Cyclic immonium ion of lactyllysine reveals widespread lactylation in the human proteome.

Lactylation was initially discovered on human histones. Given its nascence, its occurrence on nonhistone proteins and downstream functional consequences remain elusive. Here we report a cyclic immonium ion of lactyllysine formed during tandem mass spectrometry that enables confident protein lactylation assignment. We validated the sensitivity and specificity of this ion for lactylation through affinity-enriched lactylproteome analysis and large-scale informatic assessment of nonlactylated spectral libraries. With this diagnostic ion-based strategy, we confidently determined new lactylation, unveiling a wide landscape beyond histones from not only the enriched lactylproteome but also existing unenriched human proteome resources. Specifically, by mining the public human Meltome Atlas, we found that lactylation is common on glycolytic enzymes and conserved on ALDOA. We also discovered prevalent lactylation on DHRS7 in the draft of the human tissue proteome. We partially demonstrated the functional importance of lactylation: site-specific engineering of lactylation into ALDOA caused enzyme inhibition, suggesting a lactylation-dependent feedback loop in glycolysis.

EphA2 promotes the transcription of KLF4 to facilitate stemness in oral squamous cell carcinoma.

Ephrin receptor A2 (EphA2), a member of the Ephrin receptor family, is closely related to the progression of oral squamous cell carcinoma (OSCC). Cancer stem cells (CSCs) play essential roles in OSCC development and occurrence. The underlying mechanisms between EphA2 and CSCs, however, are not yet fully understood. Here, we found that EphA2 was overexpressed in OSCC tissues and was associated with poor prognosis. Knockdown of EphA2 dampened the CSC phenotype and the tumour-initiating frequency of OSCC cells. Crucially, the effects of EphA2 on the CSC phenotype relied on KLF4, a key transcription factor for CSCs. Mechanistically, EphA2 activated the ERK signalling pathway, promoting the nuclear translocation of YAP. Subsequently, YAP was bound to TEAD3, leading to the transcription of KLF4. Overall, our findings revealed that EphA2 can enhance the stemness of OSCC cells, and this study identified the EphA2/KLF4 axis as a potential target for treating OSCC.

Can nonvolatile tastants be smelled during food oral processing?

While accumulating evidence implied the involvement of retro-nasal sensation in the consumption of nonvolatile taste compounds, it is still unclear whether it was caused by the taste compounds themselves, and if so, how can they migrate from the oral to nasal cavity. At first, we proposed aerosol particles as an alternative oral-nasal mass transfer mechanism. The high-speed camera approved that aerosol particles could be generated by the typical oral and pharynx actions during food oral processing; while the narrow-band imaging of nasal cleft and mass spectrometry of nostril-exhaled air approved the migration of aerosol within the oral-nasal route. Then, the "smelling" of taste compounds within the aerosol particles was testified. The four-alternative forced choices (4AFC) approved that the potential volatile residues or contaminants within the headspace air of pure taste solution cannot arouse significant smell, while the taste compounds embedded in the in vitro prepared aerosol particles can be "smelled" via the ortho route. The "smell" of sucrose is very different from its taste and the "smell" of quinine, implying its actual olfaction. The sweetness intensity of sucrose solution was also reduced when the volunteers' noses were clipped, indicating the involvement of retro-nasal sensation during its drinking. At last, the efficiency of aerosol as a mechanism of oral-nasal mass transfer was demonstrated to be comparable with the volatile molecules under the experimental condition, giving it the potential to be a substantial and unique source of retro-nasal sensation during food oral processing.

Phenotype transition of fibroblasts incorporated into patient-derived oral carcinoma organoids.

OBJECTIVE: Cancer-associated fibroblasts (CAFs) are abundantly infiltrated in oral squamous cell carcinoma (OSCC), but the contact-dependent mechanisms that regulate CAFs phenotype in precursor cells, such as paracancerous fibroblasts (PFs), remain unclear. Here, a fibroblast-attached organoid (FAO) model was initiated to determine phenotype transition of fibroblasts triggered by contact with OSCC. MATERIAL AND METHODS: Organoids and fibroblasts were generated using OSCC and adjacent tissues. Cell-clusters containing fibroblasts and tumour cells were aggregated to allow for FAOs expansion. Immunoblotting assay was performed to compare expression of Notch intracellular domain (NICD) in CAFs and PFs. Colony formation assay was employed to evaluate morphological activation of fibroblasts. RESULTS: Compared to traditional 3D co-culture, FAOs better modulated the spatial distribution of fibroblasts with tumour nests. The presence of CAFs with multiple branches was stably observed in FAOs during serial passage. Incorporation with organoids promoted the ability of PFs to form multiple branches. Immunoblotting assay confirmed higher NICD level in CAFs than PFs. Treatment with Notch inhibitor, N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (i.e. DAPT) blocked morphological activation of fibroblasts incorporated into FAO. CONCLUSION: We developed a robust strategy to study contact-dependent mechanisms underlying tumour-stromal interaction, and suggested that Notch activity contributes to biogenesis of OSCC-associated fibroblasts.

Validating stroke-induced bilateral ankle coordination deficits using bilateral ankle measure relationship with motor functions in lower limbs.

BACKGROUND: Coordinated control between the bilateral ankle joints plays an important role in performing daily life functions, such as walking and running. However, few studies have explored the impact of stroke on movement disorders that decrease the coordination control of the bilateral extremities and may decrease daily activities that require coordination control of the bilateral ankles. This study aimed to investigate the coordination control of the bilateral ankles using a novel bilateral ankle measurement system and evaluate the relationship of bilateral movement coordination control deficits with motor and functional performances of the lower extremities in patients with stroke. METHODS: Twenty-one healthy adults (36.5 ± 13.2 y/o) and 19 patients with chronic stroke (58.7 ± 10.5 y/o) were enrolled. A novel measurement device with embedded rotary potentiometers was used to evaluate bilateral ankle coordination control. Participants were asked to move their dominant (non-paretic) foot from dorsiflexion to plantarflexion position and non-dominant (paretic) foot from dorsiflexion to plantarflexion position (condition 1) simultaneously, and vice versa (condition 2). Alternating time and angle for coordination control with movements of both ankles were calculated for each condition. Motor and functional performance measurements of the lower extremities included the lower-extremity portion of the Fugl-Meyer assessment (FMA-LE), Berg Balance Test (BBS), Timed Up and Go Test (TUG), and Barthel Index (BI). RESULTS: Compared with the healthy group, alternating time was shorter in the stroke group by 8.3% (p = 0.015), and the alternating angles of conditions 1 and 2 were significantly higher than those of the healthy group by 1.4° (p = 0.001) and 2.5° (p = 0.013), respectively. The alternating angle in condition 2 showed moderate correlations with TUG (r = 0.512; p = 0.025), 10-m walk (r = 0.747; p < 0.001), gait speed (r = - 0.497 to - 0.491; p < 0.05), length (r = - 0.518 to - 0.551; p < 0.05), and BI (r = - 0.457; p = 0.049). CONCLUSION: Stroke decreases alternating time, increases alternating angle, and shows bilateral ankle coordination control deficits temporally and spatially. A higher alternating angle is moderately to highly associated with motor function and lower limb function in patients with stroke.

Integrated Transcriptome and Metabolomics to Reveal the Mechanism of Adipose Mesenchymal Stem Cells in Treating Liver Fibrosis.

Liver fibrosis (LF) is a late-stage process observed in various chronic liver diseases with bile and retinol metabolism closely associated with it. Adipose-derived mesenchymal stem cells (ADMSCs) have shown significant therapeutic potential in treating LF. In this study, the transplantation of ADMSCs was applied to a CCl4-induced LF model to investigate its molecular mechanism through a multi-omics joint analysis. The findings reveal that ADMSCs effectively reduced levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), gamma-glutamyltransferase (GGT), Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and α-Smooth muscle actin (α-SMA), thereby mitigating liver lesions, preventing liver parenchymal necrosis, and improving liver collagen deposition. Furthermore, 4751 differentially expressed genes (DEGs) and 270 differentially expressed metabolites (DMs) were detected via transcriptome and metabolomics analysis. Conjoint analysis showed that ADMSCs up-regulated the expression of Cyp7a1, Baat, Cyp27a1, Adh7, Slco1a4, Aldh1a1, and Adh7 genes to promote primary bile acids (TCDCA: Taurochenodeoxycholic acid; GCDCA: Glycochenodeoxycholic acid; GCA: glycocholic acid, TCA: Taurocholic acid) synthesis, secretion and retinol metabolism. This suggests that ADMSCs play a therapeutic role in maintaining bile acid (BA) homeostasis and correcting disturbances in retinol metabolism.

Occurrence, spatial distribution and ecological risks of antibiotics in soil in urban agglomeration.

Antibiotics in soil environment are regarded as emerging pollutants and have introduced increasing risks to soil ecosystem and human health in rapid urbanization areas. Identifying the occurrence and spatial variability of antibiotics in soils is an urgent issue in sustaining soil security. In this study, antibiotics in soils were investigated and analyzed in Beijing-Tianjin-Hebei urban agglomeration. The occurrence, spatial distribution, and related affecting factors of antibiotics in soils were identified and ecological risks of antibiotics in soil environment were assessed. Results showed that (1) The mean concentration of soil antibiotics in Beijing-Tianjin-Hebei urban agglomeration was 21.79 µg/kg. Land use substantially affected the occurrence and concentration of antibiotics in soils. Concentrations of antibiotics in cropland and orchard soils were 2-3 times higher than the other land use types. (2) The concentrations of antibiotics in soils in Beijing-Tianjin-Hebei urban agglomeration presented a spatial pattern of high values in southeast, and low values in northwest. Spatial variability of antibiotics in soils was closely related to the application of organic fertilizer and wastewater irrigation as well as topographical features. Furthermore, soil properties and land management policy had substantial influences on soil antibiotics, and soil heavy metals may aggravate the accumulation of antibiotics in soils. (3) Ecological risks assessment of antibiotics in soils demonstrated that erythromycin (ERY), sulfamethoxazole (SMX), and doxycycline (DOX) may introduce high risks to soil ecosystem health, and more attention should be paid to the areas with intensive human activities that had potential high risk to soil ecosystem health. This study suggests that scientific land and soil management should be considered to prevent soil antibiotic pollution and sustain soil security in urban agglomeration.

Caffeic acid attenuates irradiation-induced hematopoietic stem cell apoptosis through inhibiting mitochondrial damage.

Hematopoietic stem cells (HSCs) are sensitive to ionizing radiation (IR) damage, and its injury is the primary cause of bone marrow (BM) hematopoietic failure and even death after exposure to a certain dose of IR. However, the underlying mechanisms remain incompletely understood. Here we show that mitochondrial oxidative damage, which is characterized by mitochondrial reactive oxygen species overproduction, mitochondrial membrane potential reduction and mitochondrial permeability transition pore opening, is rapidly induced in both human and mouse HSCs and directly accelerates HSC apoptosis after IR exposure. Mechanistically, 5-lipoxygenase (5-LOX) is induced by IR exposure and contributes to IR-induced mitochondrial oxidative damage through inducing lipid peroxidation. Intriguingly, a natural antioxidant, caffeic acid (CA), can attenuate IR-induced HSC apoptosis through suppressing 5-LOX-mediated mitochondrial oxidative damage, thus protecting against BM hematopoietic failure after IR exposure. These findings uncover a critical role for mitochondria in IR-induced HSC injury and highlight the therapeutic potential of CA in BM hematopoietic failure induced by IR.

Effects of computer-aided rowing exercise systems on improving muscle strength and function in older adults with mild knee osteoarthritis: a randomized controlled clinical trial.

BACKGROUND: Osteoarthritis (OA) is common in aged adults and can result in muscle weakness and function limitations in lower limbs. Knee OA affects the quality of life in the elderly. Technology-supported feedback to achieve lower impact on knee joints and individualized exercise could benefit elderly patients with knee OA. Herein, a computer-aided feedback rowing exercise system is proposed, and its effects on improving muscle strength, health conditions, and knee functions of older adults with mild knee OA were investigated. METHODS: Thirty-eight older adults with mild knee OA and satisfying the American College of Rheumatology (ACR) clinical criteria participated in this randomized controlled clinical trial. Each subject was randomly assigned to a computer-aided rowing exercise (CRE) group (n = 20) or a control group (CON) (n = 18) that received regular resistance exercise programs two times per week for 12 weeks. Outcome measurements, including the Western Ontario and MacMaster Universities (WOMAC), muscle strength and functional fitness of the lower limbs, were evaluated before and after the intervention. RESULTS: Participants' functional fitness in the CRE group exhibited significantly higher adjusted mean post-tests scores, including the WOMAC (p = 0.006), hip abductors strength (kg) (MD = 2.36 [1.28, 3.44], p = 5.67 × 10-5), hip adductors strength (MD = 3.04 [1.38, 4.69], p = 0.001), hip flexors strength (MD = 4.01 [2.24, 5.78], p = 6.46 × 10-5), hip extensors strength (MD = 2.88 [1.64, 4.12], p = 4.43 × 10-5), knee flexors strength (MD = 2.03 [0.66, 3.41], p = 0.005), knee extensors strength (MD = 1.80 [0.65, 2.94], p = 0.003), and functional-reach (cm) (MD = 3.74 [0.68, 6.80], p = 0.018), with large effect sizes (η2 = 0.17-0.42), than those in the CON group after the intervention. CONCLUSIONS: Older adults with knee OA in the CRE group exhibited superior muscle strength, health conditions, and functional fitness improvements after the 12-week computer-aided rowing exercise program than those receiving the conventional exercise approach. TRIAL REGISTRATION: The Institutional Review Board of the Taipei Medical University approved the study protocol (no. N201908020, 27/05/2020) and retrospectively registered at ClinicalTrials.gov (trial registry no. NCT04919486, 09/06/2021).

Preparation and Hepatoprotective Activities of Peptides Derived from Mussels (Mytilus edulis) and Clams (Ruditapes philippinarum).

Low molecular weight (<5 kDa) peptides from mussels (Mytilus edulis) (MPs) and the peptides from clams (Ruditapes philippinarum) (CPs) were prepared through enzymatic hydrolysis by proteases (dispase, pepsin, trypsin, alcalase and papain). Both the MPs and the CPs showed excellent in vitro scavenging ability of free radicals including OH, DPPH and ABTS in the concentration range of 0.625−10.000 mg/mL. By contrast, the MPs hydrolyzed by alcalase (MPs-A) and the CPs hydrolyzed by dispase (CPs-D) had the highest antioxidant activities. Furthermore, MPs-A and CPs-D exhibited protective capabilities against oxidative damage induced by H2O2 in HepG2 cells in the concentration range of 25−800 µg/mL. Meanwhile, compared with the corresponding indicators of the negative control (alcohol-fed) mice, lower contents of hepatic MDA and serums ALT and AST, as well as higher activities of hepatic SOD and GSH-PX were observed in experiment mice treated with MPs-A and CPs-D. The present results clearly indicated that Mytilus edulis and Ruditapes philippinarum are good sources of hepatoprotective peptides.

In situ oral lubrication and smoothness sensory perception influenced by tongue surface roughness.

BACKGROUND: The human tongue is important in the oral processing of food and in sensory perception. Tongue topography could influence delicate differences in sensory perception. It is hypothesized that tongue surface roughness could alter oral lubrication status and affect perception of smoothness. Fifteen participants with varying levels of tongue surface roughness were recruited and tested. Participants' in situ oral lubrication status without and after consumption of fluid food (milk with varying fat content and maltodextrin solutions with different shear viscosities) was measured. Participants' smoothness sensory scores were also recorded. RESULTS: The in situ friction coefficient (0.299-1.505) was significantly positively correlated with tongue-surface roughness (54.6-140.0 µm) in all types of test fluid samples across participants. Oral lubrication was significantly decreased when participants consumed the test fluid samples compared with no liquid food consumption, for all test fluid sample types (P < 0.05). No significant differences in in situ friction coefficient were found after participants consumed different test fluid samples, and this was mainly attributed to the limited quantities of fluid residuals in the oral cavity after expectoration. Participants whose tongue surface roughness differed did not exhibit significant differences in smoothness perception with different test fluid samples. CONCLUSION: Tongue surface roughness has a strong impact on in situ oral lubrication, and fluid food intake reduces in situ oral lubrication significantly. Saliva film and tongue surface roughness might play greater roles in oral lubrication and smoothness sensory perception if fluid is expectorated after consumption. The association between oral physiology and texture perception still needs further elucidation. © 2021 Society of Chemical Industry.

Intratumoural heterogeneity and clone evolution of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common type of oral malignancy. Our study uses multipoint materials to explore the heterogeneity and metastasis mechanism of OSCC to find more accurate molecular markers and new therapeutic targets. By using whole-exome capture and sequencing and tumor evolution analysis, we found that most clone-driven mutations were located in the branches of tumor phylogenetic tree, such as COTL1, CASP8, and PROCR. Most clone-driven OSCC mutations occur mainly in tumor suppressor genes, including TP53, SFRP4, and NOTCH1. Our study on intratumor heterogeneity (ITH) and clonal evolution provides an important molecular basis for further understanding of OSCC occurrence and development and metastasis and provides potential targets for the treatment of this disease.

The characteristics and related factors of insomnia among postoperative patients with gastric cancer: a cross-sectional survey.

PURPOSE: This study aims to explore the characteristics and related factors of insomnia of patients after operation for gastric cancer. METHODS: A cross-sectional survey was carried out and finally 115 patients with insomnia after operation for gastric cancer were included. The general information, gastric cancer-related information, sleep quality, and other symptoms were investigated. RESULTS: ① The Pittsburgh sleep quality index score of most insomnia patients after gastric cancer surgery was 11-15 points, and the sleep quality rating was "poor". ② The sleep quality of patients with insomnia after surgery for gastric cancer is related to the number of chemotherapy cycles, fatigue, and depression. ③ The probability of reduced sleep quality with the number of chemotherapy cycles >6 is 3.640 times that of ≤6. The probability of reduced sleep quality during moderate to severe fatigue was 4.390 times that of patients with no or mild fatigue. CONCLUSION: Attention to related factors may be associated with improvement of sleep quality in patients with gastric cancer after surgery.

The impact of aging and reaching movements on grip stability control during manual precision tasks.

BACKGROUND: Operating an object by generating stable hand-grip force during static or dynamic posture control of the upper extremities simultaneously is an important daily activity. Older adults require different attentional resources during grip strength control and arm movements. However, the impact of aging and reaching movements on precise grip strength and stability control among older adults is not well understood. This study investigated the impact of aging and reaching movements on grip strength and stability control in both hands of the upper extremities. METHODS: Fifty healthy young adults (age: 28.8 ± 14.0 years) and 54 healthy older adults (73.6 ± 6.3 years) were recruited to perform isometric grip strength test at 20% maximal voluntary contraction as the target force during three manual precision tasks simultaneously: stationary task (without arm movements), forward-reach task, and backward-reach task. The average grip force (in kg) and coefficient of variation values (expressed as a percentage) during manual precision tasks were calculated to determine the quality of participants' grip strength. The deviation error, absolute error, and force-stability index values were calculated to determine the strength control relative to the target force. RESULTS: For both the young and older groups, the force-stability index values in both hands were significantly higher during forward- and backward-reaching movements than in the stationary condition (p < 0.05). The older group exhibited a significantly lower hand-grip strength and stability of strength control in both hands than the young group (p < 0.05). CONCLUSIONS: Aging and reaching task performance reduced the grip strength of participants and increased the variations in strength control of both hands relative to the target force, indicating that older adults exhibit poor grip strength and stability control when performing arm-reaching movements. These findings may help clinical therapists in establishing objective indexes for poor grip-stability control screening and developing appropriate rehabilitation programs or health-promotion exercises that can improve grip strength and stability control in older people.

Impacts of tai chi exercise on functional fitness in community-dwelling older adults with mild degenerative knee osteoarthritis: a randomized controlled clinical trial.

BACKGROUND: Degenerative osteoarthritis (OA) often leads to pain and stiffness of the affected joints, which may affect the physical performance and decrease the quality of life of people with degenerative knee OA. Compared to traditional exercise, tai chi is a safe exercise with slow movements which can facilitate physical functioning and psychological well being, and might be suitable for improving the physical activities of older adults with knee OA. Therefore, this study investigated the impacts of tai chi exercise on the functional fitness of community-dwelling older adults with degenerative knee OA. METHODS: Sixty-eight community-dwelling older adults with knee OA were recruited from the local community to participate in this randomized controlled clinical trial. All subjects were randomly assigned to either an TCE group that practiced tai chi exercise (TCE) (n = 36) or a control group (CON) (n = 32) that received regular health education programs twice per week for 12 weeks. Outcome measurements were determined using functional fitness tests before and after the intervention, including a 30-s chair stand (number of repeats), 30-s arm-curl (number of repeats), 2-min step (number of steps), chair sit-and-reach (reaching distance, cm), back-scratch flexibility (distance between hands, cm), single-leg stand (time, s), functional reach (reaching distance, cm), 8-foot up-and-go (time, s), and 10-m walk tests (time, s). Pre-post comparisons of functional fitness were analyzed using the ANCOVA test with SPSS software version 18.0. RESULTS: Results revealed that participants' functional fitness in the TCE group had significantly higher adjusted mean post-tests scores than that in the CON group after the intervention, including the 8-foot up-and-go (s) (mean difference [MD]=-2.92 [-3.93, -1.91], p = 2.39*10- 7), 30-s arm curl (MD = 4.75 (2.76, 6.73), p = 1.11*10- 5), 2-min step (MD = 36.94 [23.53, 50.36], p = 7.08*10- 7), 30-s chair stand (MD = 4.66 [2.97, 6.36], p = 6.96*10- 7), functional-reach (MD = 5.86 [3.52, 8.20], p = 4.72*10- 6), single-leg stand with eyes closed (MD = 3.44 [1.92, 4.97], p = 2.74*10- 5), chair sit-and-reach (MD = 3.93 [1.72, 6.15], p = 0.001), and single-leg stand with eyes opened (MD = 17.07 [6.29, 27.85], p = 0.002), with large effect sizes (η²=0.14 ~ 0.34). CONCLUSIONS: Community-dwelling older adults with knee OA in the TCE group had better functional fitness performances after the 12-week tai chi intervention than those receiving only health education.

IGF-1 facilitates thrombopoiesis primarily through Akt activation.

It is known that insulin-like growth factor-1 (IGF-1) also functions as a hematopoietic factor, although its direct effect on thrombopoiesis remains unclear. In this study, we show that IGF-1 is able to promote CD34+ cell differentiation toward megakaryocytes (MKs), as well as the facilitation of proplatelet formation (PPF) and platelet production from cultured MKs. The in vivo study demonstrates that IGF-1 administration accelerates platelet recovery in mice after 6.0 Gy of irradiation and in mice that received bone marrow transplantation following 10.0 Gy of lethal irradiation. Subsequent investigations reveal that extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt activation mediate the effect of IGF-1 on thrombopoiesis. Notably, Akt activation induced by IGF-1 is more apparent than that of ERK1/2, compared with that of thrombopoietin (TPO) treatment. Moreover, the effect of IGF-1 on thrombopoiesis is independent of TPO signaling because IGF-1 treatment can also lead to a significant increase of platelet counts in homozygous TPO receptor mutant mice. Further analysis indicates that the activation of Akt triggered by IGF-1 requires the assistance of steroid receptor coactivator-3 (SRC-3). Therefore, our data reveal a distinct role of IGF-1 in regulating thrombopoiesis, providing new insights into TPO-independent regulation of platelet generation.

SRC-3 is involved in maintaining hematopoietic stem cell quiescence by regulation of mitochondrial metabolism in mice.

Quiescence maintenance is an important property of hematopoietic stem cells (HSCs), whereas the regulatory factors and underlying mechanisms involved in HSC quiescence maintenance are not fully uncovered. Here, we show that steroid receptor coactivator 3 (SRC-3) is highly expressed in HSCs, and SRC-3-deficient HSCs are less quiescent and more proliferative, resulting in increased sensitivity to chemotherapy and irradiation. Moreover, the long-term reconstituting ability of HSCs is markedly impaired in the absence of SRC-3, and SRC-3 knockout (SRC-3-/-) mice exhibit a significant disruption of hematopoietic stem and progenitor cell homeostasis. Further investigations show that SRC-3 deficiency leads to enhanced mitochondrial metabolism, accompanied by overproduction of reactive oxygen species (ROS) in HSCs. Notably, the downstream target genes of peroxisome proliferator-activated receptor-coactivators 1α (PGC-1α) involved in the regulation of mitochondrial metabolism are significantly upregulated in SRC-3-deficient HSCs. Meanwhile, a significant decrease in the expression of histone acetyltransferase GCN5 accompanied by downregulation of PGC-1α acetylation is observed in SRC-3-null HSCs. Conversely, overexpression of GCN5 can inhibit SRC-3 deficiency-induced mitochondrial metabolism enhancement and ROS overproduction, thereby evidently rescuing the impairment of HSCs in SRC-3-/- mice. Collectively, our findings demonstrate that SRC-3 plays an important role in HSC quiescence maintenance by regulating mitochondrial metabolism.

Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease-associated thrombosis in mice.

Thrombosis is a common complication of chronic kidney disease (CKD), but the causes and mechanisms of CKD-associated thrombosis are not well clarified. Here, we show that platelet activity is remarkably enhanced in CKD mice, with increase of serum indoxyl sulfate (IS), a typical uremic toxin, which cannot be effectively cleared by routine dialysis. Ex vivo and in vitro experiments reveal that IS displays a distinct ability to enhance platelet activities, including elevated response to collagen and thrombin, increases in platelet-derived microparticles, and platelet-monocyte aggregates. The flow chamber assay and carotid artery thrombosis model demonstrate that IS-induced platelet hyperactivity contributes to thrombus formation. Further investigations disclose that reactive oxygen species (ROS)-mediated p38MAPK signaling plays a key role in IS-induced platelet hyperactivity. Moreover, we show that Klotho, which is expressed dominantly in the kidneys, has the capacity to counteract IS-induced platelet hyperactivity by inhibiting ROS/p38MAPK signaling, whereas Klotho reduction may aggravate the effect of IS on platelet activation in CKD and klotho+/- mice. Finally, we demonstrate that Klotho protein treatment can protect against IS-induced thrombosis and atherosclerosis in apoE-/- mice. Our findings uncover the mechanism of platelet hyperactivity induced by IS and provide new insights into the pathogenesis and treatment of CKD-associated thrombosis.

Tannic acid attenuated irradiation-induced apoptosis in megakaryocytes.

Ionizing radiation (IR) triggers the generation of reactive oxygen species (ROS), which shows potential roles in damaging the DNA and proteins at the nucleus, and eventually results in apoptosis and even cell death. Antioxidant agents can inhibit the generation of ROS after IR exposure. Tannic acid (TA), has an antioxidant activity involving in preventing cardiovascular and cerebrovascular diseases. However, little is known about the effects of TA on irradiation-induced apoptosis in megakaryocytes. Here, we evaluated the anti-radiation activity of TA in megakaryocytes. Our results showed that TA protected megakaryocytes from apoptosis induced by IR, attenuated IR-induced increases in the production of ROS, and inhibited the changes of mitochondrial membrane potential (MMP). Moreover, TA down-regulated NAPDH oxidase 1 (Nox1) expression, and decreased the phosphorylated levels of JNK and p38. Furthermore, JNK inhibitor could reduce apoptosis induced by X-irradiation in M07e cells. In vivo experiments confirmed that TA could promote the platelet recovery, reduce the percentage of apoptosis CD41+ megakaryocytes in bone marrow and raise survival during 30 days in mice by total body irradiation. In conclusion, TA can protecte the megakaryocytes from apoptosis caused by IR through inhibiting Nox1 expression to reduce ROS generation and repressing JNK/p38 MAPK pathway activation.

Innate Lymphoid Cells: A Link between the Nervous System and Microbiota in Intestinal Networks.

Innate lymphoid cells (ILCs) are a novel family of innate immune cells that act as key coordinators of intestinal mucosal surface immune defense and are essential for maintaining intestinal homeostasis and barrier integrity by responding to locally produced effector cytokines or direct recognition of exogenous or endogenous danger patterns. ILCs are also involved in the pathogenesis of inflammatory bowel disease (IBD). Many studies have demonstrated the occurrence of crosstalk between ILCs and intestinal microbiota, and ILCs have recently been shown to be connected to the enteric nervous system (ENS). Thus, ILCs may act as a key link between the nervous system and microbiota in intestinal networks. In this review, we briefly summarize the role of the ILCs in the intestinal tract (particularly in the context of IBD) and discuss the relationship between ILCs and the microbiota/ENS.