Biomarkers of Cellular Senescence and Aging: Current State-of-the-Art, Challenges and Future Perspectives.

Population aging has increased the global prevalence of aging-related diseases, including cancer, sarcopenia, neurological disease, arthritis, and heart disease. Understanding aging, a fundamental biological process, has led to breakthroughs in several fields. Cellular senescence, evinced by flattened cell bodies, vacuole formation, and cytoplasmic granules, ubiquitously plays crucial roles in tissue remodeling, embryogenesis, and wound repair as well as in cancer therapy and aging. The lack of universal biomarkers for detecting and quantifying senescent cells, in vitro and in vivo, constitutes a major limitation. The applications and limitations of major senescence biomarkers, including senescence-associated ß-galactosidase staining, telomere shortening, cell-cycle arrest, DNA methylation, and senescence-associated secreted phenotypes are discussed. Furthermore, explore senotherapeutic approaches for aging-associated diseases and cancer. In addition to the conventional biomarkers, this review highlighted the in vitro, in vivo, and disease models used for aging studies. Further, technologies from the current decade including multi-omics and computational methods used in the fields of senescence and aging are also discussed in this review. Understanding aging-associated biological processes by using cellular senescence biomarkers can enable therapeutic innovation and interventions to improve the quality of life of older adults.

Gonadal efficacy of Thymus quinquecostatus Celakovski: Regulation of testosterone levels in aging mouse models.

Late-onset hypogonadism (LOH) is an age-related disease in men characterized by decreased testosterone levels with symptoms such as decreased libido, erectile dysfunction, and depression. Thymus quinquecostatus Celakovski (TQC) is a plant used as a volatile oil in traditional medicine, and its bioactive compounds have anti-inflammatory potential. Based on this knowledge, the present study aimed to investigate the effects of TQC extract (TE) on LOH in TM3 Leydig cells and in an in vivo aging mouse model. The aqueous extract of T. quinquecostatus Celakovski (12.5, 25, and 50 µg/mL concentrations) was used to measure parameters such as cell viability, testosterone level, body weight, and gene expression, via in vivo studies. Interestingly, TE increased testosterone levels in TM3 cells in a dose-dependent manner without affecting cell viability. Furthermore, TE significantly increased the expression of genes involved in the cytochrome P450 family (Cyp11a1, Cyp17a1, Cyp19a1, and Srd5a2), which regulate testosterone biosynthesis. In aging mouse models, TE increased testosterone levels without affecting body weight and testicular tissue weight tissue of an aging animal group. In addition, the high-dose TE-treated group (50 mg/kg) showed significantly increased expression of the cytochrome p450 enzymes, similar to the in vitro results. Furthermore, HPLC-MS analysis confirmed the presence of caffeic acid and rosmarinic acid as bioactive compounds in TE. Thus, the results obtained in the present study confirmed that TQC and its bioactive compounds can be used for LOH treatment to enhance testosterone production.

Spontaneous Fusion with Transformed Mesenchymal Stromal Cells Results in Complete Heterogeneity in Prostate Cancer Cells.

Tumor cells gain advantages in growth and survival by acquiring genotypic and phenotypic heterogeneity. Interactions with bystander cells in the tumor microenvironment contribute to the progression of heterogeneity. We have shown that fusion between tumor and bystander cells is one form of interaction, and that tumor-bystander cell fusion has contrasting effects. By trapping fusion hybrids in the heterokaryon or synkaryon state, tumor-bystander cell fusion prevents the progression of heterogeneity. However, if trapping fails, fusion hybrids will resume replication to form derivative clones with diverse genomic makeups and behavioral phenotypes. To determine the characteristics of bystander cells that influence the fate of fusion hybrids, we co-cultured prostate mesenchymal stromal cell lines and their spontaneously transformed sublines with LNCaP as well as HPE-15 prostate cancer cells. Subclones derived from cancer-stromal fusion hybrids were examined for genotypic and phenotypic diversifications. Both stromal cell lines were capable of fusing with cancer cells, but only fusion hybrids with the transformed stromal subline generated large numbers of derivative subclones. Each subclone had distinct cell morphologies and growth behaviors and was detected with complete genomic hybridization. The health conditions of the bystander cell compartment play a crucial role in the progression of tumor cell heterogeneity.

Overcoming Resistance in Prostate Cancer Therapy Using a DZ-Simvastatin Conjugate.

Prostate cancer (PC), particularly its metastatic castration-resistant form (mCRPC), is a leading cause of cancer-related deaths among men in the Western world. Traditional systemic treatments, including hormonal therapy and chemotherapy, offer limited effectiveness due to tumors' inherent resistance to these therapies. Moreover, they often come with significant side effects. We have developed a delivery method using a tumor-cell-specific heptamethine carbocyanine dye (DZ) designed to transport therapeutic agents directly to tumor cells. This research evaluated simvastatin (SIM) as the antitumor payload because of its demonstrated chemopreventive effects on human cancers and its well-documented safety profile. We designed and synthesized a DZ-SIM conjugate for tumor cell targeting. PC cell lines and xenograft tumor models were used to assess tumor-cell targeting specificity and killing activity and to investigate the corresponding mechanisms. DZ-SIM treatment effectively killed PC cells regardless of their androgen receptor status or inherent therapeutic resistance. The conjugate targeted and suppressed xenograft tumor formation without harming normal cells of the host. In cancer cells, DZ-SIM was enriched in subcellular organelles, including mitochondria, where the conjugate formed adducts with multiple proteins and caused the loss of transmembrane potential, promoting cell death. The DZ-SIM specifically targets PC cells and their mitochondria, resulting in a loss of mitochondrial function and cell death. With a unique subcellular targeting strategy, the conjugate holds the potential to outperform existing chemotherapeutic drugs. It presents a novel strategy to circumvent therapeutic resistance, offering a more potent treatment for mCRPC.

Anti-Inflammatory Effects of Spirodela polyrhiza (L.) SCHLEID. Extract on Contact Dermatitis in Mice-Its Active Compounds and Molecular Targets.

Spirodela polyrhiza (L.) SCHLEID. has been used to treat epidemic fever, dysuria, and various skin ailments, such as measles eruptions, eczema, and pruritus, in China, Japan, and Korea. In this study, the active compounds in S. polyrhiza and their target genes were identified by network-based analysis. Moreover, the study evaluated the effects of a 70% ethanolic extract of S. polyrhiza (EESP) on skin lesions, histopathological changes, inflammatory cytokines, and chemokines in mice with contact dermatitis (CD) induced by 1-fluoro-2,4-dinitrobenzene (DNFB), and examined the inhibitory effects of EESP on mitogen-activated protein kinase (MAPK) signalling pathways. In our results, 14 active compounds and 29 CD-related target genes were identified. Among them, tumour necrosis factor (TNF) and interleukin 6 (IL-6) were identified as hub genes, and luteolin and apigenin showed a strong binding affinity with TNF (<-8 kcal/mol) and IL-6 (<-6 kcal/mol). Our in vivo studies showed that topical EESP ameliorated DNFB-induced skin lesions and histopathological abnormalities, and reduced the levels of TNF-α, interferon (IFN)-É£, IL-6, and monocyte chemotactic protein (MCP)-1 in inflamed tissues. In conclusion, our findings suggest the potential for dermatological applications of S. polyrhiza and suggest that its anti-dermatitis action is related to the inhibition of TNF and IL-6 by luteolin and luteolin glycosides.

The Anti-Inflammatory and Skin Barrier Function Recovery Effects of Schisandra chinensis in Mice with Atopic Dermatitis.

Background and Objectives: The fruit of Schisandra chinensis (Turcz.) Baill. is widely used medicinally to treat coughs, asthma, exhaustion, eczema, and pruritus in Northeast Asian countries, including Korea, China, and Japan. This study was designed to investigate the effects of S. chinensis on dermatitis in mice with calcipotriol (MC-903)-induced atopic dermatitis (AD), and its effects on skin barrier dysfunction was also investigated. Materials and Methods: The inhibitory effects of an ethanolic extract of S. chinensis (EESC) on skin lesions, water content, water-holding capacity (WHC), histopathological abnormalities, and inflammatory cytokine and chemokine levels were evaluated in mice with AD induced by MC903. Results: Topical EESC ameliorated skin lesions, reduced skin water content, and increased MC903-induced WHC. EESC also prevented MC-903-induced histopathological abnormalities such as epidermal disruption, hyperkeratosis, spongiotic changes, and immune cell infiltration in inflamed tissue. Moreover, topical EESC reduced MC-903-induced levels of pro-inflammatory cytokines and chemokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-4, IL-6, IL-8, monocyte chemotactic protein (MCP)-1, and thymic stromal lymphopoietin (TSLP). Furthermore, unlike dexamethasone, EESC did not reduce the spleen/body weight ratio. Conclusions: These results suggest that S. chinensis can be used as an alternative to external corticosteroids and that its anti-inflammatory and skin barrier dysfunction-restoring effects are related to the downregulation of pro-inflammatory cytokines and chemokines, such as TNF-α, IL-4, IL-6, IL-8, and TSLP.

Understanding the relationship between cancer associated cachexia and hypoxia-inducible factor-1.

Cancer-associated cachexia (CAC) is a multifactorial disorder characterized by an unrestricted loss of body weight as a result of muscle and adipose tissue atrophy. Cachexia is influenced by several factors, including decreased metabolic activity and food intake, an imbalance between energy uptake and expenditure, excessive catabolism, and inflammation. Cachexia is highly associated with all types of cancers responsible for more than half of cancer-related mortalities worldwide. In healthy individuals, adipose tissue significantly regulates energy balance and glucose homeostasis. However, in metastatic cancer patients, CAC occurs mainly because of an imbalance between muscle protein synthesis and degradation which are organized by certain extracellular ligands and associated signaling pathways. Under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1α) accumulated and translocated to the nucleus and activate numerous genes involved in cell survival, invasion, angiogenesis, metastasis, metabolic reprogramming, and cancer stemness. On the other hand, the ubiquitination proteasome pathway is inhibited during low O2 levels which promote muscle wasting in cancer patients. Therefore, understanding the mechanism of the HIF-1 pathway and its metabolic adaptation to biomolecules is important for developing a novel therapeutic method for cancer and cachexia therapy. Even though many HIF inhibitors are already in a clinical trial, their mechanism of action remains unknown. With this background, this review summarizes the basic concepts of cachexia, the role of inflammatory cytokines, pathways connected with cachexia with special reference to the HIF-1 pathway and its regulation, metabolic changes, and inhibitors of HIFs.

Effect of screw speed and die temperature on physicochemical, textural, and morphological properties of soy protein isolate-based textured vegetable protein produced via a low-moisture extrusion.

In this study, textured vegetable protein (TVP) based on soy protein isolate, wheat gluten, and corn starch was prepared at a 5:3:2 (w/w) ratio using a low-moisture extrusion process. To evaluate the effects of extrusion parameters, die temperature and screw rotation speed, on the properties of TVP, these two parameters were manipulated at a constant barrel temperature and moisture content. The results indicated that increasing the die temperature increased the expansion ratio while decreasing the density of the extrudates. Simultaneously, increasing the screw rotation speed clearly increased the specific mechanical energy of the TVP. Furthermore, mathematical modelling suggested that the expansion ratio increases exponentially to the die temperature. However, extreme process conditions bring about a decrease in water absorption capacity and expansion ratio, as well as undesirable texture and microstructure. The results suggested that the properties of SPI-based TVP are directly influenced by the extrusion process parameters, screw speed and die temperature. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01207-8.

The Related Mechanisms Predicted through Network-Based Pharmacological Analysis and the Anti-Inflammatory Effects of Fraxinus rhynchophylla Hance Bark on Contact Dermatitis in Mice.

Fraxinus rhynchophylla Hance bark has been used to treat patients with inflammatory or purulent skin diseases in China, Japan, and Korea. This study was undertaken to determine the mechanism responsible for the effects of F. rhynchophylla and whether it has a therapeutic effect in mice with contact dermatitis (CD). In this study, the active compounds in F. rhynchophylla, their targets, and target gene information for inflammatory dermatosis were investigated using network-based pharmacological analysis. Docking analysis was conducted using AutoDock Vina. In addition, the therapeutic effect of an ethanolic extract of F. rhynchophylla (EEFR) on skin lesions and its inhibitory effects on histopathological abnormalities, inflammatory cytokines, and chemokines were evaluated. Finally, its inhibitory effects on the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways were observed in RAW 264.7 cells. In our results, seven active compounds were identified in F. rhynchophylla, and six were associated with seven genes associated with inflammatory dermatosis and exhibited a strong binding affinity (<-6 kcal/mol) to prostaglandin G/H synthase 2 (PTGS2). In a murine 1-fluoro-2,4-dinitrobenzene (DNFB) model, topical EEFR ameliorated the surface symptoms of CD and histopathological abnormalities. EEFR also reduced the levels of tumour necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-6, and monocyte chemotactic protein (MCP)-1 in inflamed tissues and inhibited PTGS2, the nuclear translocation of NF-κB (p65), and the activation of c-Jun N-terminal kinases (JNK) in RAW 264.7 cells. In conclusion, the bark of F. rhynchophylla has potential use as a therapeutic or cosmetic agent, and the mechanism responsible for its effects involves the suppression of inflammatory mediators, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (IκB)-α degradation, the nuclear translocation of NF-κB, and JNK phosphorylation.

Unlocking Prognostic Genes and Multi-Targeted Therapeutic Bioactives from Herbal Medicines to Combat Cancer-Associated Cachexia: A Transcriptomics and Network Pharmacology Approach.

Cachexia is a devastating fat tissue and muscle wasting syndrome associated with every major chronic illness, including cancer, chronic obstructive pulmonary disease, kidney disease, AIDS, and heart failure. Despite two decades of intense research, cachexia remains under-recognized by oncologists. While numerous drug candidates have been proposed for cachexia treatment, none have achieved clinical success. Only a few drugs are approved by the FDA for cachexia therapy, but a very low success rate is observed among patients. Currently, the identification of drugs from herbal medicines is a frontier research area for many diseases. In this milieu, network pharmacology, transcriptomics, cheminformatics, and molecular docking approaches were used to identify potential bioactive compounds from herbal medicines for the treatment of cancer-related cachexia. The network pharmacology approach is used to select the 32 unique genes from 238 genes involved in cachexia-related pathways, which are targeted by 34 phytocompounds identified from 12 different herbal medicines used for the treatment of muscle wasting in many countries. Gene expression profiling and functional enrichment analysis are applied to decipher the role of unique genes in cancer-associated cachexia pathways. In addition, the pharmacological properties and molecular interactions of the phytocompounds were analyzed to find the target compounds for cachexia therapy. Altogether, combined omics and network pharmacology approaches were used in the current study to untangle the complex prognostic genes involved in cachexia and phytocompounds with anti-cachectic efficacy. However, further functional and experimental validations are required to confirm the efficacy of these phytocompounds as commercial drug candidates for cancer-associated cachexia.

Formic acid induces hypertension-related hemorrhage in hSSAOTG in mice and human.

Hypertension is a confirmed risk factor for cerebral hemorrhage in humans. Which endogenous factor directly induces hypertension-related hemorrhage is unclear. In this study, 42 hemorrhagic patients with hypertension and hyperlipidemia and 42 age-matched healthy controls were enrolled. The contents of serum semicarbazide-sensitive amine oxidase (SSAO) and formic acid (FC, FC is a final product of SSAO through the oxidation of endogenous formaldehyde, which results from the enzymatic oxidative deamination of the SSAO substrate, methylamine) were examined in the patients after stroke. Hemorrhagic areas were quantified by computer tomography. In the animal study, hemorrhagic degree was assessed by hemotoxylin & eosin or tissue hemoglobin kits. The relationship between FC and blood pressure/hemorrhagic degree was examined in wild-type mice and hSSAOTG mice fed with high-fat diets or high-fat and -salt diets. The results showed that the levels of serum FC were positively correlated with blood pressure and hemorrhagic areas in hemorrhagic patients. Transfection of microRNA-134 could enhance SSAO expression in human vascular smooth muscle cells. Consistently, after treatment with high-fat and -salt diets, hSSAOTG mice exhibited higher levels of miR134 and FC, higher blood pressure, and more severe hemorrhage than wild-type mice. Interestingly, folic acid reduced hypertension and hemorrhage in hSSAOTG mice fed with high-fat diets. These findings suggest that FC is a crucial endogenous factor for hypertension and hemorrhage.

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Human activities related with construction and destruction are one of the important drivers for vegetation dynamics. Using remote sensing to explore the quantitative monitoring process and driving force of vegetation succession can well reveal the impacts of human activities on ecological background. Based on the vegetation formation group and vegetation formation scales, this study used the European Space Agency's annual land cover data and geo-information TUPU analysis to investigate vegetation succession direction, succession speed, and succession sequence in the Inner Mongolia from 1992 to 2018. The vegetation succession characteristics and its driving forces were then clarified. Results showed that vegetation structure changed dramatically with increasing vegetation and decreasing barren during the study period. The specific annual growth rate was cultivated land (353.10 km2) > grassland (243.92 km2) > forest (-16.22 km2) > shrubland (-120.37 km2) > desert (-556.31 km2). There was a trade-off between the area changes of adjacent grasslands, deserts, and shrublands. Vegetation succession presented a spatial pattern of vegetation expansion and desert reduction, with the succession hotspots concentrated in the West Liaohe River Plain, the desert-grassland junction of central Inner Mongolia, and along the Yellow River. The structure of vegetation succession sequence was complex with progressive succession and regressive succession intermixed. The retention rate of succession flow differed among different communities. Most of the succession flow was intercepted by the grassland and shrubland community of vegetation formation group and the grassland and cropland rainfed community of vegetation formation. The core driving forces of vegetation dynamic succession are agriculture and animal husbandry production, economic development level, population size, ecological engineering, and climate change. As a case study of plantsociology and landscape ecology, our results could provide scientific guidance for optimizing vegetation patterns and enhancing the spatial division and succession level of ecological measures.

Rab11a Regulates the Development of Cilia and Establishment of Planar Cell Polarity in Mammalian Vestibular Hair Cells.

Vestibular organs have unique planar cell polarity (Figure 1A), and their normal development and function are dependent on the regular polarity of cilia (Figure 1B) requires. Rab11a is a small G protein that participates in the transportation of intracellular and extracellular materials required for polarity formation; however, our understanding of the mechanisms of the actions of Rab11a in vestibular organs is limited. Here, we showed that the general shape of the utricle was abnormal in Rab11a CKO/CKO mice. These mice also showed abnormal morphology of the stereocilia bundles, which were reduced in both length and number, as well as disturbed tissue-level polarity. Rab11a affected the distribution of polarity proteins in the vestibular organs, indicating that the normal development of cilia requires Rab11a and intraflagellar transportation. Furthermore, small G protein migration works together with intraflagellar transportation in the normal development of cilia. FIGURE 1Morphological changes of stereocilia in the extrastriolar hair cells from Rab11a single or Rab11a/IFT88 double-mutant utricles. (A) Medial view of a mouse left inner ear with its five vestibular sensory organs (gray). Enlarged are the utricle showing their subdivisions, LPR (yellow line), and striola (blue). LES, lateral extrastriola; MES, medial extrastriola; LPR, line of polarity reversal. (B) Schematic view of vestibular hair cell. Kinocilium is marked with ace-tubulin. Basal body is marked with γ-tubulin. (C,C1,D,D1) Normal appearance of the stereocilia of extrastriolar hair cells of wild-type controls. (E,E1,F,F1) Altered morphology in Rab11a CKO/CKO animals. (G,G1,H,H1) The changes in the stereocilia morphology were more severe in Rab11a CKO/CKO /IFT 88 CKO/+ mice. (I-L) Higher magnification of confocal images of hair cells. (M-P) Scanning electron microscopy images of hair cells from wild-type controls and Rab11a mutants. (I,M) Morphology of normal. hair cells of wild-type controls. (J,N) The number of stereocilia on a single hair cell was deceased in the Rab11a mutant. (K,O) Stereocilia were shorter in mutants compared to the wild-type controls. (L,P) The staircase-like hair bundle architecture of hair cells was lost in Rab11a mutant mice. (Q) The percentage of hair cells with abnormal development of static cilia bundles in the extrastriola region was counted as a percentage of the total (n = 5). The percentage of abnormal hair cells was higher in Rab11a CKO/CKO , IFT88 CKO/+ mice compared to Rab11a CKO/CKO . The abnormal ratios of single and double knockout hair cells were 42.1 ± 5.7 and 71.5 ± 10.4, respectively. In (A-J), for all primary panels, hair cell stereociliary bundles were marked with phalloidin (green), the actin-rich cuticular plate of hair cells was labeled with ß-spectrin (red), while the basal body of the hair cell was labeled with γ-tubulin (blue). Scale bars: 10 µm (C-H1), 5 µm (J-N). *P < 0.05.

A Novel Urine Exosomal lncRNA Assay to Improve the Detection of Prostate Cancer at Initial Biopsy: A Retrospective Multicenter Diagnostic Feasibility Study.

PURPOSE: This study aimed at developing and validating a novel noninvasive urinary exosome-based post-DRE (digital rectal examination) lncRNA assay to diagnose PCa (prostate cancer) and clinically significant PCa (Gleason score ≥ 7) from the initial prostate biopsy. METHODS: A total of 602 urine samples from eligible participants were collected. The expression levels of urinary exosomal PCA3 (prostate cancer antigen 3) and MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) were detected by qPCR (quantitative real-time PCR). Receiver operating characteristic (ROC) analysis was applied to evaluate the diagnostic performance of PCA3, MALAT1 and the lncRNA assay. A decision curve analysis (DCA) and waterfall plots were used to assess the clinical value of the lncRNA assay. RESULTS: Urinary exosomal PCA3 and MALAT1 were overexpressed in PCa and clinically significant PCa (p < 0.001). The lncRNA assay combining PCA3 and MALAT1 had a better diagnostic performance (AUC 0.828) than the current clinical parameters in detecting PCa. More importantly, the lncRNA assay yielded an AUC of 0.831 to detect clinically significant PCa, which is much higher than that of the current clinical parameters. The lncRNA assay was superior to PSA, f/tPSA and the base model for detecting PCa and clinically significant PCa, with a higher net benefit for almost all threshold probabilities. At the cutoff value of 95% sensitivity, the lncRNA assay could avoid 24.2% unnecessary biopsies while only missing 1.2% of the cases of clinically significant PCa. CONCLUSION: We developed and validated a novel noninvasive post-DRE urine-based lncRNA assay that presented good diagnostic power and clinical utility for the early diagnosis of PCa and high-grade PCa.

The application of virtual reality training for anastomosis during robot-assisted radical prostatectomy.

OBJECTIVE: To investigate the application of virtual reality training in vesicourethral anastomosis during robot-assisted radical prostatectomy (RARP). METHODS: Three certified robotic urologists who underwent virtual reality training were enrolled in the study group. The other three without training were enrolled in the control group. Parameters were recorded before and after the training. Then a total of 18 patients undergoing RARP were enrolled and randomized assigned to receive anastomosis procedures with certified urologists who either obtained or did not obtain training. The quality of the anastomosis was evaluated. RESULTS: For the virtual training evaluation, the overall score was significantly improved from 65.0±10.8 to 92.7±3.5 (p=0.014); the time of anastomosis was shortened; the economy of motion improved; instrument collisions decreased after training (p<0.05). Besides, the effectiveness of the virtual training was evaluated in the 18 real anastomosis procedures which were completed either by three urologists with training or three urologists without training. Most intriguingly, the average time of anastomosis was shortened from 40.0±12.4 min to 25.1±7.1 min (p=0.015). The parameters including time of operation, creatinine level of drainage, postoperative hospital stay and duration of catheter drainage were comparable before and after training. Two leakages, which were observed in procedures by doctors without training, needed salvage sutures by a senior doctor. CONCLUSIONS: Virtual reality training enabled surgeons to become quickly familiar with robotic system manipulation, improved their skills for vesicourethral anastomosis and shortened the learning curve, thus helping them operate with high efficacy and quality.

Circulating exosomal mRNA profiling identifies novel signatures for the detection of prostate cancer.

The landscape and characteristics of circulating exosomal messenger RNAs (emRNAs) are poorly understood, which hampered the accurate detection of circulating emRNAs. Through comparing RNA sequencing data of circulating exosomes with the corresponding data in tissues, we illustrated the different characteristics of emRNAs compared to tissue mRNAs. We then developed an improved strategy for emRNA detection based on the features of circulating emRNAs. Using the optimized detection strategy, we further validated prostate cancer (PCa) associated emRNAs discovered by emRNA-seq in a large cohort of patients and identified emRNA signatures for PCa screening and diagnosis using logistic regression analysis. The receiver operating characteristic curve (ROC) analysis showed that the circulating emRNA-based screening signature yielded an area under the ROC curve (AUC) of 0.948 in distinguishing PCa patients from healthy controls. The circulating emRNA-based diagnostic signature also showed a great performance in predicting prostate biopsy results (AUC: 0.851). In conclusion, our study developed an optimized emRNA detection strategy and identified novel emRNA signatures for the detection of PCa.

Relationship Between Alzheimer's Disease and Retinal Choroidal Thickness: A Cross-Sectional Study.

BACKGROUND: The choroid is involved directly or indirectly in many pathological conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). OBJECTIVE: The objective of this study was to investigate the association between retinal choroidal properties and the pathology of AD by determining choroidal thickness, hippocampus volume, cognitive functions, and plasma BACE1 activity. METHODS: In this cross-sectional study, 37 patients with AD and 34 age-matched controls were included. Retinal choroidal thickness was measured via enhanced depth imaging optical coherence tomography. Hippocampal volume was measured via 3.0T MRI. Cognitive functions were evaluated using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog). Plasma BACE1 activity was analyzed using a fluorescence substrate-based plasma assay, and regression model were to analyze the data. RESULTS: Retinal choroidal thickness was significantly thinner in the AD group than in the control group [(114.81±81.30) µm versus (233.79±38.29) µm, p < 0.05]. Multivariable regression analysis indicated that the ADAS-cog scores (ß=-0.772, p = 0.000) and age (ß=-0.176, p = 0.015) were independently associated with choroidal thickness. The logistic regression model revealed that the subfoveal choroidal thickness was a significant predictor for AD (OR = 0.984, 95% CI: 0.972-0.997). CONCLUSION: There was a general tendency of choroid thinning as the cognitive function declined. Although choroidal thickness was not a potential indicator for early stage AD, it was valuable in monitoring AD progression.

Multi-stage glucose/pachymaran co-feeding enhanced endo-ß-1,3-glucanase production by Trichoderma harzianum via simultaneous increases in cell concentration and inductive effect.

Endo-ß-1,3-glucanase is used to hydrolyze curdlan in a wide range of oligosaccharides production processes. Using pachymaran as the sole carbon source resulted in an endo-ß-1,3-glucanase activity of 86.1 U/mL and an Eendo/Etotal ratio of 0.43, which were 3.2 and 1.65 folds of the values from control (glucose as the sole carbon source), due to the inductive effect of pachymaran as a polysaccharide. However, the cell concentration decreased from 25 to 12 g/L during the late fermentation phase. Therefore, a novel multi-stage feeding strategy was developed wherein glucose was fed twice during the cell logarithmic growth phase (24 and 48 h) and pachymaran once during the early stage of the enzyme accumulation phase (72 h). Consequently, the cell concentration remained around 30 g/L during the late fermentation phase. Endo-ß-1,3-glucanase activity and Eendo/Etotal reached 160.0 U/mL and 0.76, respectively, which were 6.0 and 2.92 folds of the values from control. In addition, three typical polysaccharides with ß-1,3-linked glucose residues were successfully hydrolyzed by endo-ß-1,3-glucanase to produce multifunctional ß-1,3-oligoglucosides.

Homocysteine and IgA nephropathy: observational and Mendelian randomization analyses.

BACKGROUND: High levels of plasma homocysteine occur almost uniformly in patients with end-stage renal disease (ESRD). IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a common cause of ESRD in young adults. Here, we aimed to detect whether homocysteine was elevated and associated with clinical-pathologic manifestations of IgAN patients and tested its causal effects using a two-sample Mendelian randomization (MR) approach. METHODS: For observational analysis, 108 IgAN patients, 30 lupus nephritis (LN) patients, 50 minimal change disease (MCD) patients, and 206 healthy controls were recruited from April 2014 to April 2015. Their plasma homocysteine was measured and clinical-pathologic manifestations were collected from medical records. For MR analysis, we further included 1686 IgAN patients. The missense variant methylenetetrahydrofolate reductase C677T (rs1801133) was selected as an instrument, which was genotyped by TaqMan allele discrimination assays. RESULTS: Majority of IgAN patients (93.52%, 101/108) showed elevated levels of plasma homocysteine (>10 µmol/L). Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients (median: 18.32 vs. 11.15 µmol/L, Z = -5.29, P < 0.01) and in healthy controls (median: 18.32 vs. 10.00 µmol/L, Z = -8.76, P < 0.01), but comparable with those in LN patients (median: 18.32 L vs. 14.50 µmol/L, Z = -1.32, P = 0.19). Significant differences were observed in sub-groups of IgAN patients according to quartiles of plasma homocysteine for male ratio (22.22% vs. 51.85% vs. 70.37% vs. 70.37%, χ = 14.29, P < 0.01), serum creatinine (median: 77.00 vs. 100.00 vs. 129.00 vs. 150.00 µmol/L, χ = 34.06, P < 0.01), estimated glomerular filtration rate (median: 100.52 vs. 74.23 vs. 52.68 vs. 42.67 mL·min·1.73 m, χ = 21.75, P < 0.01), systolic blood pressure (median: 120.00 vs. 120.00 vs. 125.00 vs. 130.00 mmHg, χ = 2.97, P = 0.05), diastolic blood pressure (median 80.00 vs. 75.00 vs. 80.00 vs. 81.00 mmHg, χ = 11.47, P < 0.01), and pathologic tubular atrophy and interstitial fibrosis (T) (T0/T1/T2: 62.96%/33.33%/3.70% vs. 29.63%/40.74%/29.63% vs. 24.00%/48.00%/28.00% vs. 14.81%/37.04%/48.15%, χ = 17.66, P < 0.01). The coefficient of each rs1801133-T allele on homocysteine levels after controlling age and sex was 7.12 (P < 0.01). MR estimates showed causal positive effects of homocysteine on serum creatine (ß = 0.76, P = 0.02), systolic blood pressure (ß = 0.26, P = 0.02), diastolic blood pressure (ß = 0.20, P = 0.01), and pathologic T lesion (ß = 0.01, P = 0.01) in IgAN. CONCLUSIONS: By observational and MR analyses, consistent results were observed for associations of plasma homocysteine with serum creatinine, blood pressures, and pathologic T lesion in IgAN patients.

Autonomic nerve regulation for prostate cancer: study based on the tissue transcriptional analysis.

BACKGROUND: The whole-body energy metabolism is regulated by autonomic nerves which also play important roles in the regulation of the generation and development of different kinds of cancers. This study is to analyze the expression of autonomic nerve receptors and their relationship with the development of prostate cancer (PCa) and to further understand the central regulation of the prostate. METHODS: RNA sequencing data concerning autonomic nerve receptors from paired tumor and adjacent benign tissues from 65 patients were collected. The mRNA expression and patient data were analyzed. The Cancer Genome Atlas (TCGA) data confirmed the results, and Pearson analysis, Pearson heat maps, gene heat maps, multivariate logistic regression models, receiver operating characteristic (ROC) curves and Gene Set Enrichment Analysis (GSEA) and Pearson's analysis were analyzed for correlation analysis in this study. RESULTS: Reads with eight receptors associated with PCa generation were finally retained in this report. Favorable relationships were found among the different autonomic nerve regulators for the prostate. In univariate logistic regression analysis, adrenoceptor alpha 1A (ADRA1A) was the most positively correlated [OR (95% CI): 1.707 (1.209, 2.410)]; the area under the curve (AUC) in the ROC for ADRA1A was 0.866 (P<0.001). In multivariate logistic regression analysis, a predicted formulation for PCa diagnosis was evident. The GSEA results also showed the effect of autonomic nerves on cancer generation and some of the key cancer-related pathways, as well as Notch, Wnt and steroid biosynthesis pathways. Finally, five articles were reviewed to elucidate the center-autonomic nerve system-periphery circuit in the prostate. CONCLUSIONS: Central regulation plays an important role in the development of PCa, presenting the opportunity to treat the disease, and additional studies are warranted.