). There were also no effects of ZF2001 on the mating performance, fertility or reproductive performance of parental females, embryo-fetal development, postnatal survival, growth, physical development, reflex ontogeny, behavioural and neurofunctional development, or reproductive performance of the offspring. The strong immune responses associated with binding and neutralising antibodies were both confirmed in dams and fetuses or offspring in these two studies. These results would support clinical trials or the use of ZF2001 in maternal immunisation campaigns, including those involving women with childbearing potential, regardless of pregnancy status.

The coronavirus disease 19 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has a rapidly increasing prevalence and has caused significant morbidity/mortality. Despite the availability of many vaccines that can offer widespread immunization, it is also important to reach effective treatment for COVID-19 patients. However, the development of novel drug therapeutics is usually a time-consuming and costly process, and therefore, repositioning drugs that were previously approved for other purposes could have a major impact on the fight against COVID-19. Here, we first identified lung-specific gene regulatory/interaction subnetworks (COVID-19-related genes modules) enriched for COVID-19-associated genes obtained from GWAS and text mining. We then screened the targets of 220 approved drugs from DrugBank, obtained their drug-induced gene expression profiles in the LINCS database, and constructed lung-specific drug-related gene modules. By applying an integrated network-based approach to quantify the interactions of the COVID-19-related gene modules and drug-related gene modules, we prioritized 13 approved drugs (e.g., alitretinoin, clocortolone, terazosin, doconexent, and pergolide) that could potentially be repurposed for the treatment of COVID-19. These findings provide important and timely insights into alternative therapeutic options that should be further explored as COVID-19 continues to spread.

Background: The effects of lipid‐lowering drugs [including statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors] on hyperlipidaemia have been established. Some may have treatment effects beyond their reported properties, offering potential opportunities for drug repurposing. Epidemiological studies have reported conflicting findings on the relationship between lipid‐lowering medication use and sarcopenia risk.Methods: We performed a two‐sample Mendelian randomization (MR) study to investigate the causal association between the use of genetically proxied lipid‐lowering drugs (including statins, ezetimibe, and PCSK9 inhibitors, which use low‐density lipoprotein as a biomarker), and sarcopenia risk. The inverse‐variance weighting method was used with pleiotropy‐robust methods (MR–Egger regression and weighted median) and colocalization as sensitivity analyses.Results: According to the positive control analysis, genetically proxied inhibition in lipid‐lowering drug targets was associated with a lower risk of coronary heart disease [PCSK9 (OR, 0.67; 95% CI, 0.61 to 0.72; P = 7.7E‐21); 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGCR; OR, 0.68; 95% CI, 0.57 to 0.82; P = 4.6E‐05), and Niemann–Pick C1‐like 1 (NPC1L1; OR, 0.53; 95% CI, 0.40 to 0.69; P = 3.3E‐06)], consistent with drug mechanistic actions and previous trial evidence. Genetically proxied inhibition of PCSK9 (beta, −0.040; 95% CI, −0.068 to −0.012; P = 0.005) and circulating PCSK9 levels (beta, −0.019; 95% CI, −0.033 to −0.005; P = 0.006) were associated with reduced appendicular lean mass (ALM) with concordant estimates in terms of direction and magnitude. Validation analyses using a second instrument for PCSK9 yielded consistent results in terms of direction and magnitude [(PCSK9 to ALM; beta, −0.052; 95% CI, −0.074 to −0.032; P = 7.1E‐7); (PCSK9 protein to ALM; beta, −0.060; 95% CI, −0.106 to −0.014; P = 0.010)]. Genetically proxied inhibition of PCSK9 gene expression in the liver may be associated with reduced ALM (beta, −0.013; 95% CI, −0.035 to 0.009; P = 0.25), consistent with the results of PCSK9 drug‐target and PCSK9 protein MR analyses, but the magnitude was less precise. No robust association was found between HMGCR inhibition (beta, 0.048; 95% CI, −0.015 to 0.110; P = 0.14) or NPC1L1 (beta, 0.035; 95% CI, −0.074 to 0.144; P = 0.53) inhibition and ALM, and validation and sensitivity MR analyses showed consistent estimates.Conclusions: This MR study suggested that PCSK9 is involved in sarcopenia pathogenesis and that its inhibition is associated with reduced ALM. These findings potentially pave the way for future studies that may allow personalized selection of lipid‐lowering drugs for those at risk of sarcopenia.