There is a high incidence of fractures in clinical practice and therapy. The repairment of critical size defects in the skeletal system remains a huge challenge for surgeons and researchers, which can be overcame by the application of bone tissue-engineered biomaterials. An increasing number of investigations have revealed that the immune system plays a vital role in the repair of bone defects, especially macrophages, which can modulate the integration of biomaterials and bone regeneration in multiple ways. Therefore, it has become increasingly important in regenerative medicine to regulate macrophage polarization to prevent inflammation caused by biomaterial implantation. Recent studies have stressed the importance of hydrogel-based modifications and the incorporation of various cellular and molecular signals for regulating immune responses to promote bone tissue regeneration and integrate biomaterials. In this review, we first elaborate briefly on the described the general physiological mechanism and process of bone tissue regeneration. Then, we summarized the immunomodulatory role macrophages play in bone repair. In addition, the role of hydrogel-based immune modification targeting macrophage modulation in accelerating and enhancing bone tissue regeneration was also discussed. Finally, we highlighted future directions and research strategies related to hydrogel optimization for the regulation of the immune response during bone regeneration and healing.

The development of Immune checkpoint blockade(ICB) therapy and BRAF- and MEK-targeted therapies has reshaped the survival outcomes of the patients with advanced melanoma. PD-1/PD-L1 blockade was an approved strategy in melanoma treatment. Here we design a PD-L1 xCD3 nanobody as a novel bispecific T cell engager (BiTE) in treating PD-L1 overexpression melanoma. BiTE PD-L1×CD3 Nb was predicted to bind near a large acidic surface on CD3-ε similar to UCHT1-scFv antibody based on alpha-fold and molecular docking. BiTE PD-L1×CD3 Nb and anti-CD3 Nb retained the ability to activate T cells to produce TNF-α and IFN-γ in a dose-dependent manner. The IC50 value of BiTE PD-L1×CD3 Nb was 4.208μg/mL. BiTE PD-L1×CD3 Nb showed obvious cytotoxic activity on both A375WT and A375PD-L1 related to PD-L1 expression level.

Psoriatic arthritis (PsA) is a disease that transformed from psoriasis (PsO), and its underlying mechanisms are still not fully understood. Overactivation of the immune system is a key factor driving inflammatory diseases. Our goal is to define the unbalanced subsets of peripheral blood CD4+T cells between PsO and PsA patients. Blood samples from 43 patients (23 PsA and 20 PsO) and 36 healthy donors (HD) were studied. Peripheral blood mononuclear cells (PBMC) were separated from blood and underwent fluorescent staining to assess CD4+T cell subsets by flow cytometry. We found that frequencies of various CD4+T cells including Th1, Th2, Th17, and Tfh were higher in the patients with PsO or PsA than those of healthy donors, indicating the general expansion of CD4+T cells in inflammatory conditions. More importantly, we observed the significant imbalance of Th1/Th2 between patients with PsO and PsA. Pearson correlation analysis showed that Th1/Th2 ratio was positively correlated with disease activity in psoriatic arthritis (DAPSA), Tfh/Tfr ratio was positively correlated with DAPSA score and visual analogue scale (VAS) score in PsA patients. Together, our results highlight the CD4+T cell changes in the transition from PsO to PsA, may contribute to early assessment and intervention.

Plasmodium vivax's biological complexity has restricted in vitro culture development for characterising antigens involved in erythrocyte invasion and their immunological relevance. The murine model is proposed as a suitable alternative in the search for therapeutic candidates since Plasmodium yoelii uses homologous proteins for its invasion. The AMA-1 protein is essential for parasite invasion of erythrocytes as it is considered an important target for infection control. This study has focused on functional PyAMA-1 peptides involved in host-pathogen interaction; the protein is located in regions under negative selection as determined by bioinformatics analysis. It was found that pyama1 has two highly conserved regions amongst species (>70%) under negative selection. Fourteen synthetic peptides spanning both conserved regions were evaluated; 5 PyAMA-1 peptides having high specific binding (HABP) to murine erythrocytes were identified. The parasite's invasion inhibition capability was analysed through in vitro assays, suggesting that peptides 42681 (43-ENTERSIKLINPWDKYMEKY-62), 42903 (206-RYSSNDANNENQPFSFTPEK-225) and 42904 (221-FTPEKIENYKDLSYLTKNLR-240) had greater than 50% inhibition profile and restricted P. yoelii intra-erythrocyte development. This work proposes that the screening of conserved HABPs under negative selective pressure might be good candidates for developing a synthetic anti-malarial vaccine since they share functionally-relevant characteristics, such as interspecies conservation, specific RBC binding profile, invasion and parasite development inhibition capability, and the predicted B-epitopes within were recognised by sera obtained from experimentally-infected mice.

Acetaminophen (APAP) is a common antipyretic and analgesic drug that can cause long-term liver damage after an overdose. Non-alcoholic fatty liver disease (NAFLD) increases susceptibility to APAP. In NAFLD, excessive accumulation of lipids leads to an abnormal increase in hypoxia-inducible factor-1α (HIF-1α). Caveolin-1 (CAV1) may protect against NAFLD by inhibiting HIF-1α. This research aimed to determine whether CAV1 could attenuate APAP-exacerbated liver injury in NAFLD by inhibiting oxidative stress involving HIF-1α. In this study, 7-week-old C57BL/6 mice were fed a high-fat diet (HFD) for eight weeks, followed by the instillation of APAP. Levels of oxidative stress and liver lipid deposition were determined, and p-ERK1/2 and HIF-1α protein expression were measured by the Western blot (WB) method. In the APAP-treated group, the level of CAV1 was decreased, while the levels of HIF-1α and reactive oxygen species (ROS) were significantly increased. AML12 cells were treated with a mixture of palmitic acid (PA) and oleic acid (OA) (1:2 mix) for 48h, and APAP was added for the last 24h. Overexpression of CAV1 in AML12 cells significantly inhibited the expression of ROS and HIF-1α. And the results of immunofluorescence after treatment with CAV1-SiRNA showed that the HIF-1α levels were significantly increased in mitochondria. In conclusion, our experimental results suggest that CAV1 has a protective function in the fatty liver based on preventing oxidative stress, which involves HIF-1α. Thus, upregulation of CAV1 may attenuate APAP-exacerbated liver injury in NAFLD.

Immune checkpoint inhibitor therapy has drastically improved outcomes in treating cancer, particularly in melanoma. However, half of melanoma patients are resistant to treatment. One mechanism used by tumor cells to evade immune attack is to down-regulate major histocompatibility complex (MHC) class I molecules, which are required for cytotoxic CD8 T-cells to eliminate cancer cells. To increase immunotherapeutic efficacy, it is critical to identify how to restore MHC-I expression on cancer cells so that tumor antigens are presented. We found that resveratrol elevated MHC-I expression, so that tumor antigens are presented to cytotoxic CD8 T-cell killing. Through proteomic interrogation, we identified the STING pathway as a potential mechanism of action. Further studies indicated that resveratrol-mediated regulation of STING induced MHC-I expression potentially through both interferon-independent and dependent pathways. Our results have indicated the potential of STING to induce MHC-I expression independent of interferon signaling, broadening the potential of STING modulation as a tool to improve immune checkpoint blockade.

Acute lung injury (ALI) is an acute inflammatory respiratory disease. The interaction between growth arrest-specific 6 (Gas6) and tyrosine kinases of the Tyro3, Axl, Mer (TAM) family plays an important role in a variety of physiological and pathological processes, including inflammation. In this study, we mainly clarified the mechanism of the Gas6/TAM signal pathway in lipopolysaccharide (LPS)-induced pulmonary epithelial cells (BEAS-2B cells) injury. We cultured BEAS-2B cells in vitro and established a LPS-induced BEAS-2B cells injury model. Then, the siRNA sequence (siGas6-2) was transfected into cells. The expression of Gas6/TAM was measured based on quantitative reverse transcription polymerase chain reaction (qRT-RCR) and western blot (WB). Cell proliferation and apoptosis were measured by cell counting Kit-8 (CCK-8) and flow cytometry. The expression of pro-inflammatory factors was measured by qRT-RCR and WB. Our study showed that when the 40μg/mL LPS-induced BEAS-2B cells injury model was established, cell viability was significantly reduced, but the Gas6/TAM signal pathway was activated. When transfection with siGas6-2, low expression of Gas6 directly reduced the expression of downstream TAM receptors. Furthermore, the inhibition of the Gas6/TAM signal pathway significantly reduced the occurrence of cell apoptosis and the expression of inflammatory factors, and promoted cell proliferation. Our research indicated that Gas6/TAM played an important role in cell proliferation, apoptosis, and inflammatory response in the LPS-induced BEAS-2B cells injury, and Gas6/TAM may be a new target in the treatment of ALI in the future.

Glucocorticoids have been widely used in the treatment of ulcerative colitis, but not all patients benefit from this therapy due to hormone resistance. Mir-150-5p has been reported to enhance the efficacy of glucocorticoids, and low serum mir-150-5p expression has been linked to glucocorticoid resistance in ulcerative colitis patients. The aim of this study was to elucidate the mechanisms of mir-150-5p regulation on glucocorticoid resistance. An ulcerative colitis mouse model was used to evaluate changes in ulcerative colitis symptoms, inflammatory factors, and glucocorticoid resistance-related gene expression. The results showed that mir-150-5p suppression with antagomirs did not significantly interfere with or enhance the induction of ulcerative colitis symptoms by dextran sulfate sodium, but it did attenuate the inflammation inhibitory effect of dexamethasone by abnormally regulating the expression of IL-17a, IL-10, IL-2 and IL-6 levels and myeloperoxidase activity. Mir-150-5p inhibition also induced a glucocorticoid-resistant gene expression profile in colon tissues of ulcerative colitis mice, with upregulation of p-ERK, p-JNK, and HSP90 and downregulation of p-GRa, FKBP4, and HDAC2 expression. Our results indicate that mir-150-5p suppression attenuates the anti-inflammatory effect of glucocorticoids and may function as a driver element in ulcerative colitis glucocorticoid resistance. AVAILABILITY OF DATA AND MATERIALS: All data and figures analyzed in this study are available from the corresponding author by request.