Growth Hormone-Releasing Hormone and Its Analogues: Significance for MSCs-Mediated Angiogenesis

Mesenchymal stromal cells (MSCs) are promising candidates for regenerative medicine because of their multipotency, immune-privilege, and paracrine properties including the potential to promote angiogenesis. Accumulating evidence suggests that the inherent properties of cytoprotection and tissue repair by native MSCs can be enhanced by various preconditioning stimuli implemented prior to cell transplantation. Growth hormone-releasing hormone (GHRH), a stimulator in extrahypothalamus systems including tumors, has attracted great attentions in recent years because GHRH and its agonists could promote angiogenesis in various tissues. GHRH and its agonists are proangiogenic in responsive tissues including tumors, and GHRH antagonists have been tested as antitumor agents through their ability to suppress angiogenesis and cell growth. GHRH-R is expressed by MSCs and evolving work from our laboratory indicates that treatment of MSCs with GHRH agonists prior to cell transplantation markedly enhanced the angiogenic potential and tissue reparative properties of MSCs through a STAT3 signaling pathway. In this review we summarized the possible effects of GHRH analogues on cell growth and development, as well as on the proangiogenic properties of MSCs. We also discussed the relationship between GHRH analogues and MSC-mediated angiogenesis. The analyses provide new insights into molecular pathways of MSCs-based therapies and their augmentation by GHRH analogues

The Effect of Oxidative Stress-Induced Autophagy by Cadmium Exposure in Kidney, Liver, and Bone Damage, and Neurotoxicity

Environmental and occupational exposure to cadmium has been shown to induce kidney damage, liver injury, neurodegenerative disease, and osteoporosis. However, the mechanism by which cadmium induces autophagy in these diseases remains unclear. Studies have shown that cadmium is an effective inducer of oxidative stress, DNA damage, ER stress, and autophagy, which are thought to be adaptive stress responses that allow cells exposed to cadmium to survive in an adverse environment. However, excessive stress will cause tissue damage by inducing apoptosis, pyroptosis, and ferroptosis. Evidently, oxidative stress-induced autophagy plays different roles in low- or high-dose cadmium exposure-induced cell damage, either causing apoptosis, pyroptosis, and ferroptosis or inducing cell survival. Meanwhile, different cell types have different sensitivities to cadmium, which ultimately determines the fate of the cell. In this review, we provided a detailed survey of the current literature on autophagy in cadmium-induced tissue damage. A better understanding of the complex regulation of cell death by autophagy might contribute to the development of novel preventive and therapeutic strategies to treat acute and chronic cadmium toxicity

Hard and superconducting cubic boron phase via swarm-intelligence structural prediction driven by a machine-learning potential

Boron is an intriguing element due to its electron deficiency and the ability to form multicenter bonds in allotropes and borides, exhibiting diversified structures, unique chemical bonds, and interesting properties. Using swarm-intelligence structural prediction driven by a machine learning potential, we identified a boron phase with a 24-atom cubic unit cell, called c−B24, consisting of a B6 octahedron in addition to well-known B2 pairs and B12 icosahedra at ambient pressure. There appear unusual four-center-two-electron (4c-2e) bonds in the B12 icosahedron, originating from the peculiar bonding pattern between the B2 pair and B12 icosahedron, which is in sharp contrast with the 3c-2e and 2c-2e bonds in α−B12. More interestingly, c−B24 is a metal with a superconducting critical temperature of 13.8 K at ambient pressure. The predicted Vickers hardness (23.1 GPa) indicates that c−B24 is a potential hard material. Notably, it also has a good shear/tensile resistance (48.9/29.3 GPa). Our work not only enriches the understanding of the chemical properties of boron, but also sparks efforts on trying to synthesize this particular compound, c−B24.The authors acknowledge the funding support from the Natural Science Foundation of China under Grants No. 21873017, No. 21573037, No. 11704062, and No. 51732003, the Postdoctoral Science Foundation of China under Grant No. 2013M541283, the Natural Science Foundation of Jilin Province (20190201231JC), the “111” Project (No. B13013). The work was carried out at National Supercomputer Center in Tianjin, and the calculations were performed on TianHe-1 (A). A.B. acknowledges financial support from the Spanish Ministry of Science and Innovation (PID2019-105488GBI00) and from Jilin Province Out-standing Young Talents project (Grant No. 20190103040JH).Peer reviewe

Benefits and trade-offs of replacing synthetic fertilizers by animal manures in crop production in China: A meta-analysis

Recycling of livestock manure to agricultural land may reduce the use of synthetic fertilizer and thereby enhance the sustainability of food production. However, the effects of substitution of fertilizer by manure on crop yield, nitrogen use efficiency (NUE), and emissions of ammonia (NH3), nitrous oxide (N2O) and methane (CH4) as function of soil and manure properties, experimental duration and application strategies have not been quantified systematically and convincingly yet. Here, we present a meta-analysis of these effects using results of 143 published studies in China. Results indicate that the partial substitution of synthetic fertilizers by manure significantly increased the yield by 6.6% and 3.3% for upland crop and paddy rice, respectively, but full substitution significantly decreased yields (by 9.6% and 4.1%). The response of crop yields to manure substitution varied with soil pH and experimental durations, with relatively large positive responses in acidic soils and long-term experiments. NUE increased significantly at a moderate ratio (3 emissions were significantly lower with full substitution (62%–77%), but not with partial substitution. Emissions of CH4 from paddy rice significantly increased with substitution ratio (SR), and varied by application rates and manure types, but N2O emissions decreased. The SR did not significantly influence N2O emissions from upland soils, and a relative scarcity of data on certain manure characteristic was found to hamper identification of the mechanisms. We derived overall mean N2O emission factors (EF) of 0.56% and 0.17%, as well as NH3 EFs of 11.1% and 6.5% for the manure N applied to upland and paddy soils, respectively. Our study shows that partial substitution of fertilizer by manure can increase crop yields, and decrease emissions of NH3 and N2O, but depending on site-specific conditions. Manure addition to paddy rice soils is recommended only if abatement strategies for CH4 emissions are also implemented.</p

Isolation and Genetic Characterization of <i>Toxoplasma gondii</i> from a Patas Monkey (<i>Erythrocebus patas</i>) in China

Many cases of Toxoplasma gondii infection have been reported worldwide in non-human primates (NHPs), especially in captive New World monkeys. However, few studies on toxoplasmosis in Old World monkeys have been conducted. In this study, serological and molecular biological analyses were carried out to look for T. gondii antibodies and T. gondii infection in 13 NHPs from China. T. gondii infection was confirmed in 8 NHP cases. T. gondii antibodies were detected in 1/5 New World monkeys and in 4/7 Old World monkeys. T. gondii DNA was detected in 3/5 New World monkeys and 5/7 Old World monkeys. The one ring-tailed lemur was negative for both antibodies and DNA of T. gondii. The most common clinical manifestations of T. gondii infection were malaise, poor appetite, emaciation, and foamy nasal discharge. The most common histopathological findings were interstitial pneumonia, necrotic hepatitis, necrotizing myocarditis, lymphadenitis, and necrotic splenitis. One viable T. gondii strain was successfully isolated from the myocardium of a patas monkey (Erythrocebus patas) by bioassay in mice. T. gondii tachyzoites were obtained from cell cultures and were designated as TgMonkeyCHn2. The genotype of this strain belongs to ToxoDB genotype #9, and the allele of ROP18/ROP5 gene was 3/6. TgMonkeyCHn2 tachyzoites were avirulent in Swiss mice. To our knowledge, this is the first report of fatal toxoplasmosis in a patas monkey. T. gondii infection in patas monkeys may indicate environmental contamination by oocysts. The patas monkey is a new host record for T. gondii

Exosomes derived from human umbilical cord MSCs rejuvenate aged MSCs and enhance their functions for myocardial repair

Background Age and other cardiovascular risk factors have been reported to impair the activities of mesenchymal stem cells (MSCs), which will affect the efficacy of stem cell transplantation. The objective of the study is to investigate whether exosomes derived from human umbilical cord MSCs (UMSCs) could enhance the activities of bone marrow MSCs from old person (OMSCs), and improve their capacity for cardiac repair. Methods Exosomes extracted from conditioned medium of UMSCs were used to treat OMSCs to generate OMSCsExo. The key molecule in the exosomes that have potential to rejuvenate aged MSCs were screened, and the role of OMSC was tested in the mouse model of mycardial infarction (MI). Results We found the activity of senescence-associated beta-galactosidase and the expression of aging-related factors such as p53, p21, and p16 were significantly higher in OMSCs than those in UMSCs. After treatment with UMSC exosomes, these senescence phenotypes of OMSCs were remarkably reduced. The proliferation, migration, differentiation, and anti-apoptotic and paracrine effect were increased in OMSCsExo. In vivo study, mice with cardiac infarction had significantly better cardiac function, less fibrosis, and more angiogenesis after they were injected with OMSCs(Exo)as compared with those with OMSC. There was more miR-136 expression in UMSCs and OMSCs(Exo)than in OMSCs. Upregulation of miR-136 by transfection of miR-136 mimic into OMSCs significantly attenuated the apoptosis and senescence of OMSCs. Apoptotic peptidase activating factor (Apaf1) was found to be the downstream gene that is negatively regulated by miR-136 via directly targeting at its 3 ' UTR. Conclusion Our data suggest that exosomes from young MSCs can improve activities of aged MSCs and enhance their function for myocardial repair by transferring exosomal miR-136 and downregulating Apaf1

Abstract 723: Agonist of Growth Hormone Releasing Hormone Enhances Angiogenic Therapy by Mesenchymal Stem Cells

Transplantation of bone marrow-derived mesenchymal stem cells (MSCs) represents a promising strategy for treating cardiovascular disease. However, the efficiency of such therapy is limited by poor cell survival and engraftment. Growth hormone-releasing hormone (GHRH) regulates growth and development through pleiotropic actions on multiple target cell and tissue types. Here we studied the effect of the GHRH agonist, JI-34, on MSC survival and angiogenic therapy in a mouse model of critical limb ischemia. Treatment of MSCs with JI-34 improved MSC viability and mobility and markedly enhanced endothelial tube formation in vitro. These effects were paralleled by increased phosphorylation and nuclear translocation of STAT3. In vivo, JI-34 pre-treatment enhanced the engraftment of MSCs into ischemic hindlimb muscles and augmented reperfusion and limb salvage compared with untreated MSCs. Significantly more vasculature and proliferating CD31+ and CD34+ cells were detected in ischemic muscles that received MSCs treated with JI-34. Our studies demonstrate a novel role for JI-34 to markedly improve therapeutic angiogenesis in hindlimb ischemia by increasing the viability and mobility of MSCs. These findings support additional studies to explore the full potential of GHRH agonists to augment cell therapy in the management of ischemia

Experimental Determination of the Rotational Constants of High-Lying Vibrational Levels of Ultracold Cs₂ in the 0_g^– Purely Long-Range State

We report on a quantitative experimental determination of the rotational constants for the high-lying vibrational levels of the ultracold pure long-range Cesium molecules formed via photoassociation. The scheme relies on a precise reference of frequency difference in a double photoassociation spectroscopy, which is induced by two laser beams based on an acoustic-optical modulator. The rotational constants are obtained by fitting a nonrigid rotor model into the frequency intervals of the neighboring rotational levels deduced from the reference