Cu2WS4-PEG Nanozyme as Multifunctional Sensitizers for Enhancing Immuno-Radiotherapy by Inducing Ferroptosis.

Unavoidable damage to normal tissues and tumor microenvironment (TME) resistance make it challenging to eradicate breast carcinoma through radiotherapy. Therefore, it is urgent to develop radiotherapy sensitizers that can effectively reduce radiation doses and reverse the suppressive TME. Here, a novel biomimetic PEGylated Cu2WS4 nanozyme (CWP) with multiple enzymatic activities is synthesized by the sacrificing template method to have physical radiosensitization and biocatalyzer-responsive effects on the TME. Experiment results show that CWP can improve the damage efficiency of radiotherapy on breast cancer cell 4T1 through its large X-ray attenuation coefficient of tungsten and nucleus-penetrating capacity. CWP also exhibit strong Fenton-like reactions that produced abundant ROS and GSH oxidase-like activity decreasing GSH. This destruction of redox balance further promotes the effectiveness of radiotherapy. Transcriptome sequencing reveals that CWP induced ferroptosis by regulating the KEAP1/NRF2/HMOX1/GPX4 molecules. Therefore, owing to its multiple enzymatic activities, high-atomic W elements, nucleus-penetrating, and ferroptosis-inducing capacities, CWP effectively improves the efficiency of radiotherapy for breast carcinoma in vitro and in vivo. Furthermore, CWP-mediated radiosensitization can trigger immunogenic cell death (ICD) to improve the anti-PD-L1 treatments to inhibit the growth of primary and distant tumors effectively. These results indicate that CWP is a multifunctional nano-sensitizers for radiotherapy and immunotherapy.

Ethylmalonic encephalopathy 1 initiates overactive autophagy in depleted uranium-induced cytotoxicity in the human embryonic kidney 293 cells.

The kidney is the target of the acute toxicity of depleted uranium (DU). However, the mechanism of DU-induced cytotoxicity is not clear. The study was to demonstrate the role of autophagy in DU-induced cytotoxicity and to determine the potential mechanism. We confirmed that after a 4-h exposure to DU, the autophagic vacuoles and the autophagy marker light chain 3-II in the human embryonic kidney 293 cells (HEK293) increased, and cytotoxicity decreased by abrogation of excessive autophagy using autophagy inhibitor. We also found activation of nucleus p53 and inhibiting mTOR pathways in DU-treated HEK293 cells. Meanwhile, ethylmalonic encephalopathy 1 (ETHE1) decreased as the exposure dose of DU increased, with increasing autophagy flux. We suggested that by reducing ETHE1, activation of the p53 pathway, and inhibiting mTOR pathways, DU might induce overactive autophagy, which affected the cytotoxicity. This study will provide a novel therapeutic target for the treatment of DU-induced cytotoxicity.

Ghrelin protects against depleted uranium-induced bone damage by increasing osteoprotegerin/RANKL ratio.

Depleted uranium (DU) is widely used in military and civil activities, and bone is the main target organ of chronic DU toxicity. The aim of this study was to evaluate the effects of ghrelin on rats implanted with DU and explore the underlying mechanisms. The results showed that ghrelin could increase the expression of ghrelin receptor in bone tissue, thus alleviate the apoptosis of bone tissue after 3 months of 0.3 g DU embedded in the tibia. Micro-computed tomography examination showed that after DU implantation, the density of cortical bone showed no significant difference, but the trabecular bone decreased in amount, density and connectivity. Ghrelin treatment can significantly reduce the changes caused by DU. Moreover, ghrelin can inhibit the increase of serum tartrate resistant acid phosphatase and the decrease of alkaline phosphatase and osteocalcin. Furthermore, ghrelin can also significantly reduce the receptor activator of nuclear factor κB ligand (RANKL) and phosphorylated p38-MAPK expression, and increase the level of osteoprotegerin (OPG) in tissues after exposure to DU. Based on cell experimental research, p38-MAPK specific agonist can reverse the function of ghrelin, significantly inhibit the level of OPG and increase the level of RANKL. On the contrary, the use of p38-MAPK specific inhibitor or p38-MAPK siRNA can enhance the function of ghrelin. These results suggest that ghrelin may inhibit p38 MAPK activation induced by DU, and increase the OPG/RANKL ratio caused by DU exposure, hence alleviating the bone damage caused by long-term DU exposure.

Ghrelin accelerates wound healing in combined radiation and wound injury in mice.

Impaired wound healing caused by radiation happens frequently in clinical practice, and the exact mechanisms remain partly unclear. Various countermeasures have been taken to tackle with this issue. Ghrelin was considered as a potent endogenous growth hormone-releasing peptide, and its role in enhancing wound repair and regeneration was firstly investigated in whole-body irradiated (γ-ray) mice in this study. Collagen deposition and neovascularization were mostly discussed. The results demonstrated that ghrelin administration promoted cutaneous wound healing in irradiated mice, followed with reduced average wound closure time, increased spleen index (SI) and improved haematopoiesis. After isolation and analysis of granulation tissues in combined radiation and wound injury (CRWI) mice treated with and without ghrelin, a phenomenon of increased DNA, hexosamine, nitrate and nitrite synthesis, elevated collagen content and enhanced neovascularization was observed after ghrelin treatment. Western blotting indicated that ghrelin also increased the expression of vascular endothelial growth factor (VEGF) and transforming growth factor-ß (TGF-ß), both responsible for wound healing. However, previous administration of growth hormone secretagogue receptor 1a (GHS-R1a) blocker blunted these therapeutic effects of ghrelin on CRWI mice. Our results identify ghrelin as a novel peptide that could be used for radiation-induced impaired wound healing.

Ghrelin protects against depleted uranium-induced apoptosis of MC3T3-E1 cells through oxidative stress-mediated p38-mitogen-activated protein kinase pathway.

Depleted uranium (DU) mainly accumulates in the bone over the long term. Osteoblast cells are responsible for the formation of bone, and they are sensitive to DU damage. However, studies investigating methods of reducing DU damage in osteoblasts are rarely reported. Ghrelin is a stomach hormone that stimulates growth hormones released from the hypothalamic-pituitary axis, and it is believed to play an important physiological role in bone metabolism. This study evaluates the impact of ghrelin on DU-induced apoptosis of the osteoblast MC3T3-E1 and investigates its underlying mechanisms. The results show that ghrelin relieved the intracellular oxidative stress induced by DU, eliminated reactive oxygen species (ROS) and reduced lipid peroxidation by increasing intracellular GSH levels; in addition, ghrelin effectively suppressed apoptosis, enhanced mitochondrial membrane potential, and inhibited cytochrome c release and caspase-3 activation after DU exposure. Moreover, ghrelin significantly reduced the expression of DU-induced phosphorylated p38-mitogen-activated protein kinase (MAPK). A specific inhibitor (SB203580) or specific siRNA of p38-MAPK could significantly suppress DU-induced apoptosis and related signals, whereas ROS production was not affected. In addition, ghrelin receptor inhibition could reduce the anti-apoptosis effect of ghrelin on DU and reverse the effect of ghrelin on intracellular ROS and p38-MAPK after DU exposure. These results suggest that ghrelin can suppress DU-induced apoptosis of MC3T3-E1 cells, reduce DU-induced oxidative stress by interacting with its receptor, and inhibit downstream p38-MAPK activation, thereby suppressing the mitochondrial-dependent apoptosis pathway.

Metallothionein deficiency aggravates depleted uranium-induced nephrotoxicity.

Depleted uranium (DU) has been widely used in both civilian and military activities, and the kidney is the main target organ of DU during acute high-dose exposures. In this study, the nephrotoxicity caused by DU in metallothionein-1/2-null mice (MT-/-) and corresponding wild-type (MT+/+) mice was investigated to determine any associations with MT. Each MT-/- or MT+/+ mouse was pretreated with a single dose of DU (10mg/kg, intraperitoneal injection) or an equivalent volume of saline. After 4days of DU administration, kidney changes were assessed. After DU exposure, serum creatinine and serum urea nitrogen in MT-/- mice significantly increased than in MT+/+ mice, with more severe kidney pathological damage. Moreover, catalase and superoxide dismutase (SOD) decreased, and generation of reactive oxygen species and malondialdehyde increased in MT-/- mice. The apoptosis rate in MT-/- mice significantly increased, with a significant increase in both Bax and caspase 3 and a decrease in Bcl-2. Furthermore, sodium-glucose cotransporter (SGLT) and sodium-phosphate cotransporter (NaPi-II) were significantly reduced after DU exposure, and the change of SGLT was more evident in MT-/- mice. Finally, exogenous MT was used to evaluate the correlation between kidney changes induced by DU and MT doses in MT-/- mice. The results showed that, the pathological damage and cell apoptosis decreased, and SOD and SGLT levels increased with increasing dose of MT. In conclusion, MT deficiency aggravated DU-induced nephrotoxicity, and the molecular mechanisms appeared to be related to the increased oxidative stress and apoptosis, and decreased SGLT expression.

[Expression of interferon-induced protein with tetratricopetide repeats 1 and liver cell apoptosis in mice with severe burns].

OBJECTIVE: To explore the relationship between the expression of interferon-induced protein with tetratricopetide repeats 1 (IFIT1) and liver cell apoptosis in the acute stress period after severe burns.
 METHODS: A total of 25 C57/129 adult mice were randomly divided into the normal control group (0 h) and the groups at 1, 6, 12 or 24 after severe burns (n=5 per group). A model with third degree (20% of the total body surface area) burn injury was established and then liver tissues were taken. IFIT1 expression was examined by Western blot. The expression of caspase-3 and -8 was measured by immunohistochemistry. Liver cell apoptosis was detected by terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL).
 RESULTS: After burns, IFIT1 expression was increased at 1 h, which reached the highest level at 6 h followed by a decrease at 12 h, which reached minimum level at 24 h. The differences between groups were significant (P<0.01). The caspase-3 and -8 levels significantly increased after burns in a time-dependent manner (P<0.01). Although at 0 h and 1 h there was no significant increase in liver cell apoptosis, the increase reached significance from 6 h to 24 h (P<0.01).
 CONCLUSION: The increase in IFIT1 expression after severe burns promotes liver cell apoptosis.

Enhanced uranium sequestration through selenite-modified nano-chitosan loaded with melatonin: Facilitating U(IV) conversion.

The combined chemotoxicity and radiotoxicity associated with uranium, utilized in nuclear industry and military applications, poses significant threats to human health. Among uranium pollutants, uranyl is particularly concerning due to its high absorptivity and potent nephrotoxicity in its + 6 valence state. Here, we have serendipitously found Na2SeO3 facilitates the conversion of U(VI) to U(IV) precipitates. A novel approach involving nano-chitosan loaded internally with melatonin and externally modified with selenite (NPs Cs-Se/MEL) was introduced. This modification not only enhances the conversion of U(VI) to U(IV) but also preserves the spherical nanostructure and specific surface area, leading to increased adsorption of U(VI) compared to unmodified samples. Selenite modification improves lysosomal delivery in HEK-293 T cells and kidney distribution of the nanoparticles. Furthermore, NPs Cs-Se/MEL demonstrated a heightened uranium concentration in urine and exhibited remarkable efficiency in uranium removal, resulting in a reduction of uranium deposition in serum, kidneys, and femurs by up to 52.02 %, 46.79 %, and 71.04 %, respectively. Importantly, NPs Cs-Se/MEL can be excreted directly from the kidneys into urine when carrying uranium. The results presented a novel mechanism for uranium adsorption, making selenium-containing nano-materials attractive for uranium sequestration and detoxification.

Enteric α-Defensin Contributes to Recovery of Radiation-Induced Intestinal Injury by Modulating Gut Microbiota and Fecal Metabolites.

The effect of ionizing radiation on the gastrointestinal tract is a common complication of abdominal and pelvic radiotherapy. However, the pathological features of radiation enteropathy and its effective medical intervention regimen is still a global challenge. Here, we explored the role and mechanism of enteric alpha-defensins (EαDs) in protecting against radiation enteropathy. To address this, we utilized EαDs-deficiency mice, in which the matrix metallopeptidase 7 to activate Paneth cell α-defensins was knockout (KO) mice, and the complementary wild-type (WT) control mice for this study. Remarkably, the KO mice were more susceptible to 5.0 Gy total-body irradiation, resulting in worse clinic scores and lower survival rate, compared with the wild-type mice. Histological examination indicated that the KO mice were subjected to slow recovery of intestinal villus and mucosa function, characterized by the reduced expression of TFF3, Glut1 and Muc2. In addition, compared with the wild-type controls, the KO mice experienced serious inflammation response in intestinal tissue, indicated by the remarkably increased expression level of IL-1ß, IL-6 and IL-12. Using high-throughput sequencing analysis, we found that the intestinal bacterial community of the KO mice was more prone to dysbiosis than that of the WT mice, with significantly increased abundance of opportunistic pathogenic bacteria, such as Streptococcus sp. and Escherichia-Shigella sp., whereas remarkably decreased probiotics harboring Lactobacillus sp., Desulfovibrio sp. etc. Fecal metabolomics analysis indicated that the relative abundance of 31 metabolites arose significantly different between WT and KO mice on day 10 after radiation exposure. A subset of differential metabolites to regulate host metabolism and immunity, such as acetic acid, acetate, butanoic acid, was negatively correlated with the alteration of gut microbiota in the irradiated KO mice. This study provides new insight into EαDs contribution to the recovery of radiation-induced intestinal damage, and suggests a potential novel target to prevent the adverse effects of radiotherapy.

The role of BTG2/PI3K/AKT pathway-mediated microglial activation in T-2 toxin-induced neurotoxicity.

T-2 toxin is one of the mycotoxins widely distributed in human food and animal feed. Our recent work has shown that microglial activation may contribute to T-2 toxin-induced neurotoxicity. However, the molecular mechanisms involved need to be further clarified. To address this, we employed high-throughput transcriptome sequencing and found altered B cell translocation gene 2 (BTG2) expression levels in microglia following T-2 toxin treatment. It has been shown that altered BTG2 expression is involved in a range of neurological pathologies, but whether it's involved in the regulation of microglial activation is unclear. The aim of this study was to investigate the role of BTG2 in T-2 toxin-induced microglial activation. The results of animal experiments showed that T-2 toxin caused neurobehavioral disorders and promoted the expression of microglial BTG2 and pro-inflammatory activation of microglia in hippocampus and cortical, while microglial inhibitor minocycline inhibited these changes. The results of in vitro experiments showed that T-2 toxin enhanced BTG2 expression and pro-inflammatory microglial activation, and inhibited BTG2 expression weakened T-2 toxin-induced microglial activation. Moreover, T-2 toxin activated PI3K/AKT and its downstream NF-κB signaling pathway, which could be reversed after knock-down of BTG2 expression. Meanwhile, the PI3K inhibitor LY294002 also blocked this process. Therefore, BTG2 may be involved in T-2 toxin's ability to cause microglial activation through PI3K/AKT/NF-κB pathway.

Depleted uranium induces thyroid damage through activation of ER stress via the thrombospondin 1-PERK pathway.

Depleted uranium (DU) can cause damage to the body, but its effects on the thyroid are unclear. The purpose of this study was to investigate the DU-induced thyroid damage and its potential mechanism in order to find new targets for detoxification after DU poisoning. A model of acute exposure to DU was constructed in rats. It was observed that DU accumulated in the thyroid, induced thyroid structure disorder and cell apoptosis, and decreased the serum T4 and FT4 levels. Gene screening showed that thrombospondin 1 (TSP-1) was a sensitive gene of DU, and the expression of TSP-1 decreased with the increase of DU exposure dose and time. TSP-1 knockout mice exposed to DU had more severe thyroid damage and lower serum FT4 and T4 levels than wild-type mice. Inhibiting the expression of TSP-1 in FRTL-5 cells aggravated DU-induced apoptosis, while exogenous TSP-1 protein alleviated the decreased viability in FRTL-5 cells caused by DU. It was suggested that DU may caused thyroid damage by down-regulating TSP-1. It was also found that DU increased the expressions of PERK, CHOP, and Caspase-3, and 4-Phenylbutyric (4-PBA) alleviated the DU-induced FRTL-5 cell viability decline and the decrease levels of rat serum FT4 and T4 caused by DU. After DU exposure, the PERK expression was further up-regulated in TSP-1 knockout mice, and the increased expression of PERK was alleviated in TSP-1 over-expressed cells, as well as the increased expression of CHOP and Caspase-3. Further verification showed that inhibition of PERK expression could reduce the DU-induced increased expression of CHOP and Caspase-3. These findings shed light on the mechanism that DU may activate ER stress via the TSP 1-PERK pathway, thereby leading to thyroid damage, and suggest that TSP-1 may be a potential therapeutic target for DU-induced thyroid damage.

Depleted uranium causes renal mitochondrial dysfunction through the ETHE1/Nrf2 pathway.

The kidney is the main organ affected by acute depleted uranium (DU) toxicity. The mechanism of nephrotoxicity induced by DU is complex and needs to be further explored. This study aimed to elucidate the function of mitochondrial dysfunction in nephrotoxicity generated by DU and confirm the latent mechanism. We verified that DU (2.5-10 mg/kg) caused mitochondrial dysfunction in male rat kidneys and decreased ATP content and the mitochondrial membrane potential. In addition, melatonin (20 mg/kg), as an antioxidant, alleviated DU-induced oxidative stress and mitochondrial dysfunction in male rats, further reducing kidney damage caused by DU. These results indicate that mitochondrial dysfunction plays a vital role in DU nephrotoxicity. When ethylmalonic encephalopathy 1 (ETHE1) was knocked down, DU-induced oxidative stress and mitochondrial dysfunction were increased, and renal injury was aggravated. When exogenous ETHE1 protein was applied to renal cells, the opposite changes were observed. We also found that ETHE1 knockdown increased the expression of NF-E2-related factor 2 (Nrf2), a vital oxidative stress regulator, and its downstream molecules heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase 1 (NQO1). Nrf2 knockout also aggravated DU-induced oxidative stress, mitochondrial dysfunction, and kidney damage. In conclusion, DU causes oxidative stress and antioxidant defense imbalance in renal cells through the ETHE1/Nrf2 pathway, further causing mitochondrial dysfunction and ultimately leading to nephrotoxicity.

Mannosylated polydopamine nanoparticles alleviate radiation- induced pulmonary fibrosis by targeting M2 macrophages and inhibiting the TGF-ß1/Smad3 signaling pathway.

Radiation-induced pulmonary fibrosis (RIPF), one type of pulmonary interstitial diseases, is frequently observed following radiation therapy for chest cancer or accidental radiation exposure. Current treatments against RIPF frequently fail to target lung effectively and the inhalation therapy is hard to penetrate airway mucus. Therefore, this study synthesized mannosylated polydopamine nanoparticles (MPDA NPs) through one-pot method to treat RIPF. Mannose was devised to target M2 macrophages in the lung through CD 206 receptor. MPDA NPs showed higher efficiency of penetrating mucus, cellular uptake and ROS-scavenging than original polydopamine nanoparticles (PDA NPs) in vitro. In RIPF mice, aerosol administration of MPDA NPs significantly alleviated the inflammatory, collagen deposition and fibrosis. The western blot analysis demonstrated that MPDA NPs inhibited TGF-ß1/Smad3 signaling pathway against pulmonary fibrosis. Taken together this study provide a novel M2 macrophages-targeting nanodrugs through aerosol delivery for the prevention and targeted treatment for RIPF.

Research Progress on Therapeutic Effect and Mechanism of Propolis on Wound Healing.

Propolis is a kind of reduct collected by bees from various plant sources. Because propolis is a mixture, it has a variety of biological activities, excellent anti-inflammatory and bactericidal effects. Especially in the treatment of infectious wounds, acute wounds, burns, and scalds and promoting wound healing, more and more scientists began to apply it to the research field of wound healing. The standard preparation of propolis combined with other compound components has a safer and less toxic effect in the treatment of trauma. In order to more effectively use propolis products in wound treatment. This paper reviews the effect and treatment mechanism of propolis on different types of wound healing, as well as the synergistic effect of propolis and other compounds, in order to provide ideas for the further exploration of the biological activity and pharmacological function of propolis in the future, as well as its in-depth development in the field of wound healing. It will also provide a theoretical reference for the further development and utilization of propolis.

Research progress on radioprotective effects of bee products.

Radiation exposure is an on going and serious threat in military and public health concern. There is an unmet need for effective preventative or mitigative treatments against radiation-induced injuries. The handful of Food and Drug Administration in the US approved radiation protection agents cannot be widely used due to their side effects. Some natural nontoxic compounds such as bee products have been reported to prevent and treat radiation-induced injuries (e.g. scavenging free radicals, inhibiting cell apoptosis and reducing DNA damage), indicating that they may be a potential option as a safe radioprotective agent. Bee products are nontoxic and have no known side effects on the human body, and are effective in the field of radiation protection. They are expected to be interesting drug candidates for preventing and treating radiation-induced injuries. This article reviews the prevention and treatment of bee products on radiation-induced injuries.

Protective effect of melatonin entrapped PLGA nanoparticles on radiation-induced lung injury through the miR-21/TGF-ß1/Smad3 pathway.

Radiation-induced lung injury (RILI) is a complication commonly found in victims suffering from nuclear accidents and patients treated with chest tumor radiotherapy, and drugs are limited for effective prevention and treatment. Melatonin (MET) has an anti-radiation effect, but its metabolic period in the body is short. In order to prolong the metabolism period of MET, we prepared MET entrapped poly (lactic-co-glycolic acid) nanoparticles (MET/PLGANPS) for the treatment of RILI. As a result, the release rate of MET/PLGANPS in vitro was lower than MET, with stable physical properties, and it caused no changes in histopathology and biochemical indicators. After 2 weeks and 16 weeks of irradiation with the dose of 15 Gy, MET and MET/PLGANPS could reduce the expression of caspase-3 proteins, inflammatory factors, TGF-ß1 and Smad3 to alleviate radiation-induced lung injury. MET/PLGANPS showed better therapeutic effect on RILI than MET. In addition, we also found that high expression of miR-21 could increase the expression levels of TGF-ß1, and inhibit the protective effect of MET/PLGANPS. In conclusion, MET/PLGANPS may alleviate RILI by inhibiting the miR-21/TGF-ß1/Smad3 pathway, which would provide a new target for the treatment of radiation-induced lung injury.

Chronic oral depleted uranium leads to reproductive damage in male rats through the ROS-hnRNP A2/B1-COX-2 signaling pathway.

Depleted uranium (DU) is widely used in civil and military activities. The testis is one of the target organs of DU chronic toxicity. In this study, male SD rats were chronically exposed to DU by 3, 30, 300 mg U/kg through oral intake. After 6 months and 12 months of exposure, it was found that DU could lead to increased oxidative stress levels, decreased glutathione S-transferases (GSTs) expression, resulting in testicular injury and decreased serum testosterone (T) level in rats. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) expression increases with the increase of DU exposure dose. After upregulation of hnRNP A2/B1 expression, the GC-1 cell injury caused by DU is aggravated, suggesting that hnRNP A2/B1 may play an important role in the reproductive toxicity of DU. At the same time, 12 months after chronic oral exposure to DU, the expression level of cyclooxygenase-2 (COX-2) and proinflammatory factor prostaglandin E2 (PGE2) in testicular tissue were increased, and the level of hnRNP A2/B1 caused by DU was decreased by reactive oxygen scavenger N-acetylcysteine (NAC). As hnRNP A2/B1 is a COX-2 regulator, DU may lead to the upregulation of hnRNP A2/B1 expression through the increase of oxidative stress level in germ cells, which in turn leads to the increase of COX-2 and PGE2 level, and ultimately result in the reproductive toxicity. In this study, the regulation mechanism of the ROS-hnRNP A2/B1-COX-2 pathway on DU-induced reproductive damage in male rats was hypothesized, providing a new target for the prevention and treatment of chronic poisoning of DU.

Identification and characterization of murine adipose tissue-derived somatic stem cells of Shenque (CV8) acupoint.

BACKGROUND: Shenque (CV8) acupoint is located on the navel and has been therapeutically used for more than 2000 years in Traditional Chinese Medicine (TCM). However, clinical research on the underlying therapeutic molecular mechanisms of the CV8 acupoint lags far behind. This study aimed to study the mechanisms of umbilical acupoint therapy by using stem cells. METHODS: The morphological characteristics of CV8 acupoint were detected under a stereomicroscope using hematoxylin and eosin (H&E) staining. Oil Red, Masson, and immunohistochemical staining on multi-layered slices were used to identify the type of cells at the CV8 acupoint. Cell proliferation was measured by a cell counting kit-8 (CCK-8) method. Flow cytometry and immunohistochemistry were used for cell identification. Induced differentiation was used to compare the differentiation of cells derived from CV8 acupoint and non-acupoint somatic stem cells into other cell types, such as osteogenic, adipogenic, and neural stem cell-like cells. RESULTS: Morphological observations showed that adipose tissues at the linea alba of the CV8 acupoint in mice had a mass-like distribution. Immunohistochemical staining confirmed the distribution of stem cell antigen-1 (Sca-1) positive cells in the multi-layered slices of CV8 acupoint tissues. Cells isolated from adipose tissues at the CV8 acupoint exhibited high expression of Sca-1 and CD44 and low expression of CD31 and CD34, and these cells possessed osteogenic, adipogenic, and neurogenic stem cell-like cell differentiation ability. The cell proliferation (day 4: 0.5138 ±â€Š0.0111 vs. 0.4107 ±â€Š0.0180, t = 8.447, P = 0.0011; day 5: 0.6890 ±â€Š0.0070 vs. 0.5520 ±â€Š0.0118, t = 17.310, P < 0.0001; day 6: 0.7320 ±â€Š0.0090 vs. 0.6157 ±â€Š0.0123, t = 13.190, P = 0.0002; and day 7: 0.7550 ±â€Š0.0050 vs. 0.6313 ±â€Š0.0051, t = 42.560, P < 0.0001), adipogenic ([9.224 ±â€Š0.345]% vs. [3.933 ±â€Š1.800]%, t = 5.000, P = 0.0075), and neurogenic stem cell-like cell differentiation (diameter < 50 µm: 7.2000 ±â€Š1.3040 vs. 2.6000 ±â€Š0.5477, t = 7.273, P < 0.0001; diameter 50-100 µm: 2.6000 ±â€Š0.5477 vs. 1.0000 ±â€Š0.7071, t = 4.000, P = 0.0039; and diameter >100 µm: 2.6000 ±â€Š0.5477 vs. 0.8000 ±â€Š0.8367, t = 4.025, P = 0.0038) were significantly enhanced in somatic stem cells derived from the CV8 acupoint compared to somatic stem cells from the groin non-acupoint. However, cells possessed significantly weaker osteogenicity ([2.697 ±â€Š0.627]% vs. [7.254 ±â€Š0.958]%, t = 6.893, P = 0.0023) in the CV8 acupoint group. CONCLUSIONS: Our study showed that CV8 acupoint was rich with adipose tissues that contained abundant somatic stem cells. The biological examination of somatic stem cells derived from the CV8 acupoint provided novel insights for future research on the mechanisms of umbilical therapy.

Neutrophils-derived Spink7 as one safeguard against experimental murine colitis.

The uncontrolled abnormal intestinal immune responses play important role in eliciting inflammatory bowel disease (IBD), yet the molecular events regulating intestinal inflammation during IBD remain poorly understood. Here, we describe an endogenous, homeostatic pattern that controls inflammatory responses in experimental murine colitis. We show that Spink7 (serine peptidase inhibitor, kazal type 7), the ortholog of human SPINK7, is significantly upregulated in dextran sodium sulfate (DSS)-induced murine colitis model. Spink7-deficient mice showed highly susceptible to experimental colitis characterized by enhanced weight loss, shorter colon length, higher disease activity index and increased colonic tissue destruction. Bone marrow reconstitution experiments demonstrated that expression of Spink7 in the immune compartment makes main contribution to its protective role in colitis. What's more, neutrophils are the primary sources of Spink7 in experimental murine colitis. Loss of Spink7 leads to augmented productions of multiple chemokines and cytokines in colitis. In summary, this study identifies neutrophils-derived endogenous Spink7-mediated control of chemokines/cytokines production as a molecular mechanism contributing to inflammation resolution during colitis.

Synthesis of Mitochondria-Anchored Nitroimidazoles with a Versatile NIR Fluorophore for Hypoxic Tumor-Targeting Imaging and Chemoradiotherapy.

Nitroimidazoles are one of the most common radiosensitizers investigated to combat hypoxia-induced resistance to cancer radiotherapy. However, due to poor selectivity distinguishing cancer cells from normal cells, effective doses of radiosensitization are much closer to the doses of toxicity induced by nitroimidazoles, limiting their clinical application. In this work, a tumor-targeting near-infrared (NIR) cyanine dye (IR-808) was utilized as a targeting ligand and an NIR fluorophore tracer to chemically conjugate with different structures of hypoxia-affinic nitroimidazoles. One of the NIR fluorophore-conjugated nitroimidazoles (808-NM2) was identified to preferentially accumulate in hypoxic tumor cells, sensitively outline the tumor contour, and effectively inhibit tumor growth synergistically by chemotherapy and radiotherapy. More importantly, nitroimidazoles were successfully taken into cancer cell mitochondria via 808-NM2 conjugate to exert the synergistic effect of chemoradiotherapy. Regarding the important roles of mitochondria on cancer cell survival and metastasis under hypoxia, 808-NM2 may be hopeful to fight against hypoxic tumors.