Hepatic arterial infusion therapy for advanced hepatocellular carcinoma after systemic treatment failure: Multicenter, real-world study.

AIM: The study was conducted to evaluate the feasibility and safety profile of hepatic arterial infusion chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin (HAIC-FOLFOX) as an alternative therapeutic choice for patients with advanced hepatocellular carcinoma (HCC) that is refractory to systemic treatment including immune checkpoint blockades or molecular targeting agents. METHODS: Two hundred and forty five consecutive patients with advanced HCC who received HAIC-FOLFOX treatment after systemic treatment failure were retrospectively reviewed in six institutions and their survival, tumor response, and tolerance were assessed. RESULTS: The median overall survival (OS) and progression-free survival of the 209 included participants were 10.5 months (95% confidence interval [CI], 8.1-12.9) and 6.0 months (95% CI, 5.1-6.9), respectively. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, the objective response rate was 21.1%, and the disease control rate was 64.6%. Multivariate analysis of risk factors of OS were albumin-bilirubin grade (2 and 3 vs. 1, hazard ratio [HR] 1.57; 95% CI, 1.05-2.34; p = 0.028), tumor number (>3 vs. 1-3, HR 2.18; 95% CI, 1.10-4.34; p = 0.026), extrahepatic spread (present vs. absent, HR 1.61, 95% CI, 1.06-2.45; p = 0.027), synchronous systemic treatment (present vs. absent, HR 0.55, 95% CI, 0.37-0.83; p = 0.004) and treatment response (responder vs. nonresponder, HR 0.30, 95% CI, 0.17-0.53; p < 0.001). Grade 3-4 adverse events (AEs) occurred in 59 (28.2%) HCC patients. All AEs were manageable, and deaths related to hepatic artery infusion chemotherapy treatment were not observed. CONCLUSIONS: Our findings support the effectiveness and safety of HAIC-FOLFOX treatment for patients with advanced HCC who have failed systemic treatment.

Cells respond to space microgravity through cytoskeleton reorganization.

Decades of spaceflight studies have provided abundant evidence that individual cells in vitro are capable of sensing space microgravity and responding with cellular changes both structurally and functionally. However, how microgravity is perceived, transmitted, and converted to biochemical signals by single cells remains unrevealed. Here in this review, over 40 cellular biology studies of real space fights were summarized. Studies on cells of the musculoskeletal system, cardiovascular system, and immune system were covered. Among all the reported cellular changes in response to space microgravity, cytoskeleton (CSK) reorganization emerges as a key indicator. Based on the evidence of CSK reorganization from space flight research, a possible mechanism from the standpoint of "cellular mechanical equilibrium" is proposed for the explanation of cellular response to space microgravity. Cytoskeletal equilibrium is broken by the gravitational change from ground to space and is followed by cellular morphological changes, cell mechanical properties changes, extracellular matrix reorganization, as well as signaling pathway activation/inactivation, all of which ultimately lead to the cell functional changes in space microgravity.

Preventing Disused Bone Loss through Inhibition of Advanced Glycation End Products.

Bone loss occurs in astronauts during long-term space flight, but the mechanisms are still unclear. We previously showed that advanced glycation end products (AGEs) were involved in microgravity-induced osteoporosis. Here, we investigated the improvement effects of blocking AGEs formation on microgravity-induced bone loss by using the AGEs formation inhibitor, irbesartan. To achieve this objective, we used a tail-suspended (TS) rat model to simulate microgravity and treated the TS rats with 50 mg/kg/day irbesartan, as well as the fluorochrome biomarkers injected into rats to label dynamic bone formation. To assess the accumulation of AGEs, pentosidine (PEN), non-enzymatic cross-links (NE-xLR), and fluorescent AGEs (fAGEs) were identified in the bone; 8-hydroxydeoxyguanosine (8-OHdG) was analyzed for the reactive oxygen species (ROS) level in the bone. Meanwhile, bone mechanical properties, bone microstructure, and dynamic bone histomorphometry were tested for bone quality assessment, and Osterix and TRAP were immunofluorescences stained for the activities of osteoblastic and osteoclastic cells. Results showed AGEs increased significantly and 8-OHdG expression in bone showed an upward trend in TS rat hindlimbs. The bone quality (bone microstructure and mechanical properties) and bone formation process (dynamic bone formation and osteoblastic cells activities) were inhibited after tail-suspension, and showed a correlation with AGEs, suggesting the elevated AGEs contributed to the disused bone loss. After being treated with irbesartan, the increased AGEs and 8-OHdG expression were significantly inhibited, suggesting irbesartan may reduce ROS to inhibit dicarbonyl compounds, thus suppressing AGEs production after tail-suspension. The inhibition of AGEs can partially alter the bone remodeling process and improve bone quality. Both AGEs accumulation and bone alterations almost occurred in trabecular bone but not in cortical bone, suggesting AGEs effects on bone remodeling under microgravity are dependent on the biological milieu.

Effects of advanced glycation end products on osteocytes mechanosensitivity.

Osteocytes are extremely sensitive to mechanical loading and govern bone remodeling process. Advanced glycation end products (AGEs) have the capacity to induce osteocyte apoptosis. In order to investigate the effects of AGEs on the mechanosensitivity of osteocytes, the osteocytic-like cells (MLO-Y4) were treated with low (50 µg/ml) and high (400 µg/ml) concentrations of AGEs for 1day and exposed to 15 dyne/cm2 of fluid shear stress. Then the F-actin cytoskeleton, prostaglandin E2(PGE2), Nitric oxide (NO), the Wnt/ß-catenin signaling pathway activity mRNA expressions were detected for osteocytes mechanical response changes; osteocalcin (OCN) and receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) were detected for the regulation on bone remodeling function of osteocytes. The results showed that AGEs accumulation inhibited the sense of osteocytes to external mechincal loading, promoted shear-induced NO and PGE2 release, suppressed the mechanosensitivity of Wnt/ß-catenin signaling pathway, and furthermore promoted OCN and RANKL/OPG mRNA expressions. These indicated AGEs had an adverse impact on the mechanosensitivity of osteocytes, and led to a negative effect on their regulation of bone remodeling process under mechanical stimulation. This work provides a new perspective to interpret the alteration mechanism of osteocytes mechanosensitivity and provides a novel clue for exploring the mechanism of osteoporosis.

The microgravity induces the ciliary shortening and an increased ratio of anterograde/retrograde intraflagellar transport of osteocytes.

It is hard to explain the decrease in mechanosensitivity of osteocytes under microgravity. Primary cilia are essential mechanosensor for osteocytes. The cilia become shorter under the simulated microgravity (SMG) environment. The cilia change may be the reason for the mechanosensitivity decrease of osteocytes under SMG. To reveal the role of primary cilia in weightless-induced osteocyte dysfunction, we investigate intraflagellar transport (IFT) to understand the mechanism of the decreased cilia length of osteocytes when subjected to SMG. We measure the number of anterograde IFT particles with GFP::IFT88 and retrograde IFT particles with OFP::IFT43 that occur at a particular transverse plane of the cilia. We also measure the expression of IFT88 and IFT43 and the size of IFT particles under SMG. Herein, the ratio of anterograde/retrograde particle number and the ratio of protein expression of IFT88/IFT43 increase under SMG. The size of anterograde IFT particles with GFP::IFT88 gets a significant decrease under SMG. Fundamentally, SMG has broken the balanced operating state of IFT and makes the IFT particles smaller. The phenomenon under SMG is intriguing.

Pharmacological Regulation of Primary Cilium Formation Affects the Mechanosensitivity of Osteocytes.

Primary cilia are responsible for sensing mechanical loading in osteocytes. However, the underlying working mechanism of cilia remains elusive. An osteocyte model is necessary to reveal the role of cilia. Furthermore, the osteocyte model should be with upregulated or downregulated primary cilium expression. Herein, we used a pharmacological method to regulate the cilium formation of osteocytes. After screening, some pharmacological agents can regulate the cilium formation of osteocytes. We performed a CCK-8 assay to analyze the optimal working conditions of the drugs for MLO-Y4 cells. The agents include chloral hydrate (CH), Gd3+, Li+, and rapamycin. The expression of cilia affects the cellular functions, including mechanosensitivity, of osteocytes. Results showed that CH downregulated the cilium formation and ciliogenesis of osteocytes. In addition, Gd3+, Li+, and rapamycin upregulated the cilium expression of osteocytes. Moreover, the cilium expression positively correlated with the mechanosensitivity of osteocytes. This work reveals the role of primary cilia in the mechanosensing of osteocytes.

Visfatin regulates the production of lipopolysaccharide-induced inflammatory cytokines through p38 signaling in murine macrophages.

Visfatin plays an important role in regulation of inflammatory cytokines. However, the role of visfatin under bacterial stress condition is not fully explored yet. Therefore, the present study was conducted for the better understanding of the regulation mechanism of visfatin on the production of inflammatory cytokines under lipopolysaccharide (LPS) stress in RAW264.7 murine macrophages. Enzyme Linked Immuno-sorbent Assay (ELISA) results showed that, as compared to the control group, visfatin significantly up-regulated the levels of interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis factor (TNF)-α (P < 0.05). Compared to the LPS group, the levels of IL-1ß, IL-10, TNF-α was down-regulated in visfatin + LPS group (P < 0.05). After adding p38 inhibitor, SB203580 to culture, the production of IL-1ß, IL-6, IL-10, TNF-α was significantly reduced as compared to visfatin only (P < 0.01). The results showed that visfatin may regulate the production of IL-1ß, IL-6, IL-10, TNF-α through the p38 signaling pathway. As compared to the PBS group, phosphorylayed p38 (P-p38) level in visfatin group was significantly decreased (P < 0.05). Compared with LPS group, P-p38 level was significantly decreased in visfatin + LPS group (P < 0.05). Hence, it is concluded that visfatin can significantly increase the levels of IL-1ß, IL-10 and TNF-α in normal conditions, while their levels significantly decrease during inflammation. Moreover, visfatin participates in the inflammatory response through the p38 mitogen-activated protein kinase (MAPK) signal pathway by the up-regulation of p38 and down-regulation of P-p38 levels.

The bio-response of osteocytes and its regulation on osteoblasts under vibration.

Vibration, especially at low magnitude and high frequency (LMHF), was demonstrated to be anabolic for bone, but how the LMHF vibration signal is perceived by osteocytes is not fully studied. On the other hand, the mechanotransduction of osteocytes under shear stress has been scientists' primary focus for years. Due to the small strain caused by low-magnitude vibration, whether the previous explanation for shear stress will still work for LMHF vibration is unknown. In this study, a finite element method (FEM) model based on the real geometrical shape of an osteocyte was built to compare the mechanical behaviors of osteocytes under LMHF vibration and shear stress. The bio-response of osteocytes to vibration under different frequencies, including the secretion of soluble factors and the concentration of intracellular calcium, were studied. The regulating effect of the conditioned medium (CM) from vibrated osteocytes on osteoblasts was also studied. The FEM analysis result showed the cell membrane deformation under LMHF vibration was very small (with a peak value of 1.09%) as compared to the deformation caused by shear stress (with a peak value of 6.65%). The F-actin stress fibers of osteocytes were reorganized, especially on the nucleus periphery after LMHF vibration. The vibration at 30 Hz has a promoting effect on osteocytes and the osteogenesis of osteoblasts, whereas vibration at 90 Hz was suppressive. These results lead to a conclusion that the bio-response of osteocytes to LMHF vibration is frequency-dependent and is more related to the cytoskeleton on nuclear periphery rather than the membrane deformation.

Genetic predictors of Stevens-Johnson syndrome and toxic epidermal necrolysis induced by aromatic antiepileptic drugs among the Chinese Han population.

BACKGROUND: Previous studies suggested that one or more HLA alleles participate in the pathogenesis of AED-induced SJS/TEN, but most of these studies focused only on the HLA-B alleles. PURPOSE: The aim of this study was to investigate the pathogenesis of AED-induced SJS/TEN across a broader spectrum of HLA alleles, including the HLA-A, -B and -DRB1 alleles, to further explore the association between each HLA allele and SJS/TEN induced by aromatic AEDs. METHODS: A total of 27 patients exhibiting AED-induced SJS/TEN (16 CBZ-SJS/TEN, seven LTG-SJS/TEN, two PHT-SJS/TEN, and two PB-SJS/TEN patients) and 64 patients who exhibited tolerance to AEDs were recruited. High-resolution HLA genotyping was performed to estimate the prevalence of the HLA-A, -B and -DRB1 alleles for each subject. RESULTS: Fifteen subjects in the SJS/TEN group (12 exhibiting CBZ-SJS/TEN, two exhibiting LTG-SJS, and one exhibiting PB-SJS) carried the HLA-B*15:02 allele, whereas only 4/64 subjects in the AED-tolerant group carried this allele; the carrier rate of HLA-B*15:02 was significantly different between the groups (P<0.001). Nine patients in the SJS/TEN group carried the HLA-DRB1*15:01 allele, while 12/64 subjects in the tolerant group carried this allele; considering that two patients in the SJS/TEN group (one exhibiting LTG-SJS and one exhibiting PB-SJS) were homozygous for this allele, the prevalence of HLA-DRB1*15:01 expression between the two groups was significantly different (P=0.041). Furthermore, the carrier rates of HLA-A*33:03, HLA-B*58:01, and HLA-DRB1*03:01 were lower in the SJS/TEN group compared with the AED-tolerant group. The carrier rates of these alleles between the two groups were significantly different (P=0.009, 0.016, and 0.009, respectively). CONCLUSIONS: The HLA-DRB1*15:01 allele may represent a risk factor for AED-induced SJS/TEN among Han Chinese. The HLA-A*33:03, HLA-B*58:01, and HLA-DRB1*03:01 alleles may be "protectors" against AED-induced SJS/TEN, especially CBZ-SJS/TEN.

Nonlinear dynamics of membrane skeleton in osteocyte.

Osteocytes play an important role in mechanosensation and conduction in bone tissue, and the change of mechanical environment can affect the sensitivity of osteocytes to external stimulation. The structure of osteocytes will be changed when they are subjected to vibrations, which influence the mechanosensitivity of osteocytes and alter the regulation of bone remodeling process. As an important mechanotransduction structure in osteocytes, the membrane skeleton greatly affects the mechanosensation and conduction of osteocytes. However, the dynamic responses of membrane skeleton to the vibration and the structural changes of membrane skeleton are unclear. Therefore, we applied a nonlinear dynamics method to explain the time-dependent changes of membrane skeleton. The semi-ellipsoidal reticulate shell structure of membrane skeleton is built based on the experimental observation in our previous work. Then, the nonlinear dynamic equations of membrane skeleton are established according to the theory of plate and shell dynamics, and the displacement-time curves, phase portraits, and Poincaré maps of membrane skeleton structure were obtained. The numeration results show that under the vibration stimulation of 15 Hz, 30 Hz, 60 Hz, and 90 Hz, the membrane skeleton is destroyed after a transient equilibrium position vibration. The vibration of 15 Hz has the most destructive effect on the membrane skeleton, the natural frequency of membrane skeleton may be less than 15 Hz. In addition, the chaos phenomenon occurs to the membrane skeleton during vibration. As a damping factor, the existence of viscosity alleviates the damage of structure. This study can help us to understand the oscillation characteristic of membrane skeleton in osteocyte.

Structural insights into substrate recognition and translocation of human peroxisomal ABC transporter ALDP.

Dysfunctions of ATP-binding cassette, subfamily D, member 1 (ABCD1) cause X-linked adrenoleukodystrophy, a rare neurodegenerative disease that affects all human tissues. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long-chain fatty acids for their ß-oxidation. Here, the six cryo-electron microscopy structures of ABCD1 in four distinct conformational states were presented. In the transporter dimer, two transmembrane domains form the substrate translocation pathway, and two nucleotide-binding domains form the ATP-binding site that binds and hydrolyzes ATP. The ABCD1 structures provide a starting point for elucidating the substrate recognition and translocation mechanism of ABCD1. Each of the four inward-facing structures of ABCD1 has a vestibule that opens to the cytosol with variable sizes. Hexacosanoic acid (C26:0)-CoA substrate binds to the transmembrane domains (TMDs) and stimulates the ATPase activity of the nucleotide-binding domains (NBDs). W339 from the transmembrane helix 5 (TM5) is essential for binding substrate and stimulating ATP hydrolysis by substrate. ABCD1 has a unique C-terminal coiled-coil domain that negatively modulates the ATPase activity of the NBDs. Furthermore, the structure of ABCD1 in the outward-facing state indicates that ATP molecules pull the two NBDs together and open the TMDs to the peroxisomal lumen for substrate release. The five structures provide a view of the substrate transport cycle and mechanistic implication for disease-causing mutations.

Clinical Predictive Models for Delayed Cerebral Infarction After Ruptured Intracranial Aneurysm Clipping for Patients: A Retrospective Study.

Objective: A nomogram was developed in this work to predict the probability of delayed cerebral infarction (DCI) after ruptured intracranial aneurysms (RIA) clipping. Methods: Clinical data of patients with intracranial aneurysm were obtained from the neurosurgery department of the First Affiliated Hospital of Chongqing Medical University from January 2016 to December 2020. A total of 419 patients receiving surgery of ruptured intracranial aneurysm clipping were included and a total of 37 patients with DCI were set as the observation group. The control group consisted of 382 patients without DCI. Risk factors of DCI were screened by univariate and multivariate logistic regression analysis and included in the nomogram. Results: Univariate analysis showed that female (P = 0.009), small aneurysm (P = 0.031), intraoperative aneurysm rupture (P = 0.007) and cerebral vasospasm (P < 0.001) were risk factors for postoperative DCI while smoking history (P = 0.044) were protective factors for postoperative DCI. Multivariate Logistic regression analysis showed that small aneurysm (P = 0.002, OR = 3.332, 95%-7.104), intraoperative aneurysm rupture (P = 0.004, OR = 0.122, 95%-CI, 0.029-0.504)and cerebral vasospasm (P < 0.001, OR = 0.153, 95%-CI, 0.070-0.333) were independent risk factors of postoperative DCI. The calibration curve of the probability of occurrence showed that the nomogram was in good correspondence with the observed results with a C-index of 0.766 (95% CI, 0.684-0.848). Meanwhile, the Decision curve analysis (DCA) showed that the established predictive model had a good clinical net benefit. Conclusion: The well-established nomogram is expected to be an effective tool to predict the occurrence of DCI after intracranial ruptured aneurysm and can be used to assist clinicians to develop more effective treatment strategies and improve the prognosis of patients.

Clinical features of psychogenic nonepileptic seizures: a study of 64 cases in southwest China.

This article describes the clinical features of psychogenic nonepileptic seizures (PNES) in people in southwest China. Patients with a confirmed diagnosis of pure PNES by video/EEG monitoring were retrospectively reviewed. A total of 64 patients with PNES were included, 32 (50%) of whom were male. Twenty (31.3%) patients had previously been misdiagnosed and treated for epilepsy. Psychological trauma and head injuries were considered antecedent traumatic factors. A history of abuse was rare. The PNES cases were divided into three subtypes: psychogenic minor motor seizures, psychogenic major motor seizures, and unresponsive seizures. Age at onset was identified as a predictor of prognosis. The results of this study demonstrated a higher prevalence of PNES in males compared with previous studies. The semiology of PNES in China is similar to that in Western countries. Classification of semiology may be helpful in the differential diagnosis of PNES.

Visfatin Exerts Immunotherapeutic Effects in Lipopolysaccharide-Induced Acute Lung Injury in Murine Model.

Visfatin acts as a significant regulator of inflammatory cytokines. However, the immunological response and therapeutic effects of visfatin under bacterial stress in murine lung tissue are still not clear. To investigate the role of visfatin on lipopolysaccharide (LPS)-induced acute lung injury (ALI), thirty Kunming mice were divided into Saline, LPS, and LPS + visfatin groups. After routine blood examination, the effects of visfatin on inflammatory cytokines, lung tissue structure, and expression of inflammatory mediators were explored through hematoxylin-eosin (H&E), Masson and immunohistochemical staining, quantitative polymerase chain reaction (Q-PCR), and Western blotting. Compared with the Saline group, neutrophil percentage, peripheral blood neutrophil count, and the ratio of lymphocyte count (NLR) were upregulated in LPS group. Moreover, Masson staining showed alterations in lung tissue structure; the mRNA level of different cytokines (IL-6, IL-1ß, TNF-α, IL-10, TLR4, IFN-γ) was upregulated; and the protein expression of interleukin (IL)-6, myeloperoxidase (MPO), and transforming growth factor-ß1 (TGF-ß) was significantly (p < 0.05) different in LPS group. Compared with LPS group, neutrophil percentage significantly decreased (p < 0.01), the numbers of lymphocytes significantly (p < 0.05) increased, NLR decreased, Masson staining of the lung was extremely different (p < 0.01), the structure of the lung was slightly damaged, and the myeloperoxidase values of lung showed no differences in LPS + visfatin. Hence, visfatin inhibits the lung inflammation induced by ALI. During the ALI, visfatin acts by decreasing NLR, downregulated the expression of MPO, enhanced antioxidant capacity, and regulated the inflammatory factors IL-1ß, IL-6, IL-10, and TNF-α to reduce the lung injury.

Economic burden of epilepsy in a developing country: a retrospective cost analysis in China.

PURPOSE: To study the cost of epilepsy in China, and, therefore, provide essential information on the burden of the disease to individuals and society. METHODS: A cost-of-illness study was performed on a retrospective cohort of medically treated patients. Data on clinical characteristics, utilization of sources, and costs were collected from 289 patients in a standardized format. RESULTS: Direct medical care costs was Chinese yuan, renminbi (RMB) 2,529 (USD 372) per year per patient, of which antiepileptic drugs (RMB 1,651 or USD 243) accounted for the major cost component. Nonmedical direct costs were much less than direct health care costs, averaging approximately RMB 756 (USD 111). Costs due to loss of productivity averaged approximately RMB 1,968 (USD 289) per patient per year. Taken together, the overall mean annual cost for epilepsy per patient in our series was approximately RMB 5,253 (USD 773), and these costs accounted for more than half of the mean annual income. Total cost was significantly associated with disease severity and different responses to drug treatment. In addition, new antiepileptic drugs and the number of drugs taken were closely related with the drug cost. CONCLUSION: The results indicate that the economic burden of epilepsy to both Chinese patients and the nation is heavy, and the composition proportions of the costs in China have many similar features and some noteworthy differences with that of other countries.

[Effect of geniposide on vascular dementia in rats].

OBJECTIVE: To investigate the effect of geniposide on vascular dementia (VaD) in rats. METHODS: VaD rat model was established by permanent ligation of bilateral common carotid arteries. Morris water maze performance was assessed after 4 weeks of treatment with geniposide, followed by pathological examinations of hippocampus and cerebral cortex. RESULTS: The VaD rats had significantly longer escape latency and lower percentage of activities in platform quadrant than the rats in the sham surgery group (P<0.05). The VaD rats treated with geniposide [50 mg/(kg x d), 75 mg/(kg x d)] had significantly shorter escape latency (except the first day of the test) and significantly higher percentage of activities in platform quadrant than the VaD rats without treatment (P<0.05). No significant differences were found between the geniposide treated group and the Donepezil treated group and the sham surgery control group. Geniposide significantly alleviated neurons,apoptosis and necrosis induced by chronic cerebral hypoperfusion of cortex and hippocampus. CONCLUSION: Chronic cerebral hypoperfusion can induce cognitive impairment. Geniposide can improve cognitive ability of Vascular Dementia in rats. This may represent a potential treatment strategy for vascular dementia.

Spontaneous cellular vibratory motions of osteocytes are regulated by ATP and spectrin network.

Vibration at high frequency has been demonstrated to be anabolic for bone and embedded osteocytes. The response of osteocytes to vibration is frequency-dependent, but the mechanism remains unclear. Our previous computational study using an osteocyte finite element model has predicted a resonance effect involving in the frequency-dependent response of osteocytes to vibration. However, the cellular spontaneous vibratory motion of osteocytes has not been confirmed. In the present study, the cellular vibratory motions (CVM) of osteocytes were recorded by a custom-built digital holographic microscopy and quantitatively analyzed. The roles of ATP and spectrin network in the CVM of osteocytes were studied. Results showed the MLO-Y4 osteocytes displayed dynamic vibratory motions with an amplitude of ~80 nm, which is relied both on the ATP content and spectrin network. Spectrum analysis showed several frequency peaks in CVM of MLO-Y4 osteocytes at 30 Hz, 39 Hz, 83 Hz and 89 Hz. These peak frequencies are close to the commonly used effective frequencies in animal training and in-vitro cell experiments, and show a correlation with the computational predictions of the osteocyte finite element model. These results implicate that osteocytes are dynamic and the cellular dynamic motion is involved in the cellular mechanotransduction of vibration.

Visfatin Plays a Significant Role in Alleviating Lipopolysaccharide-Induced Apoptosis and Autophagy Through PI3K/AKT Signaling Pathway During Acute Lung Injury in Mice.

Visfatin is involved in the body's inflammation and immune response. Inflammation could promote, while visfatin may directly or indirectly mitigate the effects of apoptosis and autophagy. Whether visfatin lessens the detrimental effects of lipopolysaccharide (LPS)-induced mouse acute lung injury (ALI) is poorly understood yet. Therefore, in the current study, the regulation mechanism of visfatin on apoptosis and autophagy was explored in Kunming mice by replicating LPS-induced inflammatory ALI model. Based on the mouse model of ALI, HE staining, TUNEL, transmission electron microscopy, immunohistochemical staining, real-time fluorescence quantitative PCR and western blot were used and the results showed that the alveolar septum was thinner than that of the LPS group, slight lung interstitial and alveolar exudation appeared, and a small number of inflammatory cell infiltration was found in the visfatin intervention group, indicating reduced tissue damage in lungs. After visfatin treatment, the expression of pro-apoptotic genes Bax, Bik, and p53 decreased and the expression of anti-apoptotic genes Bcl-2 and Bcl-xl increased, and expression of autophagy factors LC3 and Beclin1 decreased, indicating that visfatin inhibits apoptosis and reduces autophagy. The expression of PI3K and p-AKT was upregulated in the visfatin intervention group, the expression of AKT was downregulated, and the PI3K/AKT signaling pathway was activated. Hence, visfatin could activate the PI3K/AKT signaling pathway, reduce the apoptotic rate in alveolar epithelial cells and the level of autophagy in ALI by regulating the expression of autophagy factors, ultimately causing a protective effect on lung tissue.

The potential role of spectrin network in the mechanotransduction of MLO-Y4 osteocytes.

The spectrin is first identified as the main component of erythrocyte membrane skeleton. It is getting growing attention since being found in multiple nonerythroid cells, providing complex mechanical properties and signal interface under the cell membrane. Recent genomics studies have revealed that the spectrin is highly relevant to bone disorders. However, in osteocytes, the important mechanosensors in bone, the role of spectrin is poorly understood. In this research, the role of spectrin in the mechanotransduction of MLO-Y4 osteocytes was studied. Immunofluorescence staining showed that, the spectrins were elaborately organized as a porous network throughout the cytoplasm, and linked with F-actin into a dense layer underlying the cell membrane. AFM results indicate that, the spectrin is pivotal for maintaining the overall elasticity of osteocytes, especially for the cell cortex stiffiness. Disruption of the spectrin network caused obvious softening of osteocytes, and resulted in a significant increase of Ca2+ influx, NO secretion, cell-cell connections and also induced a translocation of eNOS from membrane to cytoplasm. These results indicate that the spectrin network is a global structural support for osteocytes involving in the mechanotransduction process, making it a potential therapeutic target for bone disorders.

Effects of visfatin on the apoptosis of intestinal mucosal cells in immunological stressed rats.

This study was undertaken to determine if visfatin is involved in the inflammation or apoptosis introduced by LPS in rats. Forty 8-week old Wistar rats were divided into four groups (n=10 in each group) and injected with saline, visfatin, LPS and visfatin+LPS co-stimulated via caudal vein. The duodenum, jejunum and ileum were harvested from all the rats. Compared to the saline treated group, visfatin significantly increased the number of TUNEL-positive apoptotic cells and the expression of caspase-3 protein in intestinal mucosa. Similarly, ELISA and western blot analysis also showed the up-regulation of pro-caspase-3 and cleaved caspase-3 expression in the visfatin group compared to the control group. In contrast to LPS, visfatin down-regulated the expression of cleaved-caspase-3 in the visfatin+LPS co-stimulated group, resulting in a significant decrease in apoptosis in intestinal mucosal cells. We observed more pro-caspase-3 positive cells in the visfatin+LPS co-stimulated group. The results indicate that, in the presence of LPS, visfatin plays an important role in the regulation of cell apoptosis and inflammation.