Blockage of L2HGDH-mediated S-2HG catabolism orchestrates macrophage polarization to elicit antitumor immunity.

The high infiltration of tumor-associated macrophages (TAMs) in the immunosuppressive tumor microenvironment prominently attenuates the efficacy of immune checkpoint blockade (ICB) therapies, yet the underlying mechanisms are not fully understood. Here, we investigate the metabolic profile of TAMs and identify S-2-hydroxyglutarate (S-2HG) as a potential immunometabolite that shapes macrophages into an antitumoral phenotype. Blockage of L-2-hydroxyglutarate dehydrogenase (L2HGDH)-mediated S-2HG catabolism in macrophages promotes tumor regression. Mechanistically, based on its structural similarity to α-ketoglutarate (α-KG), S-2HG has the potential to block the enzymatic activity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs), consequently reshaping chromatin accessibility. Moreover, S-2HG-treated macrophages enhance CD8+ T cell-mediated antitumor activity and sensitivity to anti-PD-1 therapy. Overall, our study uncovers the role of blockage of L2HGDH-mediated S-2HG catabolism in orchestrating macrophage antitumoral polarization and, further, provides the potential of repolarizing macrophages by S-2HG to overcome resistance to anti-PD-1 therapy.

The protective mechanism of Tao Hong Si Wu decoction against breast cancer through regulation of EGFR/ERK1/2 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Tao Hong Si Wu Decoction (THSWD), a traditional Chinese herbal medicine, is widely utilized in clinical settings, either alone or in combination with other medications, for the treatment of breast cancer. AIM OF THE STUDY: The specific targeting molecule(s) of THSWD and its associated molecular mechanisms remain unclear. This research aims to elucidate the underlying molecular mechanisms of THSWD in the treatment of breast cancer. MATERIALS AND METHODS: The pharmacological properties of THSWD were investigated in breast cancer cells and tumor tissues using a range of methods including Acridine Orange/Ethidium Bromide (AO/EB) staining, Transwell assay, flow cytometry, immunofluorescence assay, and breast cancer mice models. RESULTS: Our findings demonstrate that THSWD induces necrosis and/or apoptosis in breast cancer cells, while significantly inhibiting cell migration. Target proteins of THSWD in anticancer activity include EGFR, RAS, and others. THSWD treatment for breast cancer is associated with the EGFR/ERK1/2 signaling pathway. CONCLUSION: Our findings offer initial insights into the primary mechanism of action of THSWD in breast cancer treatment, indicating its potential as a complementary therapy deserving further investigation.

[Finite element analysis of total hip replacement].

Total hip replacement is a very effective method to cure many kinds of hip joint illnesses. About a century ago, it was first used in clinic. Since then, total hip replacement has been well developed. Hip joints sustain the most load of body, so people pay great attention to the hip prothesis' mechanics property. Especially after the finite element analysis was widely used in biomechanics investigation, the stress distribution of different designs can be easily compared with each other, and the relatively better parameters of the design could be decided. The stress distribution of different materials with the same design also can be valued. However, studies have indicated that total hip joint replacement still has some disadvantages. Loosening of the hip prothesis is still the most likely cause of the failure of surgery, and generally this is believed to stem from either mechanical failure of the fixation in response to over high density stresses, or osteolysis of the surrounding bone stock responsing to particular wear debris. Many researchers on computational studies have considered the potential for the former one, but only a few have attempted to tackle the latter. The process of osteolysis of the bone is not yet completely known. Nowadays, in order to solve the problems of loosening, investigators are trying to find different methods. Some of them are working on improving the geometry parameters and the shape of the hip prothesises, some are trying to find new suitable biomaterials, and, at the same time, the fixation methods are under deliberation.