Cell signaling is a very complex network of biochemical reactions triggered by a huge number of stimuli coming from the external medium. The function of any single signaling component depends not only on its own struc...Cell signaling is a very complex network of biochemical reactions triggered by a huge number of stimuli coming from the external medium. The function of any single signaling component depends not only on its own structure but also on its connections with other biomolecules. During prokaryotic-eukaryotic transition, the rearrangement of cell organization in terms of diffusional compartmentalization exerts a deep change in cell signaling functional potentiality. In this review I briefly introduce an intriguing ancient relationship between pathways involved in cell responses to chemical agonists (growth factors, nutrients, hormones) as well as to mechanical forces (stretch, osmotic changes). Some biomolecules (ion channels and enzymes) act as "hubs", thanks to their ability to be directly or indirectly chemically/mechanically co-regulated. In particular calcium signaling machinery and arachidonic acid metabolism are very ancient networks, already present before eukaryotic appearance. A number of molecular "hubs", including phospholipase A2 and some calcium channels, appear tightly interconnected in a cross regulation leading to the cellular response to chemical and mechanical stimulations.展开更多
Focal adhesions(FAs) are large,multiprotein complexs that provides linkers between cytoskeleton to the extracellular matrix(ECM).Cells sense and respond to forces through FAs to regulate a broad range of processes,suc...Focal adhesions(FAs) are large,multiprotein complexs that provides linkers between cytoskeleton to the extracellular matrix(ECM).Cells sense and respond to forces through FAs to regulate a broad range of processes,such as cell growth,migration,differentiation展开更多
Cells sense and respond to forces and extracellular environment through FAs to regulate a broad range of processes, such as cell growth,migration,differentiation and apoptosis. Currently,the underlying mechanisms of t...Cells sense and respond to forces and extracellular environment through FAs to regulate a broad range of processes, such as cell growth,migration,differentiation and apoptosis. Currently,the underlying mechanisms of the force展开更多
Some large-conductance Ca^2＋ and voltage-activated K^＋（BK） channels are activated by membrane stretch. However, the mechanism of mechano-gating of the BK channels is still not well understood. Previous studies hav...Some large-conductance Ca^2＋ and voltage-activated K^＋（BK） channels are activated by membrane stretch. However, the mechanism of mechano-gating of the BK channels is still not well understood. Previous studies have led to the proposal that the linker-gating ring complex functions as a passive spring, transducing the force generated by intracellular Ca^2＋ to the gate to open the channel. This raises the question as to whether membrane stretch is also transmitted to the gate of mechanosensitive （MS） BK channels via the linker-gating complex. To study this, we changed the linker length in the stretch-activated BK channel （SAKCaC）, and examined the effect of membrane stretch on the gating of the resultant mutant channels. Shortening the linker increased, whereas extending the linker reduced, the channel mechanosensitivity both in the presence and in the absence of intracellular Ca^2＋. However, the voltage and Ca^2＋ sensitivities were not significantly altered by membrane stretch. Furthermore, the SAKCaC became less sensitive to membrane stretch at relatively high intracellular Ca^2＋ concentrations or membrane depolarization. These observations suggest that once the channel is in the open-state conformation, tension on the spring is partially released and membrane stretch is less effective. Our results are consistent with the idea that membrane stretch is transferred to the gate via the linker-gating ring complex of the MS BK channels.展开更多
AIM： To evaluate the effects of omeprazole on gastric mechanosensitivity in humans. METHODS： A double lumen polyvinyl tube with a plas- tic bag was introduced into the stomach of healthy volunteers under fluorograph...AIM： To evaluate the effects of omeprazole on gastric mechanosensitivity in humans. METHODS： A double lumen polyvinyl tube with a plas- tic bag was introduced into the stomach of healthy volunteers under fluorography and connected to a barostat device. Subjects were then positioned so they were sitting comfortably, and the minimal distending pressure （MDP） was determined after a 30-rain adap- tation period. Isobaric distensions were performed in stepwise increments of 2 mmHg （2 min each） starting from the MDR Subjects were instructed to score feel- ings at the end of every step using a graphic rating scale： 0, no perception; 1, weak/vague; 2, weak but significant; 3, moderate/vague; 4, moderate but signifi- cant; 5, severe discomfort; and 6, unbearable pain. Af- ter this first test, subjects received omeprazole （20 mg, after dinner） once daily for 1 wk. A second test was performed on the last day of treatment. RESULTS： No adverse effects were observed. Mean MDP before and after treatment was 6.3 - 0.3 mmHg and 6.2：1：0.5 mmHg, respectively. One subject before and 2 after treatment did not reach a score of 6 at the maximum bag volume of 750 mL. After omeprazole, there was a significant increase in the distension pres- sure required to reach scores of 1 （P = 0.019） and 2 （P = 0.017） as compared to baseline. There were no changes in pressure required to reach the other scores after treatment. Two subjects before and one after omeprazole rated their abdominal feeling 〈 1 at MDP, and mean （±SE） abdominal discomfort scores at MDP were 0.13±0.09 and 0.04±0.04, respectively. Mean scores induced by each MDP ＋ 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 （mmHg） were 1.1±0.3, 2.0±0.4, 2.9±0.5, 3.3±0.4, 4.6±0.3, 5.2±0.3, 5.5±0.2, 5.5±0.3, 5.7±0.3, and 5.4, respectively. After omepra- zole, abdominal feeling scores for the same incremen- tal pressures over MDP were 0.3±0.1, 0.8±0.1, 2.0±0.4, 2.8±0.4, 3.8±0.4, 4.6±0.4, 4.9±0.3, 5.4±0.4, 5.2±0.6, and 5.0±1.0, respectively. A signif- icant decrease in feeling score was observed at intra- bag pressures of MDP ＋ 2 mmHg （P = 0.028） and ＋ 4 mmHg （P = 0.013）, respectively, after omeprazole. No significant score changes were observed at pres- sures ≥ MDP ＋ 6 mmHg. CONCLUSION： Although the precise mechanisms are undetermined, the present study demonstrated that omeprazole decreases mechanosensitivity to mild gas- tric distension.展开更多
A bone cell population dynamics model for cor- tical bone remodeling under mechanical stimulus is devel- oped in this paper. The external experiments extracted from the literature which have not been used in the creat...A bone cell population dynamics model for cor- tical bone remodeling under mechanical stimulus is devel- oped in this paper. The external experiments extracted from the literature which have not been used in the creation of the model are used to test the validity of the model. Not only can the model compare reasonably well with these ex- perimental results such as the increase percentage of final values of bone mineral content （BMC） and bone fracture en- ergy （BFE） among different loading schemes （which proves the validity of the model）, but also predict the realtime devel- opment pattern of BMC and BFE, as well as the dynamics of osteoblasts （OBA）, osteoclasts （OCA）, nitric oxide （NO） and prostaglandin E2 （PGE2） for each loading scheme, which can hardly be monitored through experiment. In conclusion, the model is the first of its kind that is able to provide an in- sight into the quantitative mechanism of bone remodeling at cellular level by which bone cells are activated by mechan- ical stimulus in order to start resorption/formation of bone mass. More importantly, this model has laid a solid foun- dation based on which future work such as systemic control theory analysis of bone remodeling under mechanical stimu- lus can be investigated. The to-be identified control mecha- nism will help to develop effective drugs and combined non- pharmacological therapies to combat bone loss pathologies. Also this deeper understanding of how mechanical forces quantitatively interact with skeletal tissue is essential for the generation of bone tissue for tissue replacement purposes in tissue engineering.展开更多
We propose a mathematic model of muscle cell membrane based on thin-walled elastic rod theory. A deformation occurs in rodents’ skeletal and cardiac cells during a period of antiorthostatic suspension. We carried out...We propose a mathematic model of muscle cell membrane based on thin-walled elastic rod theory. A deformation occurs in rodents’ skeletal and cardiac cells during a period of antiorthostatic suspension. We carried out a quantitative evaluation of the deformation using this model. The calculations showed the deformation in cardiac cells to be greater than in skeletal ones. This data corresponds to experimental results of cell response that appears intense in cardiomyocytes than in skeletal muscle cells. Moreover, the deformation in skeletal and heart muscle cells has a different direction (stretching vs. compression), corresponding to experimental data of different adaptive response generation pathways in cells because of external mechanical condition changes.展开更多
To develop durable bone healing strategies through improved control of bone repair,it is of critical importance to understand the mechanisms of bone mechanical integrity when in contact with biomaterials and implants....To develop durable bone healing strategies through improved control of bone repair,it is of critical importance to understand the mechanisms of bone mechanical integrity when in contact with biomaterials and implants.Bone mechanical integrity is defined here as the adaptation of structural properties of remodeled bone in regard to an applied mechanical loading.Accordingly,the authors present why future investigations in bone repair and regeneration should emphasize on the matrix surrounding the osteocytes.Osteocytes are mechanosensitive cells considered as the orchestrators of bone remodeling,which is the biological process involved in bone homeostasis.These bone cells are trapped in an interconnected porous network,the lacunocanalicular network,which is embedded in a bone mineralized extracellular matrix.As a consequence of an applied mechanical loading,the bone deformation results in the deformation of this lacunocanalicular network inducing a shift in interstitial fluid pressure and velocity,thus resulting in osteocyte stimulation.The material environment surrounding each osteocyte,the so called perilacunar and pericellular matrices properties,define its mechanosensitivity.While this mechanical stimulation pathway is well known,the laws used to predict bone remodeling are based on strains developing at a tissue scale,suggesting that these strains are related to the shift in fluid pressure and velocity at the lacunocanalicular scale.While this relationship has been validated through observation in healthy bone,the fluid behavior at the bone-implant interface is more complex.The presence of the implant modifies fluid behavior,so that for the same strain at a tissue scale,the shift in fluid pressure and velocity will be different than in a healthy bone tissue.In that context,new markers for bone mechanical integrity,considering fluid behavior,have to be defined.The viewpoint exposed by the authors indicates that the properties of the pericellular and the perilacunar matrices have to be systematically investigated and used as structural markers of fluid behavior in the course of bone biomaterial development.展开更多
Cell as elastic rod behavior model is proposed to describe its contractile activity. The model takes into account the result of the transduction of external influences, which is resulting in the formation of internal ...Cell as elastic rod behavior model is proposed to describe its contractile activity. The model takes into account the result of the transduction of external influences, which is resulting in the formation of internal deformation, and evaluates the mobility and/or the tension in the muscle cells under the external influence.展开更多
Mechanosensation is an important process in biological fluid-structure interaction. To understand the biophysics underlying mechanosensation, it is essential to quantify the correlation between membrane deformation, m...Mechanosensation is an important process in biological fluid-structure interaction. To understand the biophysics underlying mechanosensation, it is essential to quantify the correlation between membrane deformation, membrane tension, external fluid shear stress, and conformation of mechanosensitive (MS) channels. Smoothed dissipative particle dynamics (SDPD) simulations of vesicle/cell in three types of flow configurations are conducted to calculate the tension in lipid membrane due to fluid shear stress from the surrounding viscous flow. In combination with a simple continuum model for an MS channel, SDPD simulation results suggest that shearing adhered vesicles/cells is more effective to induce membrane tension sufficient to stretch MS channels open than a free shear flow or a constrictive channel flow. In addition, we incorporate the bilayer-cytoskeletal interaction in a two-component model to probe the effects of a cytoskeletal network on the gating of MS channels.展开更多
Compelling evidence shows that intracellular free magnesium [Mg^2＋]i may be a critical regulator of cell activity in eukaryotes. However, membrane transport mechanisms mediating Mg^2＋ influx in mammalian cells are p...Compelling evidence shows that intracellular free magnesium [Mg^2＋]i may be a critical regulator of cell activity in eukaryotes. However, membrane transport mechanisms mediating Mg^2＋ influx in mammalian cells are poorly understood. Here, we show that mechanosensitive （MS） cationic channels activated by stretch are permeable for Mg^2＋ ions at different extracellular concentrations including physiological ones. Single-channel currents were recorded from cell-attached and inside-out patches on K562 leukaemia cells at various concentrations of MgCl2 when Mg^2＋ was the only available carrier of inward currents. At 2 mM Mg^2＋, inward mechanogated currents representing Mg^2＋ influx through MS channels corresponded to the unitary conductance of about 5 pS. At higher Mg^2＋ levels, only slight increase of single-channel currents and conductance occurred, implying that Mg^2＋ permeation through MS channels is characterized by strong saturation. At 20 and 90 mM Mg^2＋, mean conductance values for inward currents carried by Mg^2＋ were rather similar, being equal to 6.8 ± 0.5 and 6.4 ± 0.5 pS, respectively. The estimation of the channel-selective permeability according to constant field equation is obviously limited due to saturation effects. We conclude that the detection of single currents is the main evidence for Mg^2＋ permeation through membrane channels activated by stretch. Our single-current measurements document Mg^2＋ influx through MS channels in the plasma membrane of leukaemia cells.展开更多
Molecular dynamics simulation(MDS)is a powerful technology for investigating evolution dynamics of target proteins,and it is used widely in various fields from materials to biology.This mini-review introduced the prin...Molecular dynamics simulation(MDS)is a powerful technology for investigating evolution dynamics of target proteins,and it is used widely in various fields from materials to biology.This mini-review introduced the principles,main preforming procedures,and advances of MDS,as well as its applications on the studies of conformational and allosteric dynamics of proteins especially on that of the mechanosensitive integrins.Future perspectives were also proposed.This review could provide clues in understanding the potentiality of MD simulations in structure–function relationship investigation of biological proteins.展开更多
BK channels are widely expressed in both excitable and non-excitable cells and known to be involved in many physiological processes,such as vascular smooth tone regulation,neuronal firing and endocrine cell secretion[...BK channels are widely expressed in both excitable and non-excitable cells and known to be involved in many physiological processes,such as vascular smooth tone regulation,neuronal firing and endocrine cell secretion[1].Recently, the BK channels have展开更多
To explore the role of mechanosensitive potassium channel TREK-1, Western blot analysis was used to investigate the expression changes of TREK-1 in left ventricle in acute mechanically stretched heart. Forty Wistar ra...To explore the role of mechanosensitive potassium channel TREK-1, Western blot analysis was used to investigate the expression changes of TREK-1 in left ventricle in acute mechanically stretched heart. Forty Wistar rats were randomly divided into 8 groups （n=5 in each group）, subject to single Langendorff perfusion for 0, 30, 60, 120 min and acute mechanical stretch for 0, 30, 60, 120 min respectively. With Langendorff apparatus, an acute mechanically stretched heart model was established. There was no significant difference in the expression of TREK-1 among single Langendorff perfusion groups （P〉0.05）. As compared to non-stretched Langendorff-perfused heart, only the expression of TREK-1 in acute mechanically stretched heart （120 min） was greatly increased （P〈0.05）. This result suggested that some course of mechanical stretch could up-regulate the expression of TREK-1 in left ventricle. TREK-1 might play an important role in mechanoelectric feedback, so it could reduce the occurrence of arrhythmia that was induced by extra mechanical stretch.展开更多
Purpose:This study aimed to assess the influence of older vs.younger age and previous anterior cruciate ligament(ACL)injury on resting serum cartilage oligomeric matrix protein(sCOMP(t_(pre)))concentration,on immediat...Purpose:This study aimed to assess the influence of older vs.younger age and previous anterior cruciate ligament(ACL)injury on resting serum cartilage oligomeric matrix protein(sCOMP(t_(pre)))concentration,on immediate load-induced sCOMP kinetics after a 30-min treadmill walking stress(ΔsCOMP(t_(post))),and on the dose-response relationship between ambulatory load magnitude andΔsCOMP(t_(post)).Methods:A total of 85 participants were recruited in 4 groups(20-30 years:24 healthy,23 ACL-injured;40-60 years:23 healthy,15 ACL-injured).Blood samples were collected immediately before and after a walking stress at 80%,100%,or 120%bodyweight(BW)on 3 test days and analyzed for sCOMP concentration.Linear models were used to estimate the effect of age,knee status(unilateral ACL injury,2-10 years prior),and sex on sCOMP(t_(pre)),ΔsCOMP(t_(post)),and the dose-re sponse between ambulatory load magnitude andΔsCOMP(t_(post)).Results:We found that sCOMP(t_(pre))was 21%higher in older than younger participants(p<0.001)but did not differ between ACL-injured and healthy participants(p=0.632).Also,ΔsCOMP(t_(post))was 19%lower in older than younger participants(p=0.030)and increased with body mass index(p<0.001),sCOMP(t_(pre))(p=0.008),and with 120%BW(p<0.001),independent of age,ACL injury,or sex.Conclusion:Age but not prior ACL injury influences resting sCOMP and load-induced sCOMP.The dose-response relationship between ambulatory load magnitude and load-induced sCOMP changes is not affected by age,ACL injury,or sex.A better understanding of systemic sCOMP and the role of its mechanoresponse for the understanding of osteoarthritis pathophysiology and monitoring intervention efficacy may require knowledge of individual cartilage composition and tissue-level loading parameters.展开更多
Atherosclerotic cardiovascular disease and its complications are a high-incidence disease worldwide.Numerous studies have shown that blood flow shear has a huge impact on the function of vascular endothelial cells,and...Atherosclerotic cardiovascular disease and its complications are a high-incidence disease worldwide.Numerous studies have shown that blood flow shear has a huge impact on the function of vascular endothelial cells,and it plays an important role in gene regulation of pro-inflammatory,pro-thrombotic,pro-oxidative stress,and cell permeability.Many impor-tant endothelial cell mechanosensitive genes have been discovered,including KLK10,CCN gene family,NRP2,YAP,TAZ,HIF-1α,NF-kB,FOS,JUN,TFEB,KLF2/KLF4,NRF2,and ID1.Some of them have been intensively studied,whereas the relevant regulatory mechanism of other genes remains unclear.Focusing on these mechanosensitive genes will provide new strategies for therapeutic intervention in atherosclerotic vascular disease.Thus,this article reviews the mechanosensitive genes affecting vascular endothelial cells,including classical pathways and some newly screened genes,and summarizes the latest research progress on their roles in the pathogenesis of atherosclerosis to reveal effective therapeutic targets of drugs and provide new insights foranti-atherosclerosis.展开更多
Mechanical models offer a quantitative framework for understanding scientific problems,predicting novel phenomena,and guiding experimental designs.Over the past few decades,the emerging field of cellular mechanobiolog...Mechanical models offer a quantitative framework for understanding scientific problems,predicting novel phenomena,and guiding experimental designs.Over the past few decades,the emerging field of cellular mechanobiology has greatly benefited from the substantial contributions of new theoretical tools grounded in mechanical models.Within the expansive realm of mechanobiology,the investigation of how cells sense and respond to their microenvironment has become a prominent research focus.There is a growing acknowledgment that cells mechanically interact with their external surroundings through an integrated machinery encompassing the cell membrane,cytoskeleton,and nucleus.This review provides a comprehensive overview of mechanical models addressing three pivotal components crucial for force transmission within cells,extending from mechanosensitive receptors on the cell membrane to the actomyosin cytoskeleton and ultimately to the nucleus.We present the existing numerical relationships that form the basis for understanding the structures,mechanical properties,and functions of these components.Additionally,we underscore the significance of developing mechanical models in advancing cellular mechanobiology and propose potential directions for the evolution of these models.展开更多
Recent advancements in biomedical research have underscored the importance of noninvasive cellular manipulation techniques.Sonogenetics,a method that uses genetic engineering to produce ultrasound-sensitive proteins i...Recent advancements in biomedical research have underscored the importance of noninvasive cellular manipulation techniques.Sonogenetics,a method that uses genetic engineering to produce ultrasound-sensitive proteins in target cells,is gaining prominence along with optogenetics,electrogenetics,and magnetogenetics.Upon stimulation with ultrasound,these proteins trigger a cascade of cellular activities and functions.Unlike traditional ultrasound modalities,sonogenetics offers enhanced spatial selectivity,improving precision and safety in disease treatment.This technology broadens the scope of non-surgical interventions across a wide range of clinical research and therapeutic applications,including neuromodulation,oncologic treatments,stem cell therapy,and beyond.Although current literature predominantly emphasizes ultrasonic neuromodulation,this review offers a comprehensive exploration of sonogenetics.We discuss ultrasound properties,the specific ultrasound-sensitive proteins employed in sonogenetics,and the technique’s potential in managing conditions such as neurological disorders,cancer,and ophthalmic diseases,and in stem cell therapies.Our objective is to stimulate fresh perspectives for further research in this promising field.展开更多
Clinical trials and animal experimental studies have demonstrated an association of arterial baroreflex impairment with the prognosis and mortality of cardiovascular diseases and diabetes. As a primary part of the art...Clinical trials and animal experimental studies have demonstrated an association of arterial baroreflex impairment with the prognosis and mortality of cardiovascular diseases and diabetes. As a primary part of the arterial baroreflex arc, the pressure sensitivity of arterial baroreceptors is blunted and involved in arterial baroreflex dysfunction in cardiovascular diseases and diabetes.Changes in the arterial vascular walls, mechanosensitive ion channels, and voltage-gated ion channels contribute to the attenuation of arterial baroreceptor sensitivity. Some endogenous substances(such as angiotensin II and superoxide anion) can modulate these morphological and functional alterations through intracellular signaling pathways in impaired arterial baroreceptors. Arterial baroreceptors can be considered as a potential therapeutic target to improve the prognosis of patients with cardiovascular diseases and diabetes.展开更多
Post-amputation pain causes great sufering to amputees,but still no efective drugs are available due to its elusive mechanisms.Our previous clinical studies found that surgical removal or radiofrequency treatment of t...Post-amputation pain causes great sufering to amputees,but still no efective drugs are available due to its elusive mechanisms.Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump efectively relieves the phantom pain aficting patients after amputation.This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain(CPAP).However,the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery.In this study,we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infltrated into the dorsal root ganglion(DRG)neurons worked synergistically to promote CPAP.Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG,and the expression of TMEM63A increased signifcantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer(TNT).Behavioral tests showed that the mechanical,heat,and cold sensitivity were not afected in the Tmem63a-/-mice in the naïve state,suggesting the basal pain was not afected.In the infammatory and post-amputation state,the mechanical allodynia but not the heat hyperalgesia or cold allodynia was signifcantly decreased in Tmem63a-/-mice.Further study showed that there was severe neuronal injury and macrophage infltration in the DRG,tibial nerve,residual stump,and the neuromalike structure of the TNT mouse model,Consistent with this,expression of the pro-infammatory cytokines TNFα,IL-6,and IL-1βall increased dramatically in the DRG.Interestingly,the deletion of Tmem63a signifcantly reduced the macrophage infltration in the DRG but not in the tibial nerve stump.Furthermore,the ablation of macrophages signifcantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model,indicating an interaction between nociceptors and macrophages,and that these two factors gang up together to regulate the formation of CPAP.This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.展开更多
文摘Cell signaling is a very complex network of biochemical reactions triggered by a huge number of stimuli coming from the external medium. The function of any single signaling component depends not only on its own structure but also on its connections with other biomolecules. During prokaryotic-eukaryotic transition, the rearrangement of cell organization in terms of diffusional compartmentalization exerts a deep change in cell signaling functional potentiality. In this review I briefly introduce an intriguing ancient relationship between pathways involved in cell responses to chemical agonists (growth factors, nutrients, hormones) as well as to mechanical forces (stretch, osmotic changes). Some biomolecules (ion channels and enzymes) act as "hubs", thanks to their ability to be directly or indirectly chemically/mechanically co-regulated. In particular calcium signaling machinery and arachidonic acid metabolism are very ancient networks, already present before eukaryotic appearance. A number of molecular "hubs", including phospholipase A2 and some calcium channels, appear tightly interconnected in a cross regulation leading to the cellular response to chemical and mechanical stimulations.
文摘Focal adhesions(FAs) are large,multiprotein complexs that provides linkers between cytoskeleton to the extracellular matrix(ECM).Cells sense and respond to forces through FAs to regulate a broad range of processes,such as cell growth,migration,differentiation
基金supported by grants from the National Natural Science Foundation of China,Nos 10628205,10732050,and 10872115
文摘Cells sense and respond to forces and extracellular environment through FAs to regulate a broad range of processes, such as cell growth,migration,differentiation and apoptosis. Currently,the underlying mechanisms of the force
基金Acknowledgments We thank Ms Mekie Takahashi, Ms Ritsuko Kanda （Nagaya University, Japan）, Dr Changliang Fu and Dr Shouqing Lu （Institute of Mechanics, Chinese Academy of Sciences） for technical assistance. This work was partly supported by research grants from the National Natural Science Foundation of China （10602031） and Grants-in-aid for Scientific Research on Priority Areas （#15086270 to M.S.） and Creative Research （# 16GS0308 to M.S.） from the Ministry of Education Science Sports and Culture, Japan.
文摘Some large-conductance Ca^2＋ and voltage-activated K^＋（BK） channels are activated by membrane stretch. However, the mechanism of mechano-gating of the BK channels is still not well understood. Previous studies have led to the proposal that the linker-gating ring complex functions as a passive spring, transducing the force generated by intracellular Ca^2＋ to the gate to open the channel. This raises the question as to whether membrane stretch is also transmitted to the gate of mechanosensitive （MS） BK channels via the linker-gating complex. To study this, we changed the linker length in the stretch-activated BK channel （SAKCaC）, and examined the effect of membrane stretch on the gating of the resultant mutant channels. Shortening the linker increased, whereas extending the linker reduced, the channel mechanosensitivity both in the presence and in the absence of intracellular Ca^2＋. However, the voltage and Ca^2＋ sensitivities were not significantly altered by membrane stretch. Furthermore, the SAKCaC became less sensitive to membrane stretch at relatively high intracellular Ca^2＋ concentrations or membrane depolarization. These observations suggest that once the channel is in the open-state conformation, tension on the spring is partially released and membrane stretch is less effective. Our results are consistent with the idea that membrane stretch is transferred to the gate via the linker-gating ring complex of the MS BK channels.
基金Supported by A Grant-in-Aid for Scientific Research from the Aichi Medical University Alumni Association, in part
文摘AIM： To evaluate the effects of omeprazole on gastric mechanosensitivity in humans. METHODS： A double lumen polyvinyl tube with a plas- tic bag was introduced into the stomach of healthy volunteers under fluorography and connected to a barostat device. Subjects were then positioned so they were sitting comfortably, and the minimal distending pressure （MDP） was determined after a 30-rain adap- tation period. Isobaric distensions were performed in stepwise increments of 2 mmHg （2 min each） starting from the MDR Subjects were instructed to score feel- ings at the end of every step using a graphic rating scale： 0, no perception; 1, weak/vague; 2, weak but significant; 3, moderate/vague; 4, moderate but signifi- cant; 5, severe discomfort; and 6, unbearable pain. Af- ter this first test, subjects received omeprazole （20 mg, after dinner） once daily for 1 wk. A second test was performed on the last day of treatment. RESULTS： No adverse effects were observed. Mean MDP before and after treatment was 6.3 - 0.3 mmHg and 6.2：1：0.5 mmHg, respectively. One subject before and 2 after treatment did not reach a score of 6 at the maximum bag volume of 750 mL. After omeprazole, there was a significant increase in the distension pres- sure required to reach scores of 1 （P = 0.019） and 2 （P = 0.017） as compared to baseline. There were no changes in pressure required to reach the other scores after treatment. Two subjects before and one after omeprazole rated their abdominal feeling 〈 1 at MDP, and mean （±SE） abdominal discomfort scores at MDP were 0.13±0.09 and 0.04±0.04, respectively. Mean scores induced by each MDP ＋ 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 （mmHg） were 1.1±0.3, 2.0±0.4, 2.9±0.5, 3.3±0.4, 4.6±0.3, 5.2±0.3, 5.5±0.2, 5.5±0.3, 5.7±0.3, and 5.4, respectively. After omepra- zole, abdominal feeling scores for the same incremen- tal pressures over MDP were 0.3±0.1, 0.8±0.1, 2.0±0.4, 2.8±0.4, 3.8±0.4, 4.6±0.4, 4.9±0.3, 5.4±0.4, 5.2±0.6, and 5.0±1.0, respectively. A signif- icant decrease in feeling score was observed at intra- bag pressures of MDP ＋ 2 mmHg （P = 0.028） and ＋ 4 mmHg （P = 0.013）, respectively, after omeprazole. No significant score changes were observed at pres- sures ≥ MDP ＋ 6 mmHg. CONCLUSION： Although the precise mechanisms are undetermined, the present study demonstrated that omeprazole decreases mechanosensitivity to mild gas- tric distension.
文摘A bone cell population dynamics model for cor- tical bone remodeling under mechanical stimulus is devel- oped in this paper. The external experiments extracted from the literature which have not been used in the creation of the model are used to test the validity of the model. Not only can the model compare reasonably well with these ex- perimental results such as the increase percentage of final values of bone mineral content （BMC） and bone fracture en- ergy （BFE） among different loading schemes （which proves the validity of the model）, but also predict the realtime devel- opment pattern of BMC and BFE, as well as the dynamics of osteoblasts （OBA）, osteoclasts （OCA）, nitric oxide （NO） and prostaglandin E2 （PGE2） for each loading scheme, which can hardly be monitored through experiment. In conclusion, the model is the first of its kind that is able to provide an in- sight into the quantitative mechanism of bone remodeling at cellular level by which bone cells are activated by mechan- ical stimulus in order to start resorption/formation of bone mass. More importantly, this model has laid a solid foun- dation based on which future work such as systemic control theory analysis of bone remodeling under mechanical stimu- lus can be investigated. The to-be identified control mecha- nism will help to develop effective drugs and combined non- pharmacological therapies to combat bone loss pathologies. Also this deeper understanding of how mechanical forces quantitatively interact with skeletal tissue is essential for the generation of bone tissue for tissue replacement purposes in tissue engineering.
文摘We propose a mathematic model of muscle cell membrane based on thin-walled elastic rod theory. A deformation occurs in rodents’ skeletal and cardiac cells during a period of antiorthostatic suspension. We carried out a quantitative evaluation of the deformation using this model. The calculations showed the deformation in cardiac cells to be greater than in skeletal ones. This data corresponds to experimental results of cell response that appears intense in cardiomyocytes than in skeletal muscle cells. Moreover, the deformation in skeletal and heart muscle cells has a different direction (stretching vs. compression), corresponding to experimental data of different adaptive response generation pathways in cells because of external mechanical condition changes.
文摘To develop durable bone healing strategies through improved control of bone repair,it is of critical importance to understand the mechanisms of bone mechanical integrity when in contact with biomaterials and implants.Bone mechanical integrity is defined here as the adaptation of structural properties of remodeled bone in regard to an applied mechanical loading.Accordingly,the authors present why future investigations in bone repair and regeneration should emphasize on the matrix surrounding the osteocytes.Osteocytes are mechanosensitive cells considered as the orchestrators of bone remodeling,which is the biological process involved in bone homeostasis.These bone cells are trapped in an interconnected porous network,the lacunocanalicular network,which is embedded in a bone mineralized extracellular matrix.As a consequence of an applied mechanical loading,the bone deformation results in the deformation of this lacunocanalicular network inducing a shift in interstitial fluid pressure and velocity,thus resulting in osteocyte stimulation.The material environment surrounding each osteocyte,the so called perilacunar and pericellular matrices properties,define its mechanosensitivity.While this mechanical stimulation pathway is well known,the laws used to predict bone remodeling are based on strains developing at a tissue scale,suggesting that these strains are related to the shift in fluid pressure and velocity at the lacunocanalicular scale.While this relationship has been validated through observation in healthy bone,the fluid behavior at the bone-implant interface is more complex.The presence of the implant modifies fluid behavior,so that for the same strain at a tissue scale,the shift in fluid pressure and velocity will be different than in a healthy bone tissue.In that context,new markers for bone mechanical integrity,considering fluid behavior,have to be defined.The viewpoint exposed by the authors indicates that the properties of the pericellular and the perilacunar matrices have to be systematically investigated and used as structural markers of fluid behavior in the course of bone biomaterial development.
文摘Cell as elastic rod behavior model is proposed to describe its contractile activity. The model takes into account the result of the transduction of external influences, which is resulting in the formation of internal deformation, and evaluates the mobility and/or the tension in the muscle cells under the external influence.
文摘Mechanosensation is an important process in biological fluid-structure interaction. To understand the biophysics underlying mechanosensation, it is essential to quantify the correlation between membrane deformation, membrane tension, external fluid shear stress, and conformation of mechanosensitive (MS) channels. Smoothed dissipative particle dynamics (SDPD) simulations of vesicle/cell in three types of flow configurations are conducted to calculate the tension in lipid membrane due to fluid shear stress from the surrounding viscous flow. In combination with a simple continuum model for an MS channel, SDPD simulation results suggest that shearing adhered vesicles/cells is more effective to induce membrane tension sufficient to stretch MS channels open than a free shear flow or a constrictive channel flow. In addition, we incorporate the bilayer-cytoskeletal interaction in a two-component model to probe the effects of a cytoskeletal network on the gating of MS channels.
文摘Compelling evidence shows that intracellular free magnesium [Mg^2＋]i may be a critical regulator of cell activity in eukaryotes. However, membrane transport mechanisms mediating Mg^2＋ influx in mammalian cells are poorly understood. Here, we show that mechanosensitive （MS） cationic channels activated by stretch are permeable for Mg^2＋ ions at different extracellular concentrations including physiological ones. Single-channel currents were recorded from cell-attached and inside-out patches on K562 leukaemia cells at various concentrations of MgCl2 when Mg^2＋ was the only available carrier of inward currents. At 2 mM Mg^2＋, inward mechanogated currents representing Mg^2＋ influx through MS channels corresponded to the unitary conductance of about 5 pS. At higher Mg^2＋ levels, only slight increase of single-channel currents and conductance occurred, implying that Mg^2＋ permeation through MS channels is characterized by strong saturation. At 20 and 90 mM Mg^2＋, mean conductance values for inward currents carried by Mg^2＋ were rather similar, being equal to 6.8 ± 0.5 and 6.4 ± 0.5 pS, respectively. The estimation of the channel-selective permeability according to constant field equation is obviously limited due to saturation effects. We conclude that the detection of single currents is the main evidence for Mg^2＋ permeation through membrane channels activated by stretch. Our single-current measurements document Mg^2＋ influx through MS channels in the plasma membrane of leukaemia cells.
基金Project supported by the National Key Research and Development Program of China(Grant No.2016YFA0501601)the National Natural Science Foundation of China(Grant Nos.91642203,31627804,and 11972042)+2 种基金the Frontier Science Key Project of the Chinese Academy of Sciences(Grant No.QYZDJ-SSWJSC018)the Scientific Instrument Developing Project of the Chinese Academy of Sciences(Grant No.GJJSTU20190005)the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB22040101)。
文摘Molecular dynamics simulation(MDS)is a powerful technology for investigating evolution dynamics of target proteins,and it is used widely in various fields from materials to biology.This mini-review introduced the principles,main preforming procedures,and advances of MDS,as well as its applications on the studies of conformational and allosteric dynamics of proteins especially on that of the mechanosensitive integrins.Future perspectives were also proposed.This review could provide clues in understanding the potentiality of MD simulations in structure–function relationship investigation of biological proteins.
基金supported by Natural Science Foundation of China grants10732070,10602031
文摘BK channels are widely expressed in both excitable and non-excitable cells and known to be involved in many physiological processes,such as vascular smooth tone regulation,neuronal firing and endocrine cell secretion[1].Recently, the BK channels have
基金This project was supported by a grant from National Natu-ral Sciences Foundation of China (No 30270559)
文摘To explore the role of mechanosensitive potassium channel TREK-1, Western blot analysis was used to investigate the expression changes of TREK-1 in left ventricle in acute mechanically stretched heart. Forty Wistar rats were randomly divided into 8 groups （n=5 in each group）, subject to single Langendorff perfusion for 0, 30, 60, 120 min and acute mechanical stretch for 0, 30, 60, 120 min respectively. With Langendorff apparatus, an acute mechanically stretched heart model was established. There was no significant difference in the expression of TREK-1 among single Langendorff perfusion groups （P〉0.05）. As compared to non-stretched Langendorff-perfused heart, only the expression of TREK-1 in acute mechanically stretched heart （120 min） was greatly increased （P〈0.05）. This result suggested that some course of mechanical stretch could up-regulate the expression of TREK-1 in left ventricle. TREK-1 might play an important role in mechanoelectric feedback, so it could reduce the occurrence of arrhythmia that was induced by extra mechanical stretch.
基金funded by the Swiss National Science Foundation(#184912,in 2019)funding from the German Research Foundation(SFB 1483,in 2021).
文摘Purpose:This study aimed to assess the influence of older vs.younger age and previous anterior cruciate ligament(ACL)injury on resting serum cartilage oligomeric matrix protein(sCOMP(t_(pre)))concentration,on immediate load-induced sCOMP kinetics after a 30-min treadmill walking stress(ΔsCOMP(t_(post))),and on the dose-response relationship between ambulatory load magnitude andΔsCOMP(t_(post)).Methods:A total of 85 participants were recruited in 4 groups(20-30 years:24 healthy,23 ACL-injured;40-60 years:23 healthy,15 ACL-injured).Blood samples were collected immediately before and after a walking stress at 80%,100%,or 120%bodyweight(BW)on 3 test days and analyzed for sCOMP concentration.Linear models were used to estimate the effect of age,knee status(unilateral ACL injury,2-10 years prior),and sex on sCOMP(t_(pre)),ΔsCOMP(t_(post)),and the dose-re sponse between ambulatory load magnitude andΔsCOMP(t_(post)).Results:We found that sCOMP(t_(pre))was 21%higher in older than younger participants(p<0.001)but did not differ between ACL-injured and healthy participants(p=0.632).Also,ΔsCOMP(t_(post))was 19%lower in older than younger participants(p=0.030)and increased with body mass index(p<0.001),sCOMP(t_(pre))(p=0.008),and with 120%BW(p<0.001),independent of age,ACL injury,or sex.Conclusion:Age but not prior ACL injury influences resting sCOMP and load-induced sCOMP.The dose-response relationship between ambulatory load magnitude and load-induced sCOMP changes is not affected by age,ACL injury,or sex.A better understanding of systemic sCOMP and the role of its mechanoresponse for the understanding of osteoarthritis pathophysiology and monitoring intervention efficacy may require knowledge of individual cartilage composition and tissue-level loading parameters.
基金supported in part by the National Natural Science Foundation of China(No.31971242,12032007)the Chongqing Science and Technology Bureau(China)(No.cstc2021jsyj-yzysbA0057)the Joint Medical Research Project of Chongqing Science and Technology Bureau and Chongqing Health Commission(China)(No.2018ZDXM032).
文摘Atherosclerotic cardiovascular disease and its complications are a high-incidence disease worldwide.Numerous studies have shown that blood flow shear has a huge impact on the function of vascular endothelial cells,and it plays an important role in gene regulation of pro-inflammatory,pro-thrombotic,pro-oxidative stress,and cell permeability.Many impor-tant endothelial cell mechanosensitive genes have been discovered,including KLK10,CCN gene family,NRP2,YAP,TAZ,HIF-1α,NF-kB,FOS,JUN,TFEB,KLF2/KLF4,NRF2,and ID1.Some of them have been intensively studied,whereas the relevant regulatory mechanism of other genes remains unclear.Focusing on these mechanosensitive genes will provide new strategies for therapeutic intervention in atherosclerotic vascular disease.Thus,this article reviews the mechanosensitive genes affecting vascular endothelial cells,including classical pathways and some newly screened genes,and summarizes the latest research progress on their roles in the pathogenesis of atherosclerosis to reveal effective therapeutic targets of drugs and provide new insights foranti-atherosclerosis.
基金supported by the National Natural Science Foundation of China(12202345,12372316,12022206)China Postdoctoral Science Foundation(2022M722534)+2 种基金Natural Science Basic Research Plan in Shaanxi Province of China(2022KWZ-17)the Shaanxi Province Youth Talent Support Programthe Young Talent Support Plan of Xi'an Jiaotong University.
文摘Mechanical models offer a quantitative framework for understanding scientific problems,predicting novel phenomena,and guiding experimental designs.Over the past few decades,the emerging field of cellular mechanobiology has greatly benefited from the substantial contributions of new theoretical tools grounded in mechanical models.Within the expansive realm of mechanobiology,the investigation of how cells sense and respond to their microenvironment has become a prominent research focus.There is a growing acknowledgment that cells mechanically interact with their external surroundings through an integrated machinery encompassing the cell membrane,cytoskeleton,and nucleus.This review provides a comprehensive overview of mechanical models addressing three pivotal components crucial for force transmission within cells,extending from mechanosensitive receptors on the cell membrane to the actomyosin cytoskeleton and ultimately to the nucleus.We present the existing numerical relationships that form the basis for understanding the structures,mechanical properties,and functions of these components.Additionally,we underscore the significance of developing mechanical models in advancing cellular mechanobiology and propose potential directions for the evolution of these models.
基金the National Natural Science Foundation of China(No.81771845)the Chongqing Science and Technology Committee,Chongqing,China(No.CSTB2022NSCQ-MSX0812).
文摘Recent advancements in biomedical research have underscored the importance of noninvasive cellular manipulation techniques.Sonogenetics,a method that uses genetic engineering to produce ultrasound-sensitive proteins in target cells,is gaining prominence along with optogenetics,electrogenetics,and magnetogenetics.Upon stimulation with ultrasound,these proteins trigger a cascade of cellular activities and functions.Unlike traditional ultrasound modalities,sonogenetics offers enhanced spatial selectivity,improving precision and safety in disease treatment.This technology broadens the scope of non-surgical interventions across a wide range of clinical research and therapeutic applications,including neuromodulation,oncologic treatments,stem cell therapy,and beyond.Although current literature predominantly emphasizes ultrasonic neuromodulation,this review offers a comprehensive exploration of sonogenetics.We discuss ultrasound properties,the specific ultrasound-sensitive proteins employed in sonogenetics,and the technique’s potential in managing conditions such as neurological disorders,cancer,and ophthalmic diseases,and in stem cell therapies.Our objective is to stimulate fresh perspectives for further research in this promising field.
基金supported by the American Heart Association(0730108N)the National Institute of Health’s National Heart,Lung,and Blood Institute(R01HL-098503 and R01HL-137832),USA
文摘Clinical trials and animal experimental studies have demonstrated an association of arterial baroreflex impairment with the prognosis and mortality of cardiovascular diseases and diabetes. As a primary part of the arterial baroreflex arc, the pressure sensitivity of arterial baroreceptors is blunted and involved in arterial baroreflex dysfunction in cardiovascular diseases and diabetes.Changes in the arterial vascular walls, mechanosensitive ion channels, and voltage-gated ion channels contribute to the attenuation of arterial baroreceptor sensitivity. Some endogenous substances(such as angiotensin II and superoxide anion) can modulate these morphological and functional alterations through intracellular signaling pathways in impaired arterial baroreceptors. Arterial baroreceptors can be considered as a potential therapeutic target to improve the prognosis of patients with cardiovascular diseases and diabetes.
基金supported by grants from the Ministry of Science and Technology of China(2021ZD0203201)the National Natural Science Foundation of China(81971034,81672237)+3 种基金The Innovative Research Team of High-level Local Universities in Shanghai,Shanghai Pujiang Program(19PJ1401700)the Natural Science Foundation of Shanghai Municipality(22ZR1413800)The Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning,Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJ Lab,and Shanghai Center for Brain Science and Brain-Inspired Technology,Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(ZYYCXTD-C-202008).
文摘Post-amputation pain causes great sufering to amputees,but still no efective drugs are available due to its elusive mechanisms.Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump efectively relieves the phantom pain aficting patients after amputation.This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain(CPAP).However,the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery.In this study,we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infltrated into the dorsal root ganglion(DRG)neurons worked synergistically to promote CPAP.Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG,and the expression of TMEM63A increased signifcantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer(TNT).Behavioral tests showed that the mechanical,heat,and cold sensitivity were not afected in the Tmem63a-/-mice in the naïve state,suggesting the basal pain was not afected.In the infammatory and post-amputation state,the mechanical allodynia but not the heat hyperalgesia or cold allodynia was signifcantly decreased in Tmem63a-/-mice.Further study showed that there was severe neuronal injury and macrophage infltration in the DRG,tibial nerve,residual stump,and the neuromalike structure of the TNT mouse model,Consistent with this,expression of the pro-infammatory cytokines TNFα,IL-6,and IL-1βall increased dramatically in the DRG.Interestingly,the deletion of Tmem63a signifcantly reduced the macrophage infltration in the DRG but not in the tibial nerve stump.Furthermore,the ablation of macrophages signifcantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model,indicating an interaction between nociceptors and macrophages,and that these two factors gang up together to regulate the formation of CPAP.This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.
