The Factors Affecting the Stability of IOP Homeostasis.

Purpose: Shear-induced nitric oxide (NO) production by Schlemm's canal (SC) endothelial cells provides a fast, IOP-sensitive feedback signal that normally contributes to IOP homeostasis. Our goal was to analyze the response of this homeostatic system under constant flow perfusion (as occurs in vivo) vs. constant pressure perfusion (as typical for laboratory perfusions). Methods: A mathematical model of aqueous humor dynamics, including shear-mediated NO signaling, was formulated and analyzed for stability. The model includes Goldmann's equation, accounting for proximal and distal outflow resistance, and describes how elevated IOP causes narrowing of SC lumen that increases the shear stress on SC cells. Elevated shear stress stimulates NO production, which acts to reduce outflow resistance and relax trabecular meshwork cells to decrease trabecular meshwork stiffness, affecting the SC luminal caliber. Results: During constant flow perfusion, the outflow system is typically stable, returning to baseline IOP after a perturbation. In contrast, during constant pressure perfusion, the outflow system can become unstable and exhibit a time-dependent change in outflow resistance that diverges from baseline. Conclusions: The stability of shear mediated IOP homeostasis is predicted to differ critically between constant flow vs. constant pressure perfusion. Because outflow facility is typically measured at a constant pressure in the laboratory, this instability may contribute to the characteristic time-dependent increase in outflow facility, known as washout, observed in many nonhuman species. Studies of IOP homeostasis should consider how the outflow system may respond differently under constant pressure vs. constant flow perfusion.

Mechanisms and physiological relevance of acid-base exchange in functional units of the kidney.

This review discusses the importance of homeostasis with a particular emphasis on the acid-base (AB) balance, a crucial aspect of pH regulation in living systems. Two primary organ systems correct deviations from the standard pH balance: the respiratory system via gas exchange and the kidneys via proton/bicarbonate secretion and reabsorption. Focusing on kidney functions, we describe the complexity of renal architecture and its challenges for experimental research. We address specific roles of different nephron segments (the proximal convoluted tubule, the loop of Henle and the distal convoluted tubule) in pH homeostasis, while explaining the physiological significance of ion exchange processes maintained by the kidneys, particularly the role of bicarbonate ions (HCO3-) as an essential buffer system of the body. The review will be of interest to researchers in the fields of physiology, biochemistry and molecular biology, which builds a strong foundation and critically evaluates existing studies. Our review helps identify the gaps of knowledge by thoroughly understanding the existing literature related to kidney acid-base homeostasis.

Melatonin in energy control: Circadian time-giver and homeostatic monitor.

Melatonin is a neurohormone synthesized from dietary tryptophan in various organs, including the pineal gland and the retina. In the pineal gland, melatonin is produced at night under the control of the master clock located in the suprachiasmatic nuclei of the hypothalamus. Under physiological conditions, the pineal gland seems to constitute the unique source of circulating melatonin. Melatonin is involved in cellular metabolism in different ways. First, the circadian rhythm of melatonin helps the maintenance of proper internal timing, the disruption of which has deleterious effects on metabolic health. Second, melatonin modulates lipid metabolism, notably through diminished lipogenesis, and it has an antidiabetic effect, at least in several animal models. Third, pharmacological doses of melatonin have antioxidative, free radical-scavenging, and anti-inflammatory properties in various in vitro cellular models. As a result, melatonin can be considered both a circadian time-giver and a homeostatic monitor of cellular metabolism, via multiple mechanisms of action that are not all fully characterized. Aging, circadian disruption, and artificial light at night are conditions combining increased metabolic risks with diminished circulating levels of melatonin. Accordingly, melatonin supplementation could be of potential therapeutic value in the treatment or prevention of metabolic disorders. More clinical trials in controlled conditions are needed, notably taking greater account of circadian rhythmicity.

Optimal input reverberation and homeostatic self-organization toward the edge of synchronization.

Transient or partial synchronization can be used to do computations, although a fully synchronized network is sometimes related to the onset of epileptic seizures. Here, we propose a homeostatic mechanism that is capable of maintaining a neuronal network at the edge of a synchronization transition, thereby avoiding the harmful consequences of a fully synchronized network. We model neurons by maps since they are dynamically richer than integrate-and-fire models and more computationally efficient than conductance-based approaches. We first describe the synchronization phase transition of a dense network of neurons with different tonic spiking frequencies coupled by gap junctions. We show that at the transition critical point, inputs optimally reverberate through the network activity through transient synchronization. Then, we introduce a local homeostatic dynamic in the synaptic coupling and show that it produces a robust self-organization toward the edge of this phase transition. We discuss the potential biological consequences of this self-organization process, such as its relation to the Brain Criticality hypothesis, its input processing capacity, and how its malfunction could lead to pathological synchronization and the onset of seizure-like activity.

Cardiorenal Syndromes and Their Role in Water and Sodium Homeostasis.

Sodium is the main osmotically active ion in the extracellular fluid and its concentration goes hand in hand with fluid volume. Under physiological conditions, homeostasis of sodium and thus amount of fluid is regulated by neural and humoral interconnection of body tissues and organs. Both heart and kidneys are crucial in maintaining volume status. Proper kidney function is necessary to excrete regulated amount of water and solutes and adequate heart function is inevitable to sustain renal perfusion pressure, oxygen supply etc. As these organs are bidirectionally interconnected, injury of one leads to dysfunction of another. This condition is known as cardiorenal syndrome. It is divided into five subtypes regarding timeframe and pathophysiology of the onset. Hemodynamic effects include congestion, decreased cardiac output, but also production of natriuretic peptides. Renal congestion and hypoperfusion leads to kidney injury and maladaptive activation of renin-angiotensin-aldosterone system and sympathetic nervous system. In cardiorenal syndromes sodium and water excretion is impaired leading to volume overload and far-reaching negative consequences, including higher morbidity and mortality of these patients. Keywords: Cardiorenal syndrome, Renocardiac syndrome, Volume overload, Sodium retention.

Association Between Triglyceride-Glucose Index and Homeostasis Model Assessment for Insulin Resistance with Estimated Glucose Disposal Rate.

This cross-sectional study was aimed to compare insulin resistance, Triglyceride- Glucose (TyG) index, fatty liver index (FLI) and hepatic steatosis index (HSI), glycaemic and lipids among groups/quartiles based upon estimated Glucose Disposal Rate (eGDR) from August 2022 to December 2022 among 249 male participants. The eGDR results in (mg/kg/min) were divided into four quartiles as: Group-I: {<6.88, n = 62}, Group-II: {<6.88-9.45, n = 63}, Group-III: {9.46-10.39, n = 62}, and Group-IV: {>10.39, n = 62}. Fasting plasma glucose (FPG), HbA1c, low density lipoprotein (LDL), homeostasis model assessment for insulin-resistance (HOMAIR), and TyG index demonstrated significant worsening increase from high to low eGDR groups. Receiver operating curve (ROC) analysis to calculate area under curve (AUC) for diagnostic efficiency candidate indices for eGDR demonstrated highest AUC for FLI as AUC: 0.736 (95% CI: 0.669-0.803), p < 0.001, followed by FPG: AUC: 0.682 (95% CI: 0.606-0.757), HOMAIR: AUC: 0.670 (95% CI: 0.602-0.739), HSI: AUC: 0.660 (95% CI: 0.589-0.731), TyG index: 0.658 (95% CI: 0.583-0.732), and HbA1c: 0.639 (95% CI: 0.583-0.732). Glycaemic measures, lipid indices, insulin resistance and TyG index deteriorated with declining eGDR. Diagnostic performance as evaluated by AUC for eGDR was highest for FLI, followed by FPG, HOMAIR, HSI, TyG index, HbA1c, and triglycerides. Key Words: Triglyceride, Insulin, Glucose, Diabetes.

Cerebral autoregulation: A reliable predictor of prognosis in patients receiving intravenous thrombolysis.

AIMS: To investigate the characteristics of dynamic cerebral autoregulation (dCA) after intravenous thrombolysis (IVT) and assess the relationship between dCA and prognosis. METHODS: Patients with unilateral acute ischemic stroke receiving IVT were prospectively enrolled; those who did not were selected as controls. All patients underwent dCA measurements, by quantifying the phase difference (PD) and gain, at 1-3 and 7-10 days after stroke onset. Simultaneously, two dCA-based nomogram models were established to verify the predictive value of dCA for patients with mild-to-moderate stroke. RESULTS: Finally, 202 patients who received IVT and 238 who did not were included. IVT was positively correlated with higher PD on days 1-3 and 7-10 after stroke onset. PD values in both sides at 1-3 days after stroke onset and in the affected side at 7-10 days after onset were independent predictors of unfavorable outcomes in patients who received IVT. Additionally, in patients with mild-to-moderate stroke who received IVT, the dCA-based nomogram models significantly improved the risk predictive ability for 3-month unfavorable outcomes. CONCLUSION: IVT has a positive effect on dCA in patients with acute stroke; furthermore, dCA may be useful to predict the prognosis of patients with IVT.

Population data evidence of interdependence of the limbs of hormonal feedback loops.

The fundamental models underlying hormonal physiological regulation and homeostasis remain poorly understood. We aimed to derive quantitative evidence regarding these models from the study of population data of balance points of different parameters and their respective controlling hormones. We studied the slopes of correlations between concentrations of circulating free thyroxine and thyrotropin, calcium and parathyroid hormone, hemoglobin and erythropoietin, and glucose and insulin in such population data, as well as the slopes of the limbs of various feedback loops estimated empirically and by reverse engineering of the population data. We used computer simulations to model the factors that influence the slopes derived from the population data, and then matched these simulations with the empirically derived slopes. Our simulations showed that changes to the population distribution of feedback loop limbs may alter the slopes of correlations within population data in specific ways. Non-random (interdependent) associations of the limbs of feedback loops may also have this effect, as well as producing discrepancies between the slopes of feedback limb loops determined experimentally and the same slopes determined by derivation from population data. Our corresponding empirical findings were consistent with the presence of such interdependence in the free thyroxine/thyrotropin, hemoglobin/erythropoietin, and glucose/insulin systems. The glucose/insulin data provided evidence consistent with increasing interdependence with age in childhood. Our findings therefore provide strong evidence that the interdependence of the limbs of feedback loops is a general feature of endocrine homeostatic regulation. This interdependence potentially bestows evolutionary homeostatic and regulatory advantages.

Homeostasis and evolution in relation to regeneration and repair.

Homeostasis constitutes a key concept in physiology and refers to self-regulating processes that maintain internal stability when adjusting to changing external conditions. It diminishes internal entropy constituting a driving force behind evolution. Natural selection might act on homeostatic regulatory mechanisms and control mechanisms including homeodynamics, allostasis, hormesis and homeorhesis, where different stable stationary states are reached. Regeneration is under homeostatic control through hormesis. Damage to tissues initiates a response to restore the impaired equilibrium caused by mild stress using cell proliferation, cell differentiation and cell death to recover structure and function. Repair is a homeorhetic change leading to a new stable stationary state with decreased functionality and fibrotic scarring without reconstruction of the 3-D pattern. Mechanisms determining entrance of the tissue or organ to regeneration or repair include the balance between innate and adaptive immune cells in relation to cell plasticity and stromal stem cell responses, and redox balance. The regenerative and reparative capacities vary in different species, distinct tissues and organs, and at different stages of development including ageing. Many cell signals and pathways play crucial roles determining regeneration or repair by regulating protein synthesis, cellular growth, inflammation, proliferation, autophagy, lysosomal function, metabolism and metalloproteinase cell signalling. Attempts to favour the entrance of damaged tissues to regeneration in those with low proliferative rates have been made; however, there are evolutionary constraint mechanisms leading to poor proliferation of stem cells in unfavourable environments or tumour development. More research is required to better understand the regulatory processes of these mechanisms.

Computational insights into colonic motility: Mechanical role of mucus in homeostasis and inflammation.

Colonic motility plays a vital role in maintaining proper digestive function. The rhythmic contractions and relaxations facilitate various types of motor functions that generate both propulsive and non-propulsive motility modes which in turn generate shear stresses on the epithelial surface. However, the interplay between colonic mucus, shear stress, and epithelium remains poorly characterized. Here, we present a colonic computational model that describes the potential roles of mucus and shear stress in both homeostasis and ulcerative colitis (UC). Our model integrates several key features, including the properties of the mucus bilayer and faeces, intraluminal pressure, and crypt characteristics to predict the time-space mosaic of shear stress. We show that the mucus thickness which could vary based on the severity of UC, may significantly reduce the amount of shear stress applied to the colonic crypts and effect faecal velocity. Our model also reveals an important spatial shear stress variance in homeostatic colonic crypts that suggests shear stress may have a modulatory role in epithelial cell migration, differentiation, apoptosis, and immune surveillance. Together, our study uncovers the rather neglected roles of mucus and shear stress in intestinal cellular processes during homeostasis and inflammation.

AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation.

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.

The effects of cerebral pressure autoregulation status and CPP levels on cerebral metabolism in pediatric traumatic brain injury.

BACKGROUND: Cerebral perfusion pressure (CPP) management in the developing child with traumatic brain injury (TBI) is challenging. The pressure reactivity index (PRx) may serve as marker of cerebral pressure autoregulation (CPA) and optimal CPP (CPPopt) may be assessed by identifying the CPP level with best (lowest) PRx. To evaluate the potential of CPPopt guided management in children with severe TBI, cerebral microdialysis (CMD) monitoring levels of lactate and the lactate/pyruvate ratio (LPR) (indicators of ischemia) were related to actual CPP levels, autoregulatory state (PRx) and deviations from CPPopt (ΔCPPopt). METHODS: Retrospective study of 21 children ≤ 17 years with severe TBI who had both ICP and CMD monitoring were included. CPP, PRx, CPPopt and ΔCPPopt where calculated, dichotomized and compared with CMD lactate and lactate-pyruvate ratio. RESULTS: Median age was 16 years (range 8-17) and median Glasgow coma scale motor score 5 (range 2-5). Both lactate (p = 0.010) and LPR (p = < 0.001) were higher when CPP ≥ 70 mmHg than when CPP < 70. When PRx ≥ 0.1 both lactate and LPR were higher than when PRx < 0.1 (p = < 0.001). LPR was lower (p = 0.012) when CPPopt ≥ 70 mmHg than when CPPopt < 70, but there were no differences in lactate levels. When ΔCPPopt > 10 both lactate (p = 0.026) and LPR (p = 0.002) were higher than when ΔCPPopt < -10. CONCLUSIONS: Increased levels of CMD lactate and LPR in children with severe TBI appears to be related to disturbed CPA (PRx). Increased lactate and LPR also seems to be associated with actual CPP levels ≥ 70 mmHg. However, higher lactate and LPR values were also seen when actual CPP was above CPPopt. Higher CPP appears harmful when CPP is above the upper limit of pressure autoregulation. The findings indicate that CPPopt guided CPP management may have potential in pediatric TBI.

Dynamic cerebral autoregulation is preserved during orthostasis and intrathoracic pressure regulation in healthy subjects: A pilot study.

Resistance breathing may restore cardiac output (CO) and cerebral blood flow (CBF) during hypovolemia. We assessed CBF and cerebral autoregulation (CA) during tilt, resistance breathing, and paced breathing in 10 healthy subjects. Blood velocities in the internal carotid artery (ICA), middle cerebral arteries (MCA, four subjects), and aorta were measured by Doppler ultrasound in 30° and 60° semi-recumbent positions. ICA blood flow and CO were calculated. Arterial blood pressure (ABP, Finometer), and end-tidal CO2 (ETCO2) were recorded. ICA blood flow response was assessed by mixed-models regression analysis. The synchronization index (SI) for the variable pairs ABP-ICA blood velocity, ABP-MCA velocities in 0.005-0.08 Hz frequency interval was calculated as a measure of CA. Passive tilting from 30° to 60° resulted in 12% decrease in CO (p = 0.001); ICA blood flow tended to fall (p = 0.04); Resistance breathing restored CO and ICA blood flow despite a 10% ETCO2 drop. ETCO2 and CO contributed to ICA blood flow variance (adjusted R2: 0.9, p < 0.0001). The median SI was low (<0.2) indicating intact CA, confirmed by surrogate date testing. The peak SI was transiently elevated during resistance breathing in the 60° position. Resistance breathing may transiently reduce CA efficiency. Paced breathing did not restore CO or ICA blood flow.

Dynamic cerebral autoregulation is governed by two time constants: Arterial transit time and feedback time constant.

Dynamic cerebral autoregulation (dCA) is the mechanism that describes how the brain maintains cerebral blood flow approximately constant in response to short-term changes in arterial blood pressure. This is known to be impaired in many different pathological conditions, including ischaemic and haemorrhagic stroke, dementia and traumatic brain injury. Many different approaches have thus been used both to analyse and to quantify this mechanism in a range of healthy and diseased subjects, including data-driven models (in both the time and the frequency domain) and biophysical models. However, despite the substantial body of work on both biophysical models and data-driven models of dCA, there remains little work that links the two together. One of the reasons for this is proposed to be the discrepancies between the time constants that govern dCA in models and in experimental data. In this study, the processes that govern dCA are examined and it is proposed that the application of biophysical models remains limited due to a lack of understanding about the physical processes that are being modelled, partly due to the specific model formulation that has been most widely used (the equivalent electrical circuit). Based on the analysis presented here, it is proposed that the two most important time constants are arterial transit time and feedback time constant. It is therefore time to revisit equivalent electrical circuit models of dCA and to develop a more physiologically realistic alternative, one that can more easily be related to experimental data. KEY POINTS: Dynamic cerebral autoregulation is governed by two time constants. The first time constant is the arterial transit time, rather than the traditional 'RC' time constant widely used in previous models. This arterial transit time is approximately 1 s in the brain. The second time constant is the feedback time constant, which is less accurately known, although it is somewhat larger than the arterial transit time. The equivalent electrical circuit model of dynamic cerebral autoregulation should be replaced with a more physiologically representative model.

The homeostatic effects of the RE-1 silencing transcription factor on cortical networks are altered under ictogenic conditions in the mouse.

AIM: The Repressor Element-1 Silencing Transcription Factor (REST) is an epigenetic master regulator playing a crucial role in the nervous system. In early developmental stages, REST downregulation promotes neuronal differentiation and the acquisition of the neuronal phenotype. In addition, postnatal fluctuations in REST expression contribute to shaping neuronal networks and maintaining network homeostasis. Here we investigate the role of the early postnatal deletion of neuronal REST in the assembly and strength of excitatory and inhibitory synaptic connections. METHODS: We investigated excitatory and inhibitory synaptic transmission by patch-clamp recordings in acute neocortical slices in a conditional knockout mouse model (RestGTi) in which Rest was deleted by delivering PHP.eB adeno-associated viruses encoding CRE recombinase under the control of the human synapsin I promoter in the lateral ventricles of P0-P1 pups. RESULTS: We show that, under physiological conditions, Rest deletion increased the intrinsic excitability of principal cortical neurons in the primary visual cortex and the density and strength of excitatory synaptic connections impinging on them, without affecting inhibitory transmission. Conversely, in the presence of a pathological excitation/inhibition imbalance induced by pentylenetetrazol, Rest deletion prevented the increase in synaptic excitation and decreased seizure severity. CONCLUSION: The data indicate that REST exerts distinct effects on the excitability of cortical circuits depending on whether it acts under physiological conditions or in the presence of pathologic network hyperexcitability. In the former case, REST preserves a correct excitatory/inhibitory balance in cortical circuits, while in the latter REST loses its homeostatic activity and may become pro-epileptogenic.

Deferasirox exerts anti-epileptic effects by improving brain iron homeostasis via regulation of ITPRIP.

Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations have revealed alterations in cerebral iron content in both epilepsy patients and animal models. However, the extant literature lacks a comprehensive exploration into the ramifications of modulating iron homeostasis as an intervention in epilepsy. This study investigated the impact of deferasirox, a iron ion chelator, on epilepsy. This study unequivocally substantiated the antiepileptic efficacy of deferasirox in a kainic acid-induced epilepsy model. Furthermore, deferasirox administration mitigated seizure susceptibility in a pentylenetetrazol-induced kindling model. Conversely, the augmentation of iron levels through supplementation has emerged as a potential exacerbating factor in the precipitating onset of epilepsy. Intriguingly, our investigation revealed a hitherto unreported discovery: ITPRIP was identified as a pivotal modulator of excitatory synaptic transmission, regulating seizures in response to deferasirox treatment. In summary, our findings indicate that deferasirox exerts its antiepileptic effects through the precise targeting of ITPRIP and amelioration of cerebral iron homeostasis, suggesting that deferasirox is a promising and novel therapeutic avenue for interventions in epilepsy.

Dopamine­iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease.

Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson's disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment resulted in increased expression of the transmembrane iron transporters transferrin receptor 1 (TFR1), ferroportin (FPN), and mitoferrin2 (MFRN2) and intracellular iron accumulation, suggesting that dopamine may promote iron uptake. Furthermore, dopamine supplementation led to reduced mitochondrial fitness including decreased mitochondrial respiration, increased cytochrome c control efficiency, reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenous SNCA mutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore the disturbed regulatory network in PD cells.

A Novel Mechanism of MSCs Responding to Occlusal Force for Bone Homeostasis.

Alveolar bone, as tooth-supporting bone for mastication, is sensitive to occlusal force. However, the mechanism of alveolar bone loss after losing occlusal force remains unclear. Here, we performed single-cell RNA sequencing of nonhematopoietic (CD45-) cells in mouse alveolar bone after removing the occlusal force. Mesenchymal stromal cells (MSCs) and endothelial cell (EC) subsets were significantly decreased in frequency, as confirmed by immunofluorescence and flow cytometry. The osteogenic and proangiogenic abilities of MSCs were impaired, and the expression of mechanotransducers yes associated protein 1 (Yap) and WW domain containing transcription regulator 1 (Taz) in MSCs decreased. Conditional deletion of Yap and Taz from LepR+ cells, which are enriched in MSCs that are important for adult bone homeostasis, significantly decreased alveolar bone mass and resisted any further changes in bone mass induced by occlusal force changes. Interestingly, LepR-Cre; Yapf/f; Tazf/f mice showed a decrease in CD31hi endomucin (Emcn)hi endothelium, and the expression of some EC-derived signals acting on osteoblastic cells was inhibited in alveolar bone. Mechanistically, conditional deletion of Yap and Taz in LepR+ cells inhibited the secretion of pleiotrophin (Ptn), which impaired the proangiogenic capacity of LepR+ cells. Knockdown in MSC-derived Ptn repressed human umbilical vein EC tube formation in vitro. More important, administration of recombinant PTN locally recovered the frequency of CD31hiEmcnhi endothelium and rescued the low bone mass phenotype of LepR-Cre; Yapf/f; Tazf/f mice. Taken together, these findings suggest that occlusal force governs MSC-regulated endothelium to maintain alveolar bone homeostasis through the Yap/Taz/Ptn axis, providing a reference for further understanding of the relationship between dysfunction and bone homeostasis.

Mechanisms and implications of podocyte autophagy in chronic kidney disease.

Autophagy is a protective mechanism through which cells degrade and recycle proteins and organelles to maintain cellular homeostasis and integrity. An accumulating body of evidence underscores the significant impact of dysregulated autophagy on podocyte injury in chronic kidney disease (CKD). In this review, we provide a comprehensive overview of the diverse types of autophagy and their regulation in cellular homeostasis, with a specific emphasis on podocytes. Furthermore, we discuss recent findings that focus on the functional role of different types of autophagy during podocyte injury in chronic kidney disease. The intricate interplay between different types of autophagy and podocyte health requires further research, which is critical for understanding the pathogenesis of CKD and developing targeted therapeutic interventions.