Engineering liquid metal-based nanozyme for enhancing microwave dynamic therapy in breast cancer PDX model.

BACKGROUNDS: The novel concept of microwave dynamic therapy (MDT) solves the problem of incomplete tumor eradication caused by non-selective heating and uneven temperature distribution of microwave thermal therapy (MWTT) in clinic, but the poor delivery of microwave sensitizer and the obstacle of tumor hypoxic microenvironment limit the effectiveness of MDT. RESULTS: Herein, we engineer a liquid metal-based nanozyme LM@ZIF@HA (LZH) with eutectic Gallium Indium (EGaIn) as the core, which is coated with CoNi-bimetallic zeolite imidazole framework (ZIF) and hyaluronic acid (HA). The flexibility of the liquid metal and the targeting of HA enable the nanozyme to be effectively endocytosed by tumor cells, solving the problem of poor delivery of microwave sensitizers. Due to the catalase-like activity, the nanozyme catalyze excess H2O2 in the tumor microenvironment to generate O2, alleviating the restriction of the tumor hypoxic microenvironment and promoting the production of ROS under microwave irradiation. In vitro cell experiments, the nanozyme has remarkable targeting effect, oxygen production capacity, and microwave dynamic effect, which effectively solves the defects of MDT. In the constructed patient-derived xenograft (PDX) model, the nanozyme achieves excellent MDT effect, despite the heterogeneity and complexity of the tumor model that is similar to the histological and pathological features of the patient. The tumor volume in the LZH + MW group is only about 1/20 of that in the control group, and the tumor inhibition rate is as high as 95%. CONCLUSION: The synthesized nanozyme effectively solves the defects of MDT, improves the targeted delivery of microwave sensitizers while regulating the hypoxic microenvironment of tumors, and achieves excellent MDT effect in the constructed PDX model, providing a new strategy for clinical cancer treatment.

Comparative Analysis of the Wood Metabolites of Three Poplar Clones Using UPLC-Triple-TOF-MS.

Poplar, a woody tree species, is widely used for industrial production and as a protective forest belt. Different clones of poplar exhibit clear variation in terms of morphological and physiological features, however, the impact of the genetic variation on the composition and abundance of wood metabolite have not been fully determined. In this study, ultra-high pressure liquid chromatography-triple time of flight-mass spectrometer (UPLC-Triple-TOF-MS) was used to explore the metabolite changes in poplar wood from three clones, including Populus deltoides CL. '55/65', P. deltoides CL. 'Danhong', and P. nigra CL. 'N179'. A total of 699 metabolites were identified. Clustering analysis and principal component analysis display that the metabolic differences of wood have allowed distinguishing different species of poplar. Meanwhile, eight significantly different metabolites were screened between P. deltoides and P. nigra, which may be considered as valuable markers for chemotaxonomy. In addition, the highly discriminant 352 metabolites were obtained among the three clones, and those may be closely related to the distinction in unique properties (e.g., growth, rigidity and tolerance) of the poplar wood cultivars. This study provides a foundation for further studies on wood metabolomics in poplar, and offers chemotaxonomic markers that will stimulate the early screening of potentially superior trees.

Recombinant human erythropoietin upregulates PPARγ through the PI3K/Akt pathway to protect neurons in rats subjected to oxidative stress.

In vitro cell experiments have suggested that recombinant human erythropoietin (rhEPO) and peroxisome proliferator activated receptor γ (PPARγ) activation exert protective effects on neurons. This study observed the learning and memory ability, antioxidant capacity and the ratio of apoptotic cells after rhEPO intervention and investigated the relationship among rhEPO, PI3K/Akt and PPARγ in the anti-neural oxidative stress injury process in vivo. The results showed that rhEPO significantly improved the learning and memory abilities of rats subjected to oxidative stress, enhanced the antioxidant capacity of cells, and reduced neuronal apoptosis. Then, the PI3K/Akt and PPARγ pathways were inhibited, and TUNEL staining were used to observe the changes in the effect of rhEPO. After the PI3K/Akt and PPARγ pathways were inhibited, the effect of rhEPO on rats subjected to oxidative stress was significantly weakened, suggesting that both the PI3K/Akt and PPARγ pathways are involved in the process by which rhEPO protects neurons. Finally, Western blotting and immunofluorescence staining were used to observe the changes in PI3K/Akt and PPARγ signalling proteins in the neurons after the rhEPO intervention and to explore the relationship among the three. The results showed that rhEPO significantly increased the levels of the p-Akt and PPARγ proteins and the level of the PPARγ protein in the nucleus, indicating that the PI3K/Akt pathway was located upstream of and regulates PPARγ. In conclusion, this study suggested that rhEPO activates the PI3K/Akt to upregulate PPARγ, enhance the cellular antioxidant capacity, and protect neurons in rats subjected to oxidative stress.

Analysis of terpenoid biosynthesis pathways in German chamomile (Matricaria recutita) and Roman chamomile (Chamaemelum nobile) based on co-expression networks.

German chamomile and Roman chamomile are the two most widely known chamomile species due to the medicinal properties of volatile compounds from their flowers. We determined the volatile compound content of different organs of these two chamomiles, and found that main volatile compounds in German chamomile were terpenoids and those in Roman chamomile were esters. Furthermore, 24 tissues from two chamomiles were sequenced and analyzed by gene co-expression network. The results showed higher terpene synthase expression levels and more modules correlated with sesquiterpenoids in German chamomile, which may explain its high sesquiterpenoid content. In both chamomiles, unigenes in volatile compound-correlated modules were significantly enriched in pathways related to plant-pathogen interactions and circadian rhythm, demonstrating that volatile compounds of chamomiles are influenced by these factors. There were ten times more unigenes related to plant-pathogen interactions in German chamomile than in Roman chamomile, which indicates German chamomile has higher resistance to pathogens.

Bone progeria diminished the therapeutic effects of bone marrow mesenchymal stem cells on retinal degeneration.

Senescence is closely related to the occurrence of retinal degeneration. Recent studies have shown that bone marrow mesenchymal stem cells (BMMSCs) have significant therapeutic effects on retinal degeneration, While BMMSCs suffer from functional decline in bone aging. Whether senescence affects BMMSCs therapy on retinal degeneration remains unknown. Here, we applied the previously established bone progeria animal model, the senescence-accelerated mice-prone 6 (SAMP6) strain, and surprisingly discovered that SAMP6 mice demonstrated retinal degeneration at 6 months old. Furthermore, BMMSCs derived from SAMP6 mice failed to prevent MNU-induced retinal degeneration in vivo. As expected, BMMSCs from SAMP6 mice exhibited impairment in the differentiation capacities, compared to those from the age-matched senescence-accelerated mice-resistant 1 (SAMR1) strain. Moreover, BMMSCs from SAMR1 mice counteracted MNU-induced retinal degeneration, with increased expression of the retina survival hallmark, N-myc downstream regulated gene 2 (NDRG2). Taken together, these findings reveal that bone progeria diminished the therapeutic effects of BMMSC on retinal degeneration.

Analyses of artificial morel soil bacterial community structure and mineral element contents in ascocarp and the cultivated soil.

This study explored the differences among various artificial morel cultivations as well as the factors that influence these differences, including soil bacterial community structure, yield, and mineral element contents of ascocarp and the cultivated soil. High-throughput sequencing results revealed that the dominant bacterial phyla in all the samples, including Proteobacteria, Acidobacteria, Chloroflexi, Bacteroides, and Gemmatimonadetes, were found not only in morel soils (experimental group) but also in wheat soil (control group); the highest richness and diversity in the soil bacteria were observed during the primordial differentiation stage. The M6 group exhibited the highest yield (271.8 g/m2) and had an unexpectedly high proportion of Pseudomonas (25.30%) during the primordial differentiation stage, which was 1.77∼194.62 times more than the proportion of Pseudomonas in other samples. Pseudomonas may influence the growth of morel. The mineral element contents of the different soil groups and the ascocarp were determined by electrothermal digestion and inductively coupled plasma mass spectrometry. The results revealed that morel had high enrichment effects on phosphorus (P, bioconcentration factor = 16.83), potassium (K, 2.18), boron (B, 1.47), zinc (Zn, 1.36), copper (Cu, 1.15), and selenium (Se, 2.27). P levels were the highest followed by Se and K, and the mineral element contents in ascocarp were positively correlated with the soil element contents.

Carboxylated multi-walled carbon nanotubes exacerbated oxidative damage in roots of Vicia faba L. seedlings under combined stress of lead and cadmium.

Multi-walled carbon nanotubes (MWCNTs) and heavy metals could be absorbed and bioaccumulated by agricultural crops, implicating ecological risks. Herein, the present study investigated the ecotoxicological effects and mechanisms of individual carboxylated MWCNTs (MWCNTs-COOH) (2.5, 5.0 and 10 mg/L) and their combination with 20 µM Pb and 5 µM Cd (shortened as Pb + Cd) on roots of Vicia faba L. seedlings after 20 days of exposure. The results showed that the tested MWCNTs-COOH induced imbalance of nutrient elements, enhanced isozymes and activities of superoxide dismutase (SOD), guaiacol peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX), resulting in accumulation of carbonylated proteins, elevation of endoproteases (EPs) isozymes, and reduction of HSP70 synthesis in the roots. However, the tested MWCNTs-COOH facilitated the enrichment of Cd, Pb and Na elements, contributing to the decrease of SOD, CAT and APX activities, and the reduction of HSP70 synthesis, whereas the elevation of carbonylated proteins, EP activities and cell necrosis in the roots when Pb + Cd was combined in comparison to the treatments of MWCNTs-COOH, or Pb + Cd alone. Thus, the tested MWCNTs-COOH not only caused oxidative stress, but also aggravated the oxidative damage in the roots exposed to Pb + Cd in the culture solution.

NDRG2 alleviates photoreceptor apoptosis by regulating the STAT3/TIMP3/MMP pathway in mice with retinal degenerative disease.

Photoreceptor apoptosis is the main pathological feature of retinal degenerative diseases; however, the underlying molecular mechanism has not been elucidated. Recent studies have shown that N-myc downstream regulated gene 2 (NDRG2) exerts a neuroprotective effect on the brain and spinal cord. In addition, our previous studies have confirmed that NDRG2 is expressed in mouse retinal photoreceptors and counteracts N-methyl-N-nitrosourea (MNU)-induced apoptosis. However, the underlying molecular mechanism remains unclear. In this study, we observed that the expression of NDRG2 was not only significantly inhibited in photoreceptors after MNU treatment but also after hydrogen peroxide treatment, and photoreceptor apoptosis was alleviated or aggravated after overexpression or knockdown of NDRG2 in the 661W photoreceptor cell line, respectively. The apoptosis inhibitor Z-VAD-FMK rescued photoreceptor apoptosis induced by MNU after NDRG2 knockdown. Next, we screened and identified tissue inhibitor of metalloproteinases 3 (TIMP3) as the downstream molecule of NDRG2 in 661W cells by using quantitative real-time polymerase chain reaction. TIMP3 exerts a neuroprotective effect by inhibiting the expression of matrix metalloproteinases (MMPs). Subsequently, we found that signal transducer and activator of transcription 3 (STAT3) mediated the NDRG2-associated regulation of TIMP3. Finally, we overexpressed NDRG2 in mouse retinal tissues by intravitreally injecting an adeno-associated virus with mouse NDRG2 in vivo. Results showed that NDRG2 upregulated the expression of phospho-STAT3 (p-STAT3) and TIMP3, while suppressing MNU-induced photoreceptor apoptosis and MMP expression. Our findings revealed how NDRG2 regulates the STAT3/TIMP3/MMP pathway and uncovered the molecular mechanism underlying its neuroprotective effect on mouse retinal photoreceptors.

Chromosome-level genome assembly and sex chromosome identification of the pink stem borer, Sesamia inferens (Lepidoptera: Noctuidae).

The pink stem borer, Sesamia inferens Walker (Lepidoptera: Noctuidae), is one of the most notorious pest insects of rice and maize crops in the world. Here, we generated a high-quality chromosome-level genome assembly of S. inferens, using a combination of Illumina, PacBio HiFi and Hi-C technologies. The total assembly size was 973.18 Mb with a contig N50 of 33.39 Mb, anchored to 31 chromosomes, revealing a karyotype of 30 + Z. The BUSCO analysis indicated a high completeness of 98.90% (n = 5286), including 5172 (97.8%) single-copy BUSCOs and 58 (1.1%) duplicated BUSCOs. The genome contains 58.59% (564.58 Mb) repeat elements and 26628 predicted protein-coding genes. The chromosome-level genome assembly of S. inferens provides in-depth knowledge and will be a helpful resource for the Lepidoptera and pest control research communities.

Deficiency of ASGR1 Alleviates Diet-Induced Systemic Insulin Resistance via Improved Hepatic Insulin Sensitivity.

Background: Insulin resistance (IR) is the key pathological basis of many metabolic disorders. Lack of asialoglycoprotein receptor 1 (ASGR1) decreased the serum lipid levels and reduced the risk of coronary artery disease. However, whether ASGR1 also participates in the regulatory network of insulin sensitivity and glucose metabolism remains unknown. Methods: The constructed ASGR1 knockout mice and ASGR1-/- HepG2 cell lines were used to establish the animal model of metabolic syndrome and the IR cell model by high-fat diet (HFD) or drug induction, respectively. Then we evaluated the glucose metabolism and insulin signaling in vivo and in vitro. Results: ASGR1 deficiency ameliorated systemic IR in mice fed with HFD, evidenced by improved insulin intolerance, serum insulin, and homeostasis model assessment of IR index, mainly contributed from increased insulin signaling in the liver, but not in muscle or adipose tissues. Meanwhile, the insulin signal transduction was significantly enhanced in ASGR1-/- HepG2 cells. By transcriptome analyses and comparison, those differentially expressed genes between ASGR1 null and wild type were enriched in the insulin signal pathway, particularly in phosphoinositide 3-kinase-AKT signaling. Notably, ASGR1 deficiency significantly reduced hepatic gluconeogenesis and glycogenolysis. Conclusion: The ASGR1 deficiency was consequentially linked with improved hepatic insulin sensitivity under metabolic stress, hepatic IR was the core factor of systemic IR, and overcoming hepatic IR significantly relieved the systemic IR. It suggests that ASGR1 is a potential intervention target for improving systemic IR in metabolic disorders.

DLM-GelMA/tumor slice sandwich structured tumor on a chip for drug efficacy testing.

The in vitro recapitulation of tumor microenvironment is of great interest to preclinical screening of drugs. Compared with culture of cell lines, tumor organ slices can better preserve the complex tumor architecture and phenotypic activity of native cells, but are limited by their exposure to fluid shear and gradual degradation under perfusion culture. Here, we established a decellularized liver matrix (DLM)-GelMA "sandwich" structure and a perfusion-based microfluidic platform to support long-term culture of tumor slices with excellent structural integrity and cell viability over 7 days. The DLM-GelMA was able to secrete cytokines and growth factors while providing shear protection to the tumor slice via the sandwich structure, leading to the preservation of the tumor microenvironment where immune cells (CD3, CD8, CD68), tumor-associated fibroblasts (α-SMA), and extracellular matrix components (collagen I, fibronectin) were well maintained. Furthermore, this chip presented anti-tumor efficacy at cisplatin (20 µM) on tumor patients, demonstrating our platform's efficacy to design patient-specific treatment regimens. Taken together, the successful development of this DLM-GelMA sandwich structure on the chip could faithfully reflect the tumor microenvironment and immune response, accelerating the screening process of drug molecules and providing insights for practical medicine.

Assessing the effectiveness of imidacloprid and thiamethoxam via root irrigation against Megalurothrips usitatus (Thysanoptera: Thripidae) and its residual effects on cowpea.

Systemic neonicotinoid insecticides (NEOs) applied by seed-treatment or root application have emerged as a prevalent strategy for early-season insect pest management. This research investigated the effectiveness of imidacloprid and thiamethoxam, administered through root irrigation, in managing thrips in cowpea [Vigna unguiculata (Linn.) Walp.], and the residual properties of both insecticides in cowpea and soil. The results show that thrips density depends on the application rate of insecticides. At the maximum application rate (1,500 µg/ml, active ingredient), imidacloprid and thiamethoxam controlled thrips densities below the economic injury level (EIL, the EIL of thrips on cowpea was 7/flower) for 20 days and 25 days with the density of 6.90 and 6.93/flower at the end of the periods, respectively. Imidacloprid and thiamethoxam residues decreased gradually over time and decreased sharply after 15 days after treatment (DAT), the 2 insecticides were not detected (<0.001 mg/kg) at 45 DAT. According to our findings, the application of imidacloprid and thiamethoxam via root irrigation proved residual control lasting up to 20-25 days for controlling thrips damage at experimental rates, with a strong association to their residual presence in cowpea (0.6223 < R2 < 0.9545). Considering the persistence of the imidacloprid and thiamethoxam, the maximum tested application rate (1,500 µg/ml) was recommended. As the residues of imidacloprid and thiamethoxam were undetectable in cowpea pods at all tested rates, it may be suggested that the use of each insecticide is safe for consumers and effective against thrips, and could be considered for integrated thrips management in the cowpea ecosystem.

A biomimetic renal fibrosis progression model on-chip evaluates anti-fibrotic effects longitudinally in a dynamic fibrogenic niche.

Although renal fibrosis can advance chronic kidney disease and progressively lead to end-stage renal failure, no effective anti-fibrotic drugs have been clinically approved. To aid drug development, we developed a biomimetic renal fibrosis progression model on-chip to evaluate anti-fibrotic effects of natural killer cell-derived extracellular vesicles and pirfenidone (PFD) across different fibrotic stages. First, the dynamic interplay between fibroblasts and kidney-derived extracellular matrix (ECM) resembling the fibrogenic niche on-chip demonstrated that myofibroblasts induced by stiff ECM in 3 days were reversed to fibroblasts by switching to soft ECM, which was within 2, but not 7 days. Second, PFD significantly down-regulated the expression of α-SMA in NRK-49F in medium ECM, as opposed to stiff ECM. Third, a study in rats showed that early administration of PFD significantly inhibited renal fibrosis in terms of the expression levels of α-SMA and YAP. Taken together, both on-chip and animal models indicate the importance of early anti-fibrotic intervention for checking the progression of renal fibrosis. Therefore, this renal fibrosis progression on-chip with a feature of recapitulating dynamic biochemical and biophysical cues can be readily used to assess anti-fibrotic candidates and to explore the tipping point when the fibrotic fate can be rescued for better medical intervention.

Hepatic DKK1-driven steatosis is CD36 dependent.

Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide; about 25% of NAFLD silently progress into steatohepatitis, in which some of them may develop into fibrosis, cirrhosis and liver failure. However, few drugs are available for NAFLD, partly because of an incomplete understanding of its pathogenic mechanisms. Here, using in vivo and in vitro gain- and loss-of-function approaches, we identified up-regulated DKK1 plays a pivotal role in high-fat diet-induced NAFLD and its progression. Mechanistic analysis reveals that DKK1 enhances the capacity of hepatocytes to uptake fatty acids through the ERK-PPARγ-CD36 axis. Moreover, DKK1 increased insulin resistance by activating the JNK signaling, which in turn exacerbates disorders of hepatic lipid metabolism. Our finding suggests that DKK1 may be a potential therapeutic and diagnosis candidate for NAFLD and metabolic disorder progression.

COVID-19-associated liver injury: Clinical characteristics, pathophysiological mechanisms and treatment management.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a global epidemic and poses a major threat to public health. In addition to COVID-19 manifesting as a respiratory disease, patients with severe disease also have complications in extrapulmonary organs, including liver damage. Abnormal liver function is relatively common in COVID-19 patients; its clinical manifestations can range from an asymptomatic elevation of liver enzymes to decompensated hepatic function, and liver injury is more prevalent in severe and critical patients. Liver injury in COVID-19 patients is a comprehensive effect mediated by multiple factors, including liver damage directly caused by SARS-CoV-2, drug-induced liver damage, hypoxia reperfusion dysfunction, immune stress and inflammatory factor storms. Patients with chronic liver disease (especially alcohol-related liver disease, nonalcoholic fatty liver disease, cirrhosis and hepatocellular carcinoma) are at increased risk of severe disease and death after infection with SARS-CoV-2, and COVID-19 aggravates liver damage in patients with chronic liver disease. This article reviews the latest SARS-CoV-2 reports, focusing on the liver damage caused by COVID-19 and the underlying mechanism, and expounds on the risk, treatment and vaccine safety of SARS-CoV-2 in patients with chronic liver disease and liver transplantation.

rhEPO Upregulates the PPARγ Pathway in Long-term Cultured Primary Nerve Cells via PI3K/Akt to Delay Cell Senescence.

Previous studies have confirmed that both recombinant human erythropoietin (rhEPO) and peroxisome proliferator-activated receptors γ (PPARγ) activator pioglitazone can protect senescent nerve cells, and their mechanisms involve enhancing cell antioxidant capacity and reducing cell apoptosis. However, whether the PPARγ pathway is involved in the rhEPO anti-aging process in neuronal cells is still unclear. In this study, to explore the relationship between rhEPO and the PPARγ pathway at the cellular level, primary nerve cells cultured for 22 days were used to simulate the natural aging process of nerve cells. Starting on the 11th day of culture, rhEPO, LY294002, and GW9662 were added for treatment. Immunochemical methods and SA-ß-gal staining were used to observe the changes in cellular antioxidant capacity and the fraction of senescent cells. The results showed that PPARγ blockade retarded the effect of rhEPO on the cellular antioxidant capacity and altered the fraction of senescent cells. It was confirmed that PPARγ was involved in rhEPO's anti-aging process in neuronal cells. Real-time fluorescent quantitative RT-PCR, Western blotting, and immunofluorescence staining were used to observe the changes in PPARγ pathway-related factors in nerve cells after rhEPO treatment. The results showed that rhEPO significantly upregulated the expression of PPARγ coactivator-1α (PGC-1α), PPARγ, and nuclear PPARγ in cells but did not affect the level of phosphorylated PPARγ protein, confirming that rhEPO has the ability to upregulate the PPARγ pathway. PI3K/Akt and PPARγ pathway blockade experiments were used to explore the relationships among rhEPO, PI3K/Akt, and PPARγ. The results showed that after PPARγ blockade, rhEPO had no significant effect on the PI3K/Akt pathway-related factor p-Akt, while after PI3K/Akt blockade, rhEPO's effects on PPARγ-related factors (PGC-1α, PPARγ, and nuclear PPARγ) were significantly decreased. It is suggested that rhEPO delays the PI3K/Akt pathway in the process of neuronal senescence, which is located upstream of PPARγ regulation. In conclusion, this study confirmed that rhEPO can upregulate the expression of PGC-1α and PPARγ in cells and the level of PPARγ protein in the nucleus to enhance the antioxidant capacity of cells and delay the senescence of nerve cells through the PI3K/Akt pathway. These findings will provide ideas for finding new targets for neuroprotection research and will also provide a theoretical basis and experimental evidence for rhEPO anti-aging research in neural cells.

Recombinant human erythropoietin protects long-term cultured ageing primary nerve cells by upregulating the PI3K/Akt pathway.

OBJECTIVE: Previous studies have found that recombinant human erythropoietin (rhEPO) protects long-term cultured ageing primary nerve cells by enhancing the endogenous antioxidant capacity of cells; however, its signalling pathways are not clear. This study aimed to explore the relationship between the rhEPO and PI3K/Akt pathways in the protection of senescent nerve cells at the cellular level. METHODS: Primary nerve cells were cultured for 22 days to mimic the natural ageing process of nerve cells. rhEPO and LY294002 were administered as an intervention on the 11th day of culture. Western blot, immunochemistry, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide, immunofluorescence double-labelling staining, Annexin V-FITC/PI double-labelling flow cytometry, and SA-ß-gal staining experiments were used to observe the expression levels of erythropoietin receptor (EPOR) and phosphorylated Akt (p-Akt) protein and the related indices of nerve cell senescence. RESULTS: Western blot experiments showed that in ageing long-term cultured primary neurons, the EPOR and p-Akt decreased and rhEPO upregulated the expression levels of EPOR and p-Akt protein. The rest showed that the PI3K/Akt pathway blockade reduced the antioxidation capacity, cell viability, cell morphology, and ratio of apoptotic cells and senescent cells of rhEPO on ageing long-term cultured primary nerve cells. CONCLUSIONS: This study explored the relationship between the rhEPO and PI3K/Akt pathways in the protection of ageing nerve cells at the cellular level and found that rhEPO protects long-term cultured ageing primary nerve cells by upregulating the PI3K/Akt pathway. These findings provide a theoretical basis and experimental evidence for the antiaeging mechanism of EPO in the nervous system.

Sympathetic Neurostress Drives Osteoblastic Exosomal MiR-21 Transfer to Disrupt Bone Homeostasis and Promote Osteopenia.

Innervation and extracellular vesicle secretion co-exist in the local tissue microenvironment for message transfer, but whether they are interconnected to regulate organ homeostasis remains unknown. Sympatho-adrenergic activation is implicated in stress-induced depression and leads to bone loss, but the mechanisms and therapeutics are incompletely elucidated. Here, it is revealed that sympathetic neurostress through the ß1/2 -adrenergic receptor (ß1/2-AR) signaling triggers the transcription response of a microRNA, miR-21, in osteoblasts, which is transferred to osteoclast progenitors via exosomes for dictating osteoclastogenesis. After confirming that miR-21 deficiency retards the ß1/2-AR agonist isoproterenol (ISO)-induced osteopenia, it is shown that the pharmacological inhibition of exosome release by two clinically-relevant drugs, dimethyl amiloride and omeprazole, suppresses osteoblastic miR-21 transfer and ameliorates bone loss under both ISO and chronic variable stress (CVS)-induced depression conditions. A targeted delivery approach to specifically silence osteoblastic miR-21 is further applied, which is effective in rescuing the bone remodeling balance and ameliorating ISO- and CVS-induced osteopenias. These results decipher a previously unrecognized paradigm that neural cues drive exosomal microRNA communication to regulate organ homeostasis and help to establish feasible strategies to counteract bone loss under psychological stresses.

17ß-Oestradiol Attenuates the Photoreceptor Apoptosis in Mice with Retinitis Pigmentosa by Regulating N-myc Downstream Regulated Gene 2 Expression.

Retinitis pigmentosa (RP) is a heterogeneous group of retinal degenerative diseases in which the final pathological feature is photoreceptor cell apoptosis. Currently, the pathogenesis of RP remains poorly understood and therapeutics are ineffective. 17ß-Oestradiol (ßE2) is universally acknowledged as a neuroprotective factor in neurodegenerative diseases and has manifested neuroprotective effects in a light-induced retinal degeneration model. Recently, we identified N-myc downstream regulated gene 2 (NDRG2) suppression as a molecular marker of mouse retinal photoreceptor-specific cell death. ßE2 has also been reported to regulate NDRG2 in salivary acinar cells. Therefore, in this study, we investigated whether ßE2 plays a protective role in RP and regulates NDRG2 in photoreceptor cells. To this end, we generated RP models and observed that ßE2 not only reduced the apoptosis of photoreceptor cells, but also restored the level of NDRG2 expression in RP models. Then, we showed that siNDRG2 inhibits the anti-apoptotic effect of ßE2 on photoreceptor cells in a cellular RP model. Subsequently, we used a classic oestrogen receptor (ER) antagonist to attenuate the effects of ßE2, suggesting that ßE2 exerted its effects on RP models via the classic ERs. In addition, we performed a bioinformatics analysis, and the results indicated that the reported oestrogen response element (ERE) sequence is present in the promoter region of the mouse NDRG2 gene. Overall, our results suggest that ßE2 attenuated the apoptosis of photoreceptor cells in RP models by maintaining NDRG2 expression via a classic ER-mediated mechanism.

Icaritin ameliorates hepatic steatosis via promoting fatty acid ß-oxidation and insulin sensitivity.

AIM: This study aimed to reveal the effects of icaritin (ICT) on lipotoxicity induced by palmitate (PA) in hepatic cells and steatosis in high-fat diet (HFD)-fed mice as well as exploring the potential mechanisms. MAIN METHODS: Primary mouse hepatocytes and human hepatoma Huh7 cells were used to evaluate ICT effect in vitro. HFD-fed mice were used to evaluate the ICT effect in vivo. RESULTS: In vitro study indicated that ICT significantly rescued PA-induced steatosis, mainly through a combination of robust increased mitochondrial respiration, fatty acid oxidation and mildly decreased synthesis of fatty acid. An HFD-fed mouse model with 8 weeks HFD-fed showed metabolic disorders, while ICT application significantly reduced the weight, serum glucose levels, insulin resistance, hepatic steatosis level and adipose contents. In consistent with the observations in cell lines, ICT rescued the HFD-impaired functions and contents of key factors related to fatty acid ß-oxidation through elevated expression of peroxisome proliferator-activated receptor α (PPARα). Meanwhile, it also reversed the decreased phosphoryl levels of AKT and glucogen synthase kinase 3 (GSK3ß), leading to the improvement of insulin resistance. SIGNIFICANCE: ICT administration had a therapeutic effect on PA- or HFD-induced hepatic steatosis and metabolic disorders. It may provide a novel strategy to construct preventive and therapeutic means for hepatic steatosis.