Vascularization is fundamental for bone formation and bone tissue homeostasis. However, in human subjects, a direct molecular relationship has not been identified between angiogenesis and agents that promote bone disease or factors related to age. Osteopenia is a condition in which bone mineral density is lower than normal, and it represents a sign of normal aging. Here we tested whether the type H vessel, which was recently identified as strongly positive for CD31 and Endomucin (CD31hiEmcnhi) in mice, is an important indicator of aging and osteopenia in human subjects. We found that age-dependent losses of type H vessels in human bone sections conform to the observations in aged mice. The abundance of human type H vessels and osteoprogenitors may be relevant to changes in the skeletal microarchitecture and advanced osteopenia. Furthermore, ovariectomized mice, a widely used model for postmenopausal osteoporosis, exhibited significantly reduced type H vessels accompanied by reduced osteoprogenitors, which is consistent with impaired bone microarchitecture and osteoporosis, suggesting that this feature is an indicator of bone mass independent of aging. More importantly, administration of desferrioxamine led to significantly increased bone mass via enhanced angiogenesis and increased type H vessels in ovariectomized mice. Altogether, these data represent a novel finding that type H vessels are regulated in aged and osteopenia subjects. The abundance of human type H vessels is an early marker of bone loss and represents a potential target for improving bone quality via the induction of type H vessels.

Host cellular receptors play key roles in the determination of virus tropism and pathogenesis. However, little is known about SARS-CoV-2 host receptors with the exception of ACE2. Furthermore, ACE2 alone cannot explain the multi-organ tropism of SARS-CoV-2 nor the clinical differences between SARS-CoV-2 and SARS-CoV, suggesting the involvement of other receptor(s). Here, we performed genomic receptor profiling to screen 5054 human membrane proteins individually for interaction with the SARS-CoV-2 capsid spike (S) protein. Twelve proteins, including ACE2, ASGR1, and KREMEN1, were identified with diverse S-binding affinities and patterns. ASGR1 or KREMEN1 is sufficient for the entry of SARS-CoV-2 but not SARS-CoV in vitro and in vivo. SARS-CoV-2 utilizes distinct ACE2/ASGR1/KREMEN1 (ASK) receptor combinations to enter different cell types, and the expression of ASK together displays a markedly stronger correlation with virus susceptibility than that of any individual receptor at both the cell and tissue levels. The cocktail of ASK-related neutralizing antibodies provides the most substantial blockage of SARS-CoV-2 infection in human lung organoids when compared to individual antibodies. Our study revealed an interacting host receptome of SARS-CoV-2, and identified ASGR1 and KREMEN1 as alternative functional receptors that play essential roles in ACE2-independent virus entry, providing insight into SARS-CoV-2 tropism and pathogenesis, as well as a community resource and potential therapeutic strategies for further COVID-19 investigations.

bThe interferon (IFN)-inducible viperin protein restricts a broad range of viruses. However, whether viperin plays a role during herpes simplex virus 1 (HSV-1) infection is poorly understood. In the present study, it was shown for the first time that wild-type (WT) HSV-1 infection couldn't induce viperin production, and ectopically expressed viperin inhibited the replication of UL41-null HSV-1 but not WT viruses. The underlying molecular mechanism is that UL41 counteracts viperin's antiviral activity by reducing its mRNA accumulation. Viperin is a highly conserved, 361-amino-acid protein. It was first identified as a gamma interferon (IFN-␥)-inducible protein which is directly induced by human cytomegalovirus (HCMV), and its constitutive expression is low (1). The viperin gene (also known as cig5 or RASD2) can also be categorized as an antiviral interferon-stimulated gene (ISG) which limits the replication of many DNA and RNA viruses (1-14). However, whether viperin plays a role during herpes simplex virus 1 (HSV-1) infection is unknown.To investigate whether HSV-1 could induce the expression of viperin, HEK293T cells were infected with wild-type (WT) HSV-1 at different multiplicities of infection (MOI) or with Sendai virus (SeV) (15). Infection with SeV induced a significant amount of viperin; however, infection with a low MOI (0.2) of HSV-1 induced only a trace amount of viperin, and infection with a moderate MOI (2) abrogated the expression of viperin (Fig. 1A).To further explore whether viperin could inhibit the replication of WT HSV-1, HEK293T cells with ectopic expression of viperin-Flag were infected with HSV-1 at an MOI of 0.2. Then cells were harvested at the time points indicated in the figures, and viral plaque assay was performed to determine viral replication (16). As a result, ectopically expressed viperin did not affect the replication of WT HSV-1 (Fig. 1B). The data from Western blot (WB) analysis also showed that viperin did not affect viral protein expression (Fig. 1C). These results demonstrated that ectopic expression of viperin failed to inhibit the replication of WT HSV-1.The aforementioned data led us to hypothesize that at least one of the HSV-1 proteins could counteract the expression of viperin. As a member of the ISGs, viperin was effectively induced by SeV ( Fig. 1) (15). With a high-throughput screen assay of all 84 proteins carried by HSV-1, dual-luciferase reporter gene assays were performed in HEK293T cells cotransfected with viperin-luciferase reporter plasmid and individual HSV-1 protein expression plasmid for 20 h and infected with SeV (17). As a result, ectopically expressed UL41 abrogated the expression of viperin; however, other HSV-1 proteins did not (data not shown). UL41 has been reported to degrade both viral and cellular mRNAs (18)(19)(20)(21)(22)(23)(24)(25)(26). Recently, mRNA of tetherin has been reported to be degraded by UL41 (27). Meanwhile, ICP0, an E3 ubiquitin ligase, promotes degradation of many cellular antiviral proteins, such as IRF3, IRF7, IFI16, and ATRX ...

Host cellular receptors are key determinants of virus tropism and pathogenesis. Virus utilizes multiple receptors for attachment, entry, or specific host responses. However, other than ACE2, little is known about SARS-CoV-2 receptors. Furthermore, ACE2 cannot easily interpret the multi-organ tropisms of SARS-CoV-2 nor the clinical differences between SARS-CoV-2 and SARS-CoV. To identify host cell receptors involved in SARS-CoV-2 interactions, we performed genomic receptor profiling to screen almost all human membrane proteins, with SARS-CoV-2 capsid spike (S) protein as the target. Twelve receptors were identified, including ACE2. Most receptors bind at least two domains on S protein, the receptor-binding-domain (RBD) and the N-terminal-domain (NTD), suggesting both are critical for virus-host interaction. Ectopic expression of ASGR1 or KREMEN1 is sufficient to enable entry of SARS-CoV-2, but not SARS-CoV and MERS-CoV. Analyzing single-cell transcriptome profiles from COVID-19 patients revealed that virus susceptibility in airway epithelial ciliated and secretory cells and immune macrophages highly correlates with expression of ACE2, KREMEN1 and ASGR1 respectively, and ACE2/ASGR1/KREMEN1 (ASK) together displayed a much better correlation than any individual receptor. Based on modeling of systemic SARS-CoV-2 host interactions through S receptors, we revealed ASK correlation with SARS-CoV-2 multi-organ tropism and provided potential explanations for various COVID-19 symptoms. Our study identified a panel of SARS-CoV-2 receptors with diverse binding properties, biological functions, and clinical correlations or implications, including ASGR1 and KREMEN1 as the alternative entry receptors, providing insights into critical interactions of SARS-CoV-2 with host, as well as a useful resource and potential drug targets for COVID-19 investigation.

ET improves cardiorespiratory fitness among obese adolescents; however, owing to lack of compliance, the influence of exercise intensity on insulin sensitivity and hepatic triglycerides remains unclear.

B7-H3 belongs to the B7 superfamily, a group of molecules that costimulate or downmodulate T cell responses. Although it has been shown that B7-H3 can inhibit T cell responses, several studies, most of them performed in murine systems, found B7-H3 to act in a co-stimulatory manner. In addition, B7-H3 is also expressed in various human cancers and is correlated with the poor outcome of cancer patients. The functional role of B7-H3 in cancer is still controversially discussed. In the present study, we compared B7-H3 expression in normal gastric tissues and gastric cancer tissue specimens and determined the effects of low B7-H3 expression on the human gastric cancer cell line SGC-7901 by using RNAi. B7-H3 expression in gastric specimens was determined by tissue qPCR and immunohistochemisty. A SGC-7901 cell line with low B7-H3 expression was established by lentiviral-mediated RNA interference to investigate the effect of B7-H3 on cancer cell migration and invasion in vitro. By establishing an orthotopic transplantation gastric cancer mouse model, the effect of B7-H3 on cell migration and invasion was studied in vivo. B7-H3 expression was significantly higher in the gastric cancer group than that in the normal gaster group. B7-H3 knockdown by RNA interference decreased cell migration and Transwell invasion up to 50% in vitro. In the orthotopic transplantation gastric cancer mouse model, the effect of inhibiting metastasis by knockdown of B7-H3 was assessed in terms of the average postmortem abdominal visceral metastatic tumor weight. The results revealed that inhibition of B7-H3 expression reduced gastric cancer metastasis in vivo. In conclusion, B7-H3 is aberrantly expressed in gastric cancer. In addition to modulating tumor immunity, B7-H3 may have a novel role in regulating SGC-7901 cell metastasis.

Quercetin (Q), a flavonoid compound, which is obtained in variety of fruits, seeds, and vegetables, has been reported to possess many pharmacological properties including cancer-preventive and anticancer effects. However, studies on the anticancer effects and underlying mechanisms of Q in human hepatocellular carcinoma (HCC) are still limited. The present study is conducted to investigate the anticancer efficacy and adjuvant chemotherapy action of Q in HCC. HCC cell lines HepG2 and SMCC-7721 were treated with different concentrations of Q. The antiproliferative effects of Q were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and the apoptosis and cell cycle dynamics were assessed by flow cytometry; the expression of apoptosis-associated proteins were evaluated by Western blot and immunohistochemistry staining; the tumor growth in vivo was evaluated in a xenograft mouse model. Our results showed that Q effectively inhibited human HCC cell proliferation and induced apoptosis by upregulating the expression of Bad and Bax and downregulating the expression of Bcl-2 and Survivin in vitro. Furthermore, Q obviously inhibited the tumor growth and enhanced the 5-fluorouracil (5-FU) therapeutic efficacy in vitro and in vivo. Taken together, our findings highlight that Q effectively inhibited the growth of tumor and enhanced the sensitivity to thermotherapy, indicating Q is a potential treatment option for HCC.

Osteoporosis (OP) is a disease associated with bone loss and microstructure degradation. Recent studies have shown that iron accumulation may be a risk factor for OP. Bone marrow mesenchymal stem cells (MSCs) are multipotent cells and precursors to osteoblasts. MSCs play an important role in OP. Therefore, we evaluated the correlation between MSCs and OP in an environment of iron accumulation. Serum P1NP was decreased in iron accumulation mice. Micro-CT revealed that iron accumulation decreased bone mineral density and spatial structural parameters. Iron accumulation inhibited MSC quantity in bone marrow. However, the iron chelator deferoxamine (DFO) rescued the suppression. Iron accumulation also changed the MSC cell cycle. Iron elevated MSC cell ROS level and NOX4 protein expression. MSC apoptosis was increased, and more caspase3 was cleaved after iron intervention. Our data suggests that iron accumulation inhibits MSC quantity and induces MSC apoptosis. Bone loss from iron accumulation may correlate with the inhibition of MSCs.