Antitumor Effect of Platinum-Modified STING Agonist MSA-2.

The stimulator of interferon genes (STING)-activated innate immune pathway is strong and durable for tumor immunotherapy. MSA-2 is an available non-nucleotide human STING agonist that promotes the tumor immunotherapy of STING activation. However, strategies for remolding and improving the immunotherapy effects of MSA-2 are of value for clinical applications. Here, we synthesized the platinum salt-modified MSA-2 (MSA-2-Pt) due to platinum salt being a classic chemotherapeutic drug. We found that MSA-2-Pt could achieve double-effect antitumor immunotherapy, including inducing cell death by platinum and activating the STING pathway by MSA-2. In the colon carcinoma MC38 model (sensitive to immune checkpoint immunotherapy tumor) and melanoma B16F10 model (poorly immunogenic and highly aggressive tumor), the MSA-2-Pt had a good antitumor effect, which was a little better than MSA-2 with intratumor injections. The results present a promising strategy for STING activation in tumor immunotherapy and broadening platinum-based drugs.

The unique interplay of mitochondrial oxidative phosphorylation (OXPHOS) and immunity and its potential implication for the sex- and age-related morbidity of severe COVID-19 patients.

Aged male patients are more vulnerable to severe or critical symptoms of COVID-19, but the underlying mechanism remains elusive. In this study, we analyzed previously published scRNA-seq data from a large cohort of COVID-19 patients, castrated and regenerated mice, and bulk RNA-seq of a RNAi library of 400 genes, and revealed that both immunity and OXPHOS displayed cell-type-, sex-, and age-related variation in the severe or critical COVID-19 patients during disease progression, with a more prominent increase in immunity and decrease in OXPHOS in myeloid cells in the males relative to the females (60-69 years old). Male severe or critical patients above 70 years old were an exception in that the compromised negative correlation between OXPHOS and immunity in these patients was associated with its disordered transcriptional regulation. Finally, the expression levels of OXPHOS and androgens were revealed to be positively correlated, and the responses of macrophages to android fluctuation were more striking than other types of detected immune cells in the castrated mice model. Therefore, the interplay of OXPHOS and immunity displayed a cell-type-specific, age-related, and sex-biased pattern, and the underlying potential regulatory role of the hormonal milieu should not be neglected.

Catalysis-Mediated Male Contraception through Black Phosphorus Nanosheets.

Nanocontraception has been proposed and received extensive attention in recent years for population control. However, currently developed methods for nanocontraception still face problems in efficacy and safety. Here, we propose catalysis-mediated oxidation as a new strategy for nanocontraception. With the catalytic production of highly oxidative species, male contraception was successfully achieved after the administration of black phosphorus nanosheets into the testes of male mice. Further mechanistic studies revealed that contraception was induced by oxidative stress and apoptosis of spermatogenesis cells. Meanwhile, the apoptosis of germ cells released testis antigen and induced immune cell infiltration, which enhanced reproductive damage. Notably, the introduced black phosphorus nanosheets naturally degraded during the catalytic oxidation process and ultimately converted to harmless phosphates, indicating the safety of the strategy. Furthermore, the catalysis-mediated strategy avoids utilizing additional inducers, such as near-infrared irradiation, magnetic fields, or ultrasound, which may cause severe pain. In summary, the proposed catalysis-mediated contraception can be a self-cleared, convenient, and safe strategy for controlling male fertility.

Effects of Radon From Hot Springs on Lymphocyte Subsets in Peripheral Blood.

OBJECTIVE: To analyze changes in immune functions by detecting lymphocyte subsets in the peripheral blood of residents in the vicinity of radon from hot springs. METHODS: Two groups were randomly selected; 61 residents in the vicinity of the hot springs were assigned to the radon group, and 51 residents with a similar lifestyle and habits but no contact with hot springs were assigned to the control group. The percentages of lymphocyte subsets (CD3+, CD4+CD8-, CD4-CD8+, CD4+/CD8+, and TCR/CD3) in the 2 groups were evaluated on a FACS Aria flow cytometer. The absolute values of lymphocytes (LYMPH#) and percentages of lymphocytes (LYMPH%) were measured by an automatic blood analyzer. RESULTS: In the radon group, the numbers of CD3+ (Z = -0.140, P > .05) and CD4+CD8- (Z = -0.964, P > .05) T cells were higher, as compared with the controls, but this difference was not significant. In addition, the number of CD4-CD8+ (t = -2.141, P < .05) T cells was significantly lower in the radon group. Furthermore, the average ratios of CD4+/CD8+ (t = -2.201, P < .05) and TCR/CD3 (t = 2.047, P < .05) cells were significantly higher in the radon group than in the controls. Compared with the control group, the LYMPH# (t = -0.485, P > .05) and LYMPH% (Z = -0.835, P > .05) showed no significant change. CONCLUSION: Radon-rich hot springs could alter the proportions of lymphocyte subsets and possibly affect immunologic functions.

The protective effects of 1,2-propanediol against radiation-induced hematopoietic injury in mice.

Agents that provide protection against irradiation-induced hematopoietic injury are urgently needed for radiotherapy. We examined the effects of the small molecule, 1,2-propanediol (PPD), on total body irradiation (TBI)-induced hematopoietic injury in C57BL/6 mice. PPD administration 1 h before TBI significantly increased hematopoietic parameters such as white blood cell, platelet, red blood cell, and lymphocyte counts in vivo and enhanced the survival of mice exposed to TBI (7.0 and 7.5 Gy). PPD administration 1 h before TBI improved bone marrow (BM) and spleen recovery after TBI, with increases in both BM cellularity and spleen index. The number of colony-forming-units in bone marrow mononuclear cells (BMNCs) in vitro also increased significantly. PPD pretreatment increased the numbers of hematopoietic stem cells and hematopoietic progenitor cells in BM. Importantly, PPD also maintained endogenous antioxidant status by decreasing levels of malondialdehyde and increasing the expression of reduced glutathione, superoxide dismutase and catalase in the serum of irradiated mice. PPD alleviated the levels of apoptosis in HSCs induced by TBI, thus increasing the proportion of dividing BMNCs. These results suggest that PPD protects against TBI-induced hematopoietic injury through the increased activities of antioxidant enzymes and the inhibition of apoptosis in HSCs. PPD increased the serum levels of granulocyte-colony stimulating factor and interleukin-6 irrespective of TBI. In conclusion, these data suggest that PPD acts as a radioprotector against radiation-induced hematopoietic injury.

17α-Ethinyl-androst-5-ene-3ß, 17ß-diol, a Novel Potent Oral Radioprotective Agent, Confers Radioprotection of Hematopoietic Stem and Progenitor Cells in a Granulocyte Colony-Stimulating Factor-Independent Manner.

PURPOSE: The risk of radiation exposure is considered to have increased in recent years. For convenience and simple administration, development of an effective orally administered radioprotective agent is highly desirable. The steroid 5-androstene-3ß, 17ß-diol (5-AED) has been evaluated as both a radioprotector and a radiomitigator in mice and nonhuman primates; however, poor oral bioavailability has limited its development. A variant compound-17α-ethinyl-androst-5-ene-3ß, 17ß-diol (EAD)-exhibits significant oral bioavailability. We investigated the radioprotective effects of EAD via oral administration in mice. METHODS AND MATERIALS: Survival assays were performed in lethally (9.0-10.0 Gy) irradiated mice. Peripheral blood cell counts were monitored in lethally (9.5 Gy) or sublethally (6.5 Gy) irradiated mice. We performed histologic analysis of bone marrow (BM) and frequency and functional analysis of hematopoietic stem and progenitor cells in mice irradiated with 6.5 Gy. To investigate multilineage engraftment of irradiated hematopoietic stem cells after BM transplantation, competitive repopulation assays were conducted. Plasma granulocyte colony-stimulating factor was measured by enzyme-linked immunosorbent assay. RESULTS: Oral administration of EAD on 3 consecutive days before irradiation conferred 100% survival in mice, against otherwise 100% death, at a 9.5-Gy lethal dose of total body irradiation. EAD ameliorated radiation-induced pancytopenia at the same dose. EAD augmented BM cellular recovery and colony-forming ability, promoted hematopoietic stem and progenitor cell recovery, and expanded the pool of functionally superior hematopoietic stem cells in the BM of sublethally irradiated mice. Unlike 5-AED, EAD did not increase granulocyte colony-stimulating factor levels in mice and exhibited no therapeutic effects on hematologic recovery after irradiation; nevertheless, its radioprotective efficacy was superior to that of 5-AED. CONCLUSIONS: Our findings demonstrate the radioprotective efficacy of EAD and reveal that the 17α-ethinyl group is essential for its oral activity. Given its oral efficacy and low toxicity, EAD has potential as an optimal radioprotector for use by first responders, as well as at-risk civilian populations.

Succinate ester derivative of δ-tocopherol enhances the protective effects against 60Co γ-ray-induced hematopoietic injury through granulocyte colony-stimulating factor induction in mice.

α-tocopherol succinate (α-TOS), γ-tocotrienol (GT3) and δ-tocotrienol (DT3) have drawn large attention due to their efficacy as radioprotective agents. α-TOS has been shown to act superior to α-tocopherol (α-TOH) in mice by reducing lethality following total body irradiation (TBI). Because α-TOS has been shown to act superior to α-tocopherol (α-TOH) in mice by reducing lethality following total body irradiation (TBI), we hypothesized succinate may be contribute to the radioprotection of α-TOS. To study the contributions of succinate and to identify stronger radioprotective agents, we synthesized α-, γ- and δ-TOS. Then, we evaluated their radioprotective effects and researched further mechanism of δ-TOS on hematological recovery post-irradiation. Our results demonstrated that the chemical group of succinate enhanced the effects of α-, γ- and δ-TOS upon radioprotection and granulocyte colony-stimulating factor (G-CSF) induction, and found δ-TOS a higher radioprotective efficacy at a lower dosage. We further found that treatment with δ-TOS ameliorated radiation-induced pancytopenia, augmenting cellular recovery in bone marrow and the colony forming ability of bone marrow cells in sublethal irradiated mice, thus promoting hematopoietic stem and progenitor cell recovery following irradiation exposure. δ-TOS appears to be an attractive radiation countermeasure without known toxicity, but further exploratory efficacy studies are still required.