Dagui Chen

Objective(s): This study aimed to investigate the protective effect and underlying mechanism of chrysophanol (CPH) on senile osteoporosis (OP) in rats. Materials and Methods: Twenty-four-month-old rats were divided into an aged OP model group and low- (10 mg/kg), medium- (20 mg/kg), and high-dose (50 mg/kg) CPH groups, with eight-month-old rats used as the control group. After 60 days of oral CPH administration, the bone mineral density (BMD), bone volume fraction (BV/TV), trabecular number (TbN), and trabecular separation (TbSp) of the femur were analysed using Micro-CT. Serum levels of bone formation markers (alkaline phosphatase, ALP; osteocalcin, OC) and bone resorption markers (type I collagen crosslinked N-telopeptide, NTX; tartrate-resistant acid phosphatase, TRACP) were determined by ELISA. Pathological changes in the femur were observed via H&E staining, and the expression of p-AKT and p-mTOR proteins in bone marrow was detected by western blotting.Results: Compared with those in the control group, the bone formation marker levels, BMD, BV/TV, and TbN in the model group significantly decreased, whereas the bone resorption marker levels, TbSp, and expression levels of p-AKT and p-mTOR significantly increased, with obvious bone structure destruction. CPH treatment reversed these changes in a dose dependent manner, significantly enhanced bone formation, inhibited bone resorption, improved bone density and microstructure, and down-regulated the expression of p-AKT and p-mTOR. Conclusion: CPH can effectively improve bone density and microstructure in aged osteoporotic rats, and its bone-protective effect may be related to the inhibition of the PI3K/AKT/mTOR signaling pathway.

Acute pneumonia (AP), triggered primarily by pathogens like bacteria and viruses, is a leading cause of human mortality. Ribavirin, a broad-spectrum antiviral agent, plays a pivotal role in the treatment of AP. However, its therapeutic use is hindered by the need for high dosages and the associated cardiac and hepatic toxicities. In this study, we synthesized polyethylene glycol-modified cationic liposomes to encapsulate ribavirin (RBV-PCL) and formulated it into a spray, aiming to enhance the effectiveness of RBV through respiratory administration. Lipopolysaccharide (LPS), a compound known to induce AP models in animals, was utilized in our research. Successfully, we established an acute pneumonia model in mice using aerosol inhalation. Through animal experiments, we investigated the therapeutic effects of RBV-PCL on mice with AP. In vivo studies revealed promising results. RBV-PCL effectively prolonged the survival of mice with AP, significantly reduced the levels of inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and inhibited the infiltration of neutrophils in the lungs and spleens of mice. These findings suggest that RBV-PCL can effectively suppress the inflammatory response in mice with AP, thus holding significant potential as a novel therapeutic approach for the treatment of acute pneumonia.

One effective treatment for postmenopausal osteoporosis is to inhibit osteoclasts and subsequent bone resorption. In our study, we demonstrated that acacetin, a flavone with potential therapeutic effects in infections, cancers, and several metabolic disorders, inhibited osteoclast differentiation and bone resorption in vitro. For improving the efficacy of acacetin in vivo, we developed an acid-sensitive bone-targeting delivery system composed of an acid-sensitive linker (N-ε-maleimidocaproic acid hydrazide, EMCH) for ensuring an effective release of acacetin at the site of action and a hydrophilic aspartic acid hexapeptide ((Asp)6, D6) as the effective bone targeting agent. Our results revealed that Acacetin-EMCH-D6 specifically bound to the bone surface once administrated in vivo, prolonged the retention time in bone and released acacetin at the osteoclastic bone resorption sites where the acidity is higher. We further demonstrated that, in ovariectomy-induced osteoporosis mice, treatment with Acacetin-EMCH-D6 inhibited osteoclast formation and increased trabecular bone mass. On the contrary, neither acacetin nor EMCH-D6 with the same dosage alone showed significant anti-osteoporosis effects in vivo. Mechanistically, targeted delivery of acacetin to the bone resorption sites by Acacetin-EMCH-D6 inhibited autophagy through activating PI3K/AKT/mTOR pathway in osteoclasts, while the activation of autophagy by rapamycin partially reversed the inhibitory effects of acacetin in vitro and in vivo. In summary, our study, for the first time, showed that the acid-sensitive bone-targeting delivery system carrying acacetin was effective for the treatment of postmenopausal osteoporosis. Thus, targeted delivery of acacetin using Acacetin-EMCH-D6 to bone resorption sites is a promising therapy for osteoporosis.

The purpose of this study is to fabricate different anti-cancer drug-eluted chitosan microspheres for combination therapy of osteosarcoma. In this study, electrospray in combination with ground liquid nitrogen was utilized to manufacture the microspheres. The size of obtained chitosan microspheres was uniform, and the average diameter was 532 μm. The model drug release rate and biodegradation rate of chitosan microspheres could be controlled by the glutaraldehyde vapor crosslinking time. Then the 5-fluorouracil (5-FU), paclitaxel (PTX), and Cis-dichlorodiammine-platinum (CDDP) eluted chitosan microspheres were prepared, and two osteosarcoma cell lines, namely, HOS and MG-63, were selected as cell models for in vitro demonstration. We found the 5-FU microspheres, PTX microspheres, and CDDP microspheres could significantly inhibit the growth and migration of both HOS and MG-63 cells. The apoptosis of both cells treated with 5-FU microspheres, PTX microspheres, and CDDP microspheres was significantly increased compared to the counterparts of control and blank groups. The anti-cancer drug-eluted chitosan microspheres show great potential for the treatment of osteosarcoma.

Accumulating evidence has suggested the significant potential of chemically modified hydrogels in bone regeneration. Despite the progress of bioactive hydrogels with different materials, structures and loading cargoes, the desires from clinical applications have not been fully validated. Multiple biological behaviors are orchestrated precisely during the bone regeneration process, including bone marrow mesenchymal stem cells (BMSCs) recruitment, osteogenic differentiation, matrix calcification and well-organized remodeling. Since matrix metalloproteinases play critical roles in such bone metabolism processes as BMSC commitment, osteoblast survival, osteoclast activation matrix calcification and microstructure remodeling, matrix metalloproteinase (MMP) cleavable peptides-based hydrogels could respond to various MMP levels and, thus, accelerate bone regeneration. In this review, we focused on the MMP-cleavable peptides, polymers, functional modification and crosslinked reactions. Applications, perspectives and limitations of MMP-cleavable peptides-based hydrogels for bone regeneration were then discussed.

Coronavirus Disease 2019 (COVID-19) infected by Severe Acute Respiratory Syndrome Coronavirus −2 (SARS-CoV-2) has been declared a public health emergency of international concerns. Cytokine storm syndrome (CSS) is a critical clinical symptom of severe COVID-19 patients, and the macrophage is recognized as the direct host cell of SARS-CoV-2 and potential drivers of CSS. In the present study, peramivir was identified to reduce TNF-α by partly intervention of NF-κB activity in LPS-induced macrophage model. In vivo, peramivir reduced the multi-cytokines in serum and bronchoalveolar lavage fluid (BALF), alleviated the acute lung injury and prolonged the survival time in mice. In human peripheral blood mononuclear cells (hPBMCs), peramivir could also inhibit the release of TNF-α. Collectively, we proposed that peramivir might be a candidate for the treatment of COVID-19 and other infections related CSS. Graphic