Natural killer cells immunosenescence and the impact of lifestyle management.

Natural killer cells (NKs) are lymphocytes of the innate immune system that quickly respond to viruses, infections, and tumors during their short cell life cycle. However, it was recently found that NKs undergo quantitative, distributional, structural, and functional phenotypic changes during aging that suppress immune responses, which is known as immunosenescence. The aging host environment, cytokine regulation, cytomegalovirus status, and hypothalamic‒pituitary‒adrenal axis have significant effects on NK function. Different lifestyle management interventions modulate the number and cytotoxic activity of NKs, which are essential for rebuilding the immune barrier against pathogens in elderly individuals. Based on recent studies, we review the phenotypic changes of and potential threats of NKs during aging and explore the underlying mechanisms. By summarizing the effects of lifestyle management on NKs and their application prospects, we aim to provide evidence for enhancing immune system function against immune diseases in elderly individuals.

The role of integrin family in bone metabolism and tumor bone metastasis.

Integrins have been the research focus of cell-extracellular matrix adhesion (ECM) and cytokine receptor signal transduction. They are involved in the regulation of bone metabolism of bone precursor cells, mesenchymal stem cells (MSCs), osteoblasts (OBs), osteoclasts (OCs), and osteocytes. Recent studies expanded and updated the role of integrin in bone metabolism, and a large number of novel cytokines were found to activate bone metabolism pathways through interaction with integrin receptors. Integrins act as transducers that mediate the regulation of bone-related cells by mechanical stress, fluid shear stress (FSS), microgravity, hypergravity, extracellular pressure, and a variety of physical factors. Integrins mediate bone metastasis of breast, prostate, and lung cancer by promoting cancer cell adhesion, migration, and survival. Integrin-mediated targeted therapy showed promising prospects in bone metabolic diseases. This review emphasizes the latest research results of integrins in bone metabolism and bone metastasis and provides a vision for treatment strategies.

Effects of follicle-stimulating hormone on fat metabolism and cognitive impairment in women during menopause.

Lipid metabolism disorder is a common pathological manifestation of menopausal women, and is also an important risk factor for many diseases at this stage of life. Epidemiological studies have shown that high levels of follicle-stimulating hormone (FSH) in menopausal women are closely associated with changes in body composition, central obesity, and cognitive decline. Exogenous FSH causes growth and proliferation of adipose, whereas blockage of the FSH signaling pathway leads to decline in adipose. Mechanistically, FSH, FSH receptor (FSHR), G protein coupling, gene mutation and other pathways are involved in adipogenesis and cognitive impairment. Here, we review the critical role and potential interactions of FSH in adipogenesis and cognitive impairment in menopausal women. Further understanding of the exact mechanisms of FSH aggravating obesity and cognitive impairment may provide a new perspective for promoting healthy aging in menopausal women.

Biological Mechanism on SIRT1/NLRP3/IL-18 Signaling Pathway of Acupuncture for Treatment of Ischemic Stroke with Center Poststroke Pain.

Objective: To evaluate the effect of acupuncture on an animal model of ischemic stroke with central poststroke pain (CPSP) through Sirtuin 1 (SIRT1)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/interleukin-18 (IL-18) signaling pathway. Methods: Data mining was performed with R package "edgeR," "limma," "pathview," etc., from NCBI Gene Expression Omnibus (GEO) database. Sprague Dawley (SD) rats were divided into 4 groups: sham operation group (Sham group, n = 5), poststroke central pain group (CPSP group, n = 5), poststroke central pain + acupuncture group (AP group, n = 5), central pain after stroke + acupuncture + SIRT1 inhibitor EX527 group (EX527 group, n = 5). Pain behavior testing was performed to determine the mechanical withdrawal threshold (MWT). Quantitative real-time PCR (qRT-PCR) was performed to verify the data mining results from the GEO database. Results: The KEGG key pathway map was created using the R package "pathview" package, demonstrating that the expression levels of NLRP3's downstream inflammatory factors IL-18 were downregulated in both of siSIRT1 group compared to the control group and the NLRP3 reconstituted group compared to NLRP3 KO group. QRT-PCR results on animal models of CPSP ischemic stroke showed that the expression levels of SIRT1 were downregulated, the activation of the NLRP3 inflammasome was upregulated, and the expression levels of IL-18 were upregulated in the brain tissues of the surrounding area of the injury. As the pain threshold of CPSP rats was increased, the expression level of S1RT1 was upregulated, and the activation of NLRP3 inflammasome was downregulated. The expression level of IL-18 was downregulated after acupuncture treatment. Conclusion: Acupuncture may inhibit CPSP in an animal model of ischemic stroke by upregulating SIRT1 expression levels, inhibition of the activation of the inflammasome, and downregulating IL-18 expression levels.

Osteopontin - The stirring multifunctional regulatory factor in multisystem aging.

Osteopontin (OPN) is a multifunctional noncollagenous matrix phosphoprotein that is expressed both intracellularly and extracellularly in various tissues. As a growth regulatory protein and proinflammatory immunochemokine, OPN is involved in the pathological processes of many diseases. Recent studies have found that OPN is widely involved in the aging processes of multiple organs and tissues, such as T-cell senescence, atherosclerosis, skeletal muscle regeneration, osteoporosis, neurodegenerative changes, hematopoietic stem cell reconstruction, and retinal aging. However, the regulatory roles and mechanisms of OPN in the aging process of different tissues are not uniform, and OPN even has diverse roles in different developmental stages of the same tissue, generating uncertainty for the future study and utilization of OPN. In this review, we will summarize the regulatory role and molecular mechanism of OPN in different tissues and cells, such as the musculoskeletal system, central nervous system, cardiovascular system, liver, and eye, during senescence. We believe that a better understanding of the mechanism of OPN in the aging process will help us develop targeted and comprehensive therapeutic strategies to fight the spread of age-related diseases.

Targeted treatment for osteoarthritis: drugs and delivery system.

The management of osteoarthritis (OA) is a clinical challenge due to the particular avascular, dense, and occluded tissue structure. Despite numerous clinical reports and animal studies, the pathogenesis and progression of OA are still not fully understood. On the basis of traditional drugs, a large number of new drugs have been continuously developed. Intra-articular (IA) administration for OA hastens the development of targeted drug delivery systems (DDS). OA drugs modification and the synthesis of bioadaptive carriers contribute to a qualitative leap in the efficacy of IA treatment. Nanoparticles (NPs) are demonstrated credible improvement of drug penetration and retention in OA. Targeted nanomaterial delivery systems show the prominent biocompatibility and drug loading-release ability. This article reviews different drugs and nanomaterial delivery systems for IA treatment of OA, in an attempt to resolve the inconsonance between in vitro and in vivo release, and explore more interactions between drugs and nanocarriers, so as to open up new horizons for the treatment of OA.

System integration of hydrothermal liquefaction and anaerobic digestion for wet biomass valorization: Biodegradability and microbial syntrophy.

Sewage sludge treatment & disposal pose environmental challenges in populated-dense urban environments. Due to its poor digestibility and dewaterability, sewage sludge contains high water content and concentrated nutrients (carbon, nitrogen, and phosphorus) even after conditioning and mechanical thickening. Regarding this, a pretreatment step and downstream anaerobic digestion (AD) are often required. To meet our societal goal towards a circular economy, system integration of hydrothermal pretreatment and AD now present an attractive approach for recovering resources from the wet sewage sludge biomass. In this study, such system integration together with struvite precipitation was applied for valorizing sewage sludge. Firstly, hydrothermal conditions of different temperatures (160 °C-230 °C) and duration (2 h-12 h) were compared to their performance of nutrients solubilization. Subsequently, the hydrothermal condition of 220°C-3 h was selected for further investigations of struvite recovery and bioenergy production. Through AD comparisons, the integrated process improved the ultimate biomethane yield by 38%. Interestingly, a lag phase occurred in the midst of the AD, which indicated the need for microbial acclimatization after the hydrothermal process. The long-term microbial monitoring revealed the efficient biomethane re-generation was closely related to the late enrichment of Syntrophus for potential H2-syntrophy. Therefore, on one hand, this study investigated an efficient and integrated approach of sewage sludge valorization. On other hand, it uncovered the microbial bottlenecks and potential biotechnological means for further system improvement. Further research about nutrients speciation in the integrated system would be desired.

The effects of biophysical stimulation on osteogenic differentiation and the mechanisms from ncRNAs.

Ample proof showed that non-coding RNAs (ncRNAs) play a crucial role in proliferation and differentiation of osteoblasts and bone marrow stromal cells (BMSCs). Varied forms of biophysical stimuli like mechanical strain, fluid shear stress (FSS), microgravity and vibration are verified to regulate ncRNAs expression in osteogenic differentiation and influence the expression of target genes associated with osteogenic differentiation and ultimately regulate bone formation. The consequences of biophysical stimulation on osteogenic differentiation validate the prospect of exercise for the prevention and treatment of osteoporosis. In this review, we tend to summarize the studies on regulation of osteogenic differentiation by ncRNAs beneath biophysical stimulation and facilitate to reveal the regulatory mechanism of biophysical stimulation on ncRNAs, and provide an update for the prevention of bone metabolism diseases by exercise.

Mixing effects on decentralized high-solid digester for horticultural waste: Startup, operation and sensitive microorganisms.

This work studied the use of a horizontal high-solid digester for the decentralized anaerobic treatment of horticultural waste (fallen leaves), where the effect of intermittent mixing by a modified double helical ribbon impeller was investigated. Before experimental verification, the flow pattern and theoretical mixing time were first characterized by CFD simulation. Subsequently, three mixing time intervals (i.e., 3 min/3 hr; 18 min/3 hr; 108 min/3 hr) and one control setup (i.e., without mixing) were compared for their performance during start-up and semi-continuous operation. It was found that minimal mixing was necessary for an efficient digester's start-up but increased mixing intensity for semi-continuous operation. The results were further interpreted by correlating the digester performance and microbial communities. Those microorganisms sensitive to increased mixing intensity were highlighted and analysed.

Circular RNAs in childhood-related diseases and cancers: A review.

Research into the diagnosis, treatment and prevention of childhood-related diseases is the key to reducing their morbidity and mortality. Circular RNAs (circRNAs) play critical roles, both in physiology and pathology, and there is ample evidence to show that they play varying roles in tissue development and gene regulation. Studies on circRNAs in different childhood-related diseases have confirmed their great potential for disease prevention and treatment. These breakthroughs highlight the pathological role of circRNAs in cancers, as well as cardiovascular and hereditary childhood illnesses. In this review, we summarize the role of circRNAs in childhood-related diseases and cancer, and provide an update of the possible diagnostic and therapeutic application of circRNAs.

Mixing strategies - Activated carbon nexus: Rapid start-up of thermophilic anaerobic digestion with the mesophilic anaerobic sludge as inoculum.

This study evaluated the mixing - activate carbon nexus in anaerobic digestion with the aim of accelerating start-up of thermophilic anaerobic co-digestion of food waste and chicken manure using mesophilic anaerobic sludge as inoculum. Results showed that the methane yield in the continuous stirred reactor is 71.3% higher than that of intermittent agitated reactor, and the addition of activated carbon can further improve the yield of methane by 18.2%. Continuous mixing mode followed by intermittent mixing was proved to be an alternative strategy to accelerate start-up of thermophilic anaerobic digestion. The optimum mixing time of 120 s/hour were obtained using computational fluid dynamics modeling. Analysis of genomic annotation metabolism indicated that the addition of activated carbon enhanced the dominant metabolism pathways of amino acid, methane and energy. Results of enzymes gene expression suggested that carbohydrates esterases, glycoside hydrolases and glycosyl transferases were dominant, respectively.

Effects of mixing time on methane production from anaerobic co-digestion of food waste and chicken manure: Experimental studies and CFD analysis.

The relationship between mixing time and methane production was investigated by anaerobically co-digesting food waste (FW) and chicken manure (CM) at four different organic loading rates. The mixing pattern and turbulence intensity obtained from CFD were adopted to evaluate the mixing performance in digesters with different viscosities. The simulated mixing time from CFD was selected as a reference for the first time to analyze the methane yield. The results showed that if the digester was well mixed under intermittent mixing mode with relatively short mixing time, then extending mixing time or changing intermittent mixing to continuous mixing would have no substantial effects on methane production. By contrast, continuously mixed digesters performed better when the intermittent mixing modes cannot make the digester get to a high degree of uniformity. Hence, the simulated mixing time from CFD can be used as a reference to determine the experimental mixing time in different cases.

Three-stage anaerobic co-digestion of food waste and waste activated sludge: Identifying bacterial and methanogenic archaeal communities and their correlations with performance parameters.

A three-stage anaerobic digester setup was configured and evaluated for enhanced methane production during co-digestion of food waste and waste activated sludge and the corresponding bacterial and methanogen communities were characterized. Results showed that the average methane yield (0.496 L/gVS) in the three-stage digester was 13-52% higher than that of one- and two-stage digesters. Compared to controls, an increase of 12-47% in volatile solids reduction was achieved in the three-stage digester (69.3 ±â€¯6.7%). Bacterial phyla Proteobacteria, Firmicutes and Bacteroidetes dominated in one-, two- and three-stage digester while genera Pseudomonas, Tissierella, and Petrimonas were selectively enriched in the three-stage digester due to functional segregation. Taxonomic analysis identified 8 dominant methanogen genera, of which Methanosarcina, Methanosaeta, Methanobacterium and Methanolinea collectively accounted for 80%. With increasing OLR and digester stage number, the dominant methanogenic pathway shifted from hydrogenotrophic pattern to acetoclastic pattern and reached a final synergy of these two.

Long non-coding RNA NIFK-AS1 inhibits M2 polarization of macrophages in endometrial cancer through targeting miR-146a.

Accumulating evidence suggested that tumor-associated macrophages played crucial roles in the progression of endometrial cancer. The aim of this study was to determine the role of lncRNA NIFK-AS1 in M2-like polarization of macrophages and further to investigate the effect of NIFK-AS1 modulating macrophage polarization on the proliferation, migration and invasion of endometrial cancer cells. Human peripheral blood mononuclear cells and tumor-associated macrophages were isolated from healthy volunteers and endometrial cancer patients, respectively. The expression of NIFK-AS1 and miR-146a were detected by qRT-PCR in tumor-associated macrophages or THP-1 monocytes differentiated macrophages. The expression of NIFK-AS1 and miR-146a were decreased and increased in tumor-associated macrophages of endometrial cancer patients, respectively. NIFK-AS1 overexpression suppressed the IL-4-induced M2 polarization of THP-1 macrophages. Moreover, we found that NIFK-AS1 overexpression inhibited the 17ß-estradiol-induced proliferation, migration and invasion of endometrial cancer cells through suppressing M2-like polarization of macrophages. NIFK-AS1 could interact with miR-146a and increased the expression of Notch1 through downregulating miR-146a. Further experiments revealed that miR-146a overexpression attenuated the effect of NIFK-AS1 on suppressing the M2 polarization of macrophages and the estrogen-induced proliferation, migration and invasion of endometrial cancer cells. These findings indicated that NIFK-AS1 inhibited the M2-like polarization of macrophages via targeting miR-146a, thereby reducing the estrogen-induced proliferation, migration and invasion of endometrial cancer cells. Our study highlights the important role of NIFK-AS1 in regulating the polarization and function of tumor-associated macrophages in endometrial cancer and provides novel insight into the TAMs-mediated progression of endometrial cancer.

Long noncoding RNA HOTAIR mediates the estrogen-induced metastasis of endometrial cancer cells via the miR-646/NPM1 axis.

LncRNA homeobox (HOX) transcript antisense intergenic RNA (HOTAIR) has been confirmed to be involved in the tumorigenic progression of endometrial carcinoma (EC). However, the molecular mechanisms of HOTAIR in EC are not fully elucidated. The expression of HOTAIR and miR-646 in human EC tissues was determined by qRT-PCR. The effect of miR-646 on EC cells was assessed by the cell viability, migration, and invasion using CCK-8 assays and transwell assays. RNA-binding protein immunoprecipitation assays and RNA pull-down assays were performed to explore the interaction between HOTAIR and miR-646. The regulation of miR-646 on nucleophosmin 1 (NPM1) was tested using luciferase reporter assays. MiR-646 expression was significantly decreased both in human EC tissues ( n = 23) and cell lines (Ishikawa and HEC-1-A) compared with the control. Moreover, miR-646 expression was negatively related to HOTAIR in human EC tissues ( n = 23). Our results also showed that miR-646 overexpression considerably attenuated the E2-promoted viability, migration, and invasion of Ishikawa and HEC-1-A cells in vitro. In addition, HOTAIR was confirmed to regulate the viability, migration, and invasion of EC cells through negative regulating miR-646. More importantly, we also demonstrated that NPM1 was the target of miR-646, and HOTAIR promoted NPM1 expression through interacting with miR-646 in EC cells. Taken together, our findings presented that HOTAIR could regulate NPM1 via interacting with miR-646, thereby governing the viability, migration, and invasion of EC cells.

Metagenomic insight into the microbial networks and metabolic mechanism in anaerobic digesters for food waste by incorporating activated carbon.

Powdered activated carbon (AC) is commonly used as an effective additive to enhance anaerobic digestion (AD), but little is known about how the metabolic pathways resulting from adding AC change the microbial association network and enhance food waste treatment. In this work, the use of AC in an anaerobic digestion system for food waste was explored. Using bioinformatics analysis, taxonomic trees and the KEGG pathway analysis, changes in microbial network and biometabolic pathways were tracked. The overall effect of these changes were used to explain and validate improved digestion performance. The results showed that AC accelerated the decomposition of edible oil in food waste, enhancing the conversion of food waste to methane with the optimized dosage of 12 g AC per reactor. Specifically, when AC was added, the proponoate metabolic pathway that converts propanoic acid to acetic acid became more prominent, as measured by 16S rRNA in the microbial community. The other two metabolic pathways, Lipid Metabolism and Methane Metabolism, were also enhanced. Bioinformatics analysis revealed that AC promoted the proliferation of syntrophic microorganisms such as Methanosaeta and Geobacter, forming a highly intensive syntrophic microbial network.

Dual roles of IL-22 at ischemia-reperfusion injury and acute rejection stages of rat allograft liver transplantation.

Interleukin-22 (IL-22) is a recently identified regulator of inflammation, but little is known about its role in liver transplantation. Therefore, in this study, we explored the roles and the underlying mechanisms of IL-22 in acute allograft rejection by using a rat allogeneic liver transplantation model. Results showed that allograft liver transplantation led to damage of the parent liver and to significantly increased IL-22 expression in the allograft liver and plasma of the recipient rats compared with the rats who received isografts. Moreover, the significantly increased IL-22 expression was accompanied by markedly increased level of phospho-STAT3 in the allogeneic liver tissues after transplantation. Of note, neutralization of the IL-22 protein in recipient rats significantly worsened the function of the allograft liver at 1 day post-transplantation (ischemia-reperfusion injury, IRI) but improved the function at 7 days post-transplantation (acute rejection, AR). At IRI stage, IL-22 protected liver function through the increase of anti-apoptosis and pro-regeneration cytokines. However, IL-22 led to the increase of pro-inflammation factors at AR stage, accompanied by the marked increase of the Th17 and the marked decrease of Treg cells in allograft recipient rats through modulating the expression of chemokines for different cell types, which however were reversed by in vivo IL-22 neutralization. Results indicate the dual roles of IL-22 and suggest the differential potential clinical application of IL-22 at different stage of allograft liver transplantation.

Rare pulmonary primitive neuroectodermal tumor metastasizing to the right atrium: a case report.

A 28-year-old man complained of intermittent irritable dry cough for 2 months with occasional bloody sputum. Positron emission tomography-computed tomography (PET-CT) suggested multiple heterogeneous soft tissue masses in the inferior lobes of both lungs, with heterogeneous increases in 18F-FDG uptake. No metabolic disorders were found in the rest of the body. CT-guided percutaneous lung puncture and biopsy and immunohistochemical study confirmed pulmonary primitive neuroectodermal tumor (PNET). PNET is characterized by small round blue cells and positive CD99 expression. After six cycles of chemotherapy with ifosfamide, dacarbazine and cisplatin, the lesions diminished substantially. At 2 months after the last cycle of chemotherapy, the patient complained of exertional dyspnea. PET-CT and echocardiogram suggested a space-occupying lesion in the right atrium. Autopsy revealed that this space-occupying lesion had the same pathomorphology and immunophenotype with pulmonary PNET, suggesting metastasis of pulmonary PNET to the right atrium. Here, we reported this rare case of pulmonary PNET metastasizing, instead of direct infiltrating or extending, into the heart.

Tumor-targeted inhibition by a novel strategy - mimoretrovirus expressing siRNA targeting the Pokemon gene.

Pokemon gene has crucial but versatile functions in cell differentiation, proliferation and tumorigenesis. It is a master regulator of the ARF-HDM2-p53 and Rb-E2F pathways. The facts that the expression of Pokemon is essential for tumor formation and many kinds of tumors over-express the Pokemon gene make it an attractive target for therapeutic intervention for cancer treatment. In this study, we used an RNAi strategy to silence the Pokemon gene in a cervical cancer model. To address the issues involving tumor specific delivery and durable expression of siRNA, we applied the Arg-Gly-Asp (RGD) peptide ligand and polylysine (K(18)) fusion peptide to encapsulate a recombinant retrovirus plasmid expressing a siRNA targeting the Pokemon gene and produced the 'mimoretrovirus'. At charge ratio 2.0 of fusion peptide/plasmid, the mimoretrovirus formed stable and homogenous nanoparticles, and provided complete DNase I protection and complete gel retardation. This nanoparticle inhibited SiHa cell proliferation and invasion, while it promoted SiHa cell apoptosis. The binding of the nanoparticle to SiHa cells was mediated via the RGD-integrin α(v)ß(3) interaction, as evidenced by the finding that unconjugated RGD peptide inhibited this binding significantly. This tumor-targeting mimoretrovirus exhibited excellent anti-tumor capacity in vivo in a nude mouse model. Moreover, the mimoretrovirus inhibited tumor growth with a much higher efficiency than recombinant retrovirus expressing siRNA or the K(18)/P4 nanoparticle lacking the RGD peptide. Results suggest that the RNAi/RGD-based mimoretrovirus developed in this study represents a novel anti-tumor strategy that may be applicable to most research involving cancer therapy and, thus, has promising potential as a cervical cancer treatment.

Heat shock protein 110 improves the antitumor effects of the cytotoxic T lymphocyte epitope E7(49-57) in mice.

Several strategies have been used to enhance the vaccine-induced immunity of peptide vaccines and effective therapeutic benefits, including the utilization of heat shock proteins (HSP), especially the HSP70 family. HSP110 exhibits a higher binding affinity with protein and is capable of enhancing the immunogenicity of protein antigens; however, whether HSP110 can also increase the efficiency of peptide vaccine remains unclear. Here, we investigated mHSP110 as a chaperone immunoadjuvant to enhance the immune response to HPV16 oncoprotein E7-derived CTL epitope E7(49-57) in a mouse model. We developed the HSP110-E7(49-57) complex and demonstrated that mHSP110 could form complexes with peptide E7(49-57) using FITC-labeled E7(49-57) as the tracer. Inoculation of the mHSP110-E7(49-57) complex was capable of priming strong epitope-specific immune response as determined by its ability to elicit an epitope-specific splenocytes proliferation and a cytotoxic T cell response, and IFNgamma production in splenocytes. Results also showed that immunization with the mHSP110-E7(49-57) complex completely protected mice against subsequent challenge with tumor cells. More importantly, immunization of this complex also significantly inhibited the growth of established tumors and prolonged the survival time of the tumor-bearing animals. Thus, mHSP110-E7(49-57) complex vaccine represents a potentially powerful approach for use in the immunotherapy of cervical cancer associated with HPV16 infection. More importantly, the multi-epitopes derived from E7 and other E proteins can be applied to the strategy described in this study to form a multi-antigenic vaccine to induce an improved antitumor immune response to cervical cancer in the future.