In addition, calcium signals participate in the accumulation process of GABA under stress. Moreover, GABA also transmits calcium signals through receptors to trigger downstream signaling cascades. In conclusion, understanding the role of GABA in this defense response provides a theoretical basis for applying GABA in agriculture and forestry and feasible coping strategies for plants in complex and changeable environments.Gamma-aminobutyric acid (GABA) is a four-carbon non-protein amino acid that acts as a defense substance and a signaling molecule in various physiological processes, and which helps plants respond to biotic and abiotic stresses. This review focuses on the role of GABA’s synthetic and metabolic pathways in regulating primary plant metabolism, redistributing carbon and nitrogen resources, reducing the accumulation of reactive oxygen species, and improving plants’ tolerance of oxidative stress. This review also highlights the way in which GABA maintains intracellular pH homeostasis by acting as a buffer and activating H Intracellular pH homeostasis is the basic cell activity required to maintain normal plant growth, regulate plant growth and development, and respond to environmental stress. ROS enhances resistance by inducing cell damage through oxidative properties to promote plant morphology and structural change. It can also interact with transcription factors to regulate the expression of defense-related genes cyt is pumped out of the cell by a “pump out” mechanism, and [Ca2+]cyt returns to its resting state [Under different environmental stimuli, intracellular Caome time . In normessenger ; this pressenger . Calciumng state .2+/CaM. When plants are subjected to temperature stress, drought, salinity, or mechanical treatment, the intracellular Ca2+ concentration increases, promoting the stimulation of Ca2+/CaM to GAD and causing the accumulation of GABA. For example, the accumulation of GABA in apples stored under controlled atmosphere conditions is due to the highly conserved CaMBD of MdGAD1 and MdGAD2, whose activity and spectral properties are regulated by Ca2+/CaM and acidic pH [2+/CaM complex in rice bran; when the concentrations of Ca2+ and CaM are 200 μmol L−1 and 150 nmol L−1, respectively, the GAD of rice bran is significantly increased, by three times [2+ and BoCaM2 levels in Broccoli sprouts have been raised to form Ca2+/CaM complexes that bind to GAD. Similarly, exogenous calcium-activated GAD promoted GABA accumulation in shredded carrots and fresh-cut pears [The accumulation of GABA under biotic and abiotic stress is related to the regulation of Cacidic pH . GAD is ee times . In the ut pears ,112,113.A receptors, which leads to calcium increases in these cells [+ dependent. ATP induces an increase in intracellular Ca2+ concentration which in turn increases the activity of the Na+/Ca2+ exchanger (NCX), and the accumulation of Na+ in astrocytes then leads to the decrease of GAT activity [GABA transmits calcium signals through receptors. The process of transporting GABA into the cell by sodium-dependent GABA receptors in horizontal cells from the skate retina causes depolarization of membrane potential and activates L-type voltage-gated calcium channels to transport extracellular calcium ions into the cell, thus triggering the release of calcium ions from the intracellular calcium pool . Similarse cells . In planse cells . ALMTs ase cells ,117. Forse cells . In addiactivity . In planactivity .+-ATPase and can affect Ca2+ transport through ALMTs, thus triggering downstream signaling cascades. Although progress has been made in the study of GABA in plants, there are still many questions to be explored, and the polyamine pathway synthesis of GABA has not been thoroughly studied. There are many Ca2+ channels in the plasma membrane of cells, but which calcium channel is activated by GABA remains unclear. Few studies have examined GABA’s signaling function through ROS.In recent years, an increasing number of studies have been conducted on the role of GABA in plant defense response. The synthesis of GABA uses Glu as a precursor and participates in the TCA cycle. Therefore, GABA can be used as a bridge to regulate carbon and nitrogen balance and participate in plant carbon and nitrogen metabolism resistance to various stresses. The accumulation of GABA reduces excess ROS in cells and improves the plant’s tolerance to oxidative stress. GABA can also act as a signaling molecule in response to various stresses. For example, GABA can maintain pH balance in plants by activating HOverall, the positive role of GABA in plant resistance was analyzed in detail in this paper, providing a theoretical basis for the application of GABA in agriculture and forestry. Exogenous GABA can be applied as an effective and sustainable strategy to improve plant tolerance under field conditions to combat complex and changeable environmental problems.


Organic anion transporters 1 and 3 (OAT1 and OAT3) play a crucial role in kidney function by regulating the secretion of multiple renally cleared small molecules and toxic metabolic by-products. Assessing the activity of these transporters is essential for drug development purposes as they can significantly impact drug disposition and safety. OAT1 and OAT3 are amongst the most abundant drug transporters expressed in human renal proximal tubules. However, their expression is lost when cells are isolated and cultured in vitro, which is a persistent issue across all human and animal renal proximal tubule cell models, including primary cells and cell lines. Although it is well known that the overall expression of drug transporters is affected in vitro, the underlying reasons for the loss of OAT1 and OAT3 are still not fully understood. Nonetheless, research into the regulatory mechanisms of these transporters has provided insights into the molecular pathways underlying their expression and activity. In this review, we explore the regulatory mechanisms that govern the expression and activity of OAT1 and OAT3 and investigate the physiological changes that proximal tubule cells undergo and that potentially result in the loss of these transporters. A better understanding of the regulation of these transporters could aid in the development of strategies, such as introducing microfluidic conditions or epigenetic modification inhibitors, to improve their expression and activity in vitro and to create more physiologically relevant models. Consequently, this will enable more accurate assessment for drug development and safety applications. Renal proximal tubule epithelial cells (RPTECs) play a critical role in the overall function of the kidney and are responsible for the secretion of waste products, reabsorption of solutes and proteins, or the regulation of acid–base balance ,2. One oOATs belong to the larger SLC22—Solute Carrier 22—family of membrane transporters, which includes organic cation transporters (OCTs), organic zwitterion/cation transporters (OCTNs), and multidrug and toxin extrusion (MATE) transporters . These tA significant number of approved small-molecule drugs are eliminated from the body through the kidneys . Among tThe tight regulation of OAT1 and OAT3 expression and activity involves intricate cellular pathways, including transcriptional, post-transcriptional, and post-translational processes, which maintain and modulate transport activity in response to variation in cellular homeostasis . ChangesRPTECs are highly metabolically active and require a significant amount of energy to fulfill their secretory functions. Typically, energy production occurs through mitochondrial respiration, which generates the high levels of ATP needed to power their prolific membrane transport machinery . HoweverHypoxia occurs when low oxygen levels disrupt normal cellular function, triggering a compensatory response to counteract its effects. Hypoxia-inducible factor (HIF)-1 plays a central role in the cellular response to hypoxia. Under normal oxygen conditions, HIF-1α, the oxygen-sensitive subunit of HIF-1, is rapidly degraded by the proteasome. However, when oxygen levels decrease, HIF 1α is stabilized and translocates to the nucleus, where it dimerizes with HIF-1β and binds to hypoxia-responsive elements (HREs) in the promoter regions of target genes ,24. HIF-The activity of OAT1 and OAT3 transporters is influenced by the intracellular concentration of αKG, which serves as a co-substrate for these transporters. αKG is synthesized within the mitochondria as an intermediate product of the tricarboxylic acid (TCA) cycle during the production of ATP . HypoxicInflammation is a complex biological response to injury or cellular stress characterized by the activation of immune cells and the release of various inflammatory mediators, including cytokines, chemokines, and reactive oxygen species. Hypoxia and metabolic impairment are major drivers of inflammation . The expThe NF-κB pathway is a major mechanism by which inflammation regulates the expression of OAT1 and OAT3. This pathway is activated in response to a variety of inflammatory stimuli, including cytokines and oxidative stress. NF-κB regulates transporter expression by directly binding to their gene promoters and inducing transcription . InflammGrowth factors are signaling molecules that play important roles in the regulation of cell growth, differentiation, and survival. Recent studies have shown that growth factors can also regulate the expression of OAT1 and OAT3, acting via regulatory pathways similar to those of immune factors. IGF-1 can increase the expression of OAT1 and OAT3 in renal proximal tubular cells by activating the phosphatidylinositol 3-kinase (PI3K) pathway. Upon PI3K activation, downstream signaling molecules such as alpha serine/threonine-protein kinase (AKT) and the mammalian target of rapamycin (mTOR) are triggered, subsequently inducing the expression of the transporters . HepatocMicroRNAs (miRs) are short non-coding RNA molecules that regulate gene expression by binding to target mRNAs, effectively suppressing protein translation . HIF-1 hThe kidneys can sense and respond to elevated levels of metabolites produced by the gut microbiome via epidermal growth factors receptors (EGFR) and downstream signaling. The uremic toxin indoxyl sulfate (IS) is a protein metabolism by-product derived from the microbiome and an endogenous OAT1 substrate. IS indirectly activates the transcriptional activity of the Aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator (AhR/ARNT) by binding to and stimulating EGFR. The activity of AhR/ARNT promotes the upregulation of OAT1 expression. The expression of miR-223 supports this apparent and complex gut-kidney communication axis by stabilizing ARNT expression and ensuring the transcription of OAT1 . This meEpigenetic modifications, including DNA methylation and histone deacetylation, are important mechanisms that regulate gene expression by altering the chromatin structure and accessibility of DNA to transcription factors . In receDNA methylation is a process by which a methyl group is added to cytosine residues in the CpG dinucleotides of DNA. This modification is catalyzed by DNA methyltransferases (DNMTs) and can lead to the repression of gene expression. Methylation acts as a regulator of tissue-specific transactivation, where differential rates of transcription dictate the expression profiles of genes across cell types and tissues. The promoter regions of OAT1 and OAT3 contain CpG islands, which are regions of DNA with a high density of CpG dinucleotides. Ex vivo studies have shown that DNA methylation of the promoter regions of OAT1 and OAT3 can lead to their repression and decrease transport activity . InteresHistone deacetylation is a process by which the acetyl groups on histone proteins are removed, leading to the condensation of chromatin structure and the repression of gene expression. Histone deacetylation is catalyzed by histone deacetylases (HDACs). Studies have shown that inhibition of HDAC activity can lead to the upregulation of OAT1 and OAT3 expression in renal proximal tubular cells ,49. The Cellular adhesion, which is governed by the binding of cells to each other or extracellular matrix components, is an important process in many biological functions, including cell migration, tissue development, and immune response. It plays a major role in the polarity of epithelial cells, and it has been associated with the expression of organic anion transporters OAT1 and OAT3 ,54,55. ECaveolins (Cavs) are integral membrane proteins that are mainly described to regulate receptor-independent endocytosis. Additionally, Cavs are also reported to stabilize focal adhesions, which act as anchoring points between cells and their extracellular environment. These proteins also induce the curvature at the plasma membrane when oligomerized and interact with multiple signaling elements ,64. Cav-Post-translational regulation of OAT1 and OAT3 transporters involves a range of mechanisms that modify the proteins after they are synthesized. These modifications can impact transporter activity, localization, and stability and ultimately influence their function . PhosphoGlycosylation involves the addition of sugar molecules to specific sites on the transporter protein and it has been shown to have a significant impact on OAT1 and OAT3 function ,68. OAT3Small ubiquitin-like modifiers (SUMOs) are a family of proteins that can covalently bind to specific lysine residues in target proteins and act as functional regulators governing, among other mechanisms, transcription and subcellular localization. This process is known as SUMOylation and is initiated when a series of ligases cooperate to attach SUMO to its target. It can be reversed by the activity of proteases that cleave the modifiers from SUMOylated proteins . The actKidney cancer is a broad term that encompasses various types of malignancies arising from different renal cells. Renal cell carcinoma (RCC) is the most common type of kidney cancer and specifically develops from RPTECs . RCCs arRCC cells re-write the native regulatory mechanisms of RPTECs in a process heavily dependent on DNA methylation. Nonetheless, they retain several characteristics of their precursors, including a significant drug transport activity. Efflux activity is preserved in malignant cells while uptake activity is dysregulated . This phThe intricate regulatory machinery of drug transporters governs their proper expression, localization, and function . While OCompelling evidence for the mechanism precluding OAT1 and OAT3 expression in vitro is the fact that RPTECs freshly isolated from kidney tissue retain the protein expression of the transporters when cultured in transwell configuration while their gene expression is lost ,82,83. TIn conventional static culture, RPTECs are subjected to atmospheric oxygen levels, which are considered to be substantially higher than what the cells experience under normal physiological conditions. In culture, both primary and cell lines predominately rely on glycolysis for energy production to the detriment of mitochondrial respiration . It is bThis behavior is similar to that of RCC cells, which maintain high glycolytic activity even though they experience physiologically normal oxygen levels . SimilarA feature considered important for the expression of OAT1 and OAT3 is the membrane polarity of RPTECs. In vivo, these transporters are expressed on the basolateral side of the proximal tubules, facing the capillary network. In vitro, cellular structure is compromised, and polarity is lost, preventing drug transporters from properly localizing to the membrane. Nonetheless, in primary cultures and cell lines remnant transport activity persists, with the proteins found in intracellular vesicles and cellular boundaries ,8. OvereThe use of Microphysiological systems (MPSs), which recapitulate the tubular architecture of the renal proximal tubule and enable continuous luminal flow, has been shown to recover organic anion transport expression and activity, albeit to a limited extent, in human primary RPTECs ,92,93,94The loss of organic anion transporters in RPTECs in vitro is initiated by significant environmental changes that occur during isolation and subsequent cell culture . One maj


Fungal periprosthetic joint infections are one of the most intractable orthopedic disorders. Continuous local antibiotic perfusion allows direct administration of the antifungal agent micafungin into the local infection area at biofilm-disruptive concentrations, while controlling the dead space in addition to conventional treatment. Although the appropriate use of continuous local antibiotic perfusion requires familiarity with the characteristics of local antibiotic perfusion, it is a versatile treatment modality that can improve the clinical outcomes of fungal periprosthetic joint infection in combination with conventional treatment methods. Periprosthetic joint infections (PJI) are one of the most intractable complications of orthopedic diseases. Bacteria that form biofilms around implants or in bone and soft tissues are known to have very different characteristics compared with floating bacteria that can be identified in isolated cultures . As biofAs well as bacterial species, fungi also cause PJI, and fungal PJI is known to have poorer postoperative outcomes than bacterial PJI because of the large loss of normal tissue, widespread infection, multiple surgical histories, and coinfection with other bacteria . AntimicContinuous local antibiotic perfusion (CLAP) locally administers high concentrations of antimicrobials. It was first induced in fracture-related infections caused by orthopedic implants ,17. CLAPThe infection area was predicted through computed tomography, magnetic resonance imaging, and scintigraphy for planning antifungal perfusion into the local infectious site of the periprosthetic joint, acetabular and femur, and soft tissues. A bone marrow puncture needle Arrow EZ-IO  or a bone marrow screw iMAP pin 4 mm in diameter   was usedThe indication for the surgical procedure was determined based on a guideline from the Infectious Diseases Society of America  except 2Staphylococcus and fungal infections (MCFG (50 μg/mL) was used for the CLAP based on previous studies . Using sfections , as ofteThe clinical outcomes of CLAP in 4 patients who were diagnosed with fungal PJI were investigated, 2 of whom had previously undergone resection arthroplasty, and the other 2 had previously undergone revision THA . Of thesCLAP was administered for an average of 19 days. In all cases, blood GM levels were measured during CLAP, and none of the cases had blood GM levels exceeding 0.3 μg/mL, which was less than the trough concentration for systemic administration. After the removal of CLAP and NPWT from the wound, 3 patients temporarily developed fever and had elevated blood C-reactive protein levels; however, all patients improved rapidly with continued systemic antimicrobial therapy. Three patients who underwent DAIR or revision were able to preserve the allogeneic bones and implants, and 1 patient who underwent resection arthroplasty showed no recurrence of joint fluid accumulation during a mean follow-up of 30 months after surgery (range: 16-54 months). Case 1 required a 4-point walker for a short walk, case 2 achieved full activity in daily life, and cases 3 and 4 required a crutch for long walking with chronic suppression therapy using oral fluconazole at the time of final follow-up.CLAP is a novel method for directly administering high concentrations of antimicrobial agents at low flow rates into the bone marrow, soft tissues, and joints ,17. The One of the advantages of CLAP with antifungal agents is that it can be an additional option to conventional treatments, including antifungal PMMA. Therefore, as observed in case 4, CLAP can also be performed at the time of revision arthroplasty to reduce the possibility of recurrent postoperative infection, along with systemic antibiotic treatment. Another advantage of CLAP is not only local perfusion of antifungal agents but also control of dead spaces by aspirating hematoma formation, especially in cases with severe bone and soft-tissue loss. The NPWT system can be used to manage soft tissue while draining dead space and is expected to be useful in terms of wound management. The disadvantages of this novel treatment are that it requires adequate training in the techniques for local antimicrobial perfusion, knowledge of the necessary supplies and their characteristics, and 2 to 3 weeks of hospitalization. Despite these disadvantages, CLAP can be useful for intractable PJI in combination with conventional surgical treatment in 1- or 2-stage THA cases and implant retention cases.We successfully performed a novel local antifungal treatment, CLAP with MCFG, in patients with fungal PJI. This versatile treatment method can be used in combination with conventional treatment methods for fungal PJI.


Objective: In rare cases, Lyme neuroborreliosis (LNB) can induce cerebral vasculitis leading to severe stenosis of the cerebral vasculature and consecutive ischemia. Therapy is based on anti-biotic treatment of the tick-borne disease, whereas interventional therapeutic options have not been assessed yet. Material and Methods: We report on a patient with LNB and concomitant stenoses and progressive and fatal vasculitis of the cerebral vessels despite all therapeutic efforts by the departments of neurology and interventional neuroradiology. In this context, we also conducted a literature review on endovascular treatment of LNB-associated cerebral ischemia. Results: A 52-year-old female presented with transient neglect and psychomotor slowdown . MRI and serology led to the diagnosis of basal meningitis due to LNB with vasculitis of cerebral arteries. Despite immediate treatment with antibiotics and steroids, neurologic deterioration (NIHSS 8) led to an emergency angiography on day 2 after admission. Hemodynamically relevant stenoses of the MCA were treated via spasmolysis and PTA, leading to almost complete neurological recovery. Despite intensified medical treatment, the vasculitis progressed and could only be transiently ameliorated via repetitive spasmolysis. On day 19, she again presented with significant neurologic deterioration (NIHSS 9), and PTA and stenting of the nearly occluded MCA were performed with a patent vessel, initially without hemorrhagic complications. Despite all therapeutic efforts and preserved stent perfusion, vasculitis worsened and the concurrent occurrence of subdural hemorrhage led to the death of the patient. Conclusion: Neuroradiological interventions, i.e., spasmolysis, PTA, and, if necessary, stenting, can and should be considered in cases of LNB-induced vasculitis and stroke that are refractory to best medical treatment alone. Key point: Neuroradiological interventions can be considered in patients with vascular complications of Lyme neuroborreliosis as an additional extension of the primary drug therapy. Borrelia burgdorferi. Borreliosis typically presents with erythema migrans, but the second most common manifestation is neuroborreliosis .,9.8,9].Neurovascular ultrasound showed bilateral high-grade stenoses in the MCA, high-grade stenosis in the right PCA, low-grade stenosis in the left PCA, low-grade stenosis in the ACA on the left, high-grade stenosis DD occlusion in the right vertebral artery in section V4 with distal refilling, and medium-grade stenosis in the proximal basilar artery.Routine laboratory tests were unremarkable, despite slightly elevated protein C levels. Initial cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis with elevated lactate and decreased glucose levels.Borrelia burgdorferi. After supplemental tuberculosis diagnostics, including mycobacteria PCR and staining for acid-fast rods, were negative, Tbc medication was stopped, while ceftriaxone was continued for 24 days.A calculated antibiotic regimen according to national guidelines with ceftriaxone was initiated and supported with dexamethasone . Since tOn the second day after admission, the patient showed severe neurological deterioration with new onset of left-sided hemiparesis, gaze paresis to the left, and tactile neglect (NIHSS 9). Diagnostic cerebral computed tomography showed stenoses of the right MCA and ACA and extensive perfusion deficits next to already demarked infarction in the territory of the right ACA, as previously diagnosed on initial cMRI a–c. An eThe patient’s neurological symptoms worsened six hours post-intervention with aggravated hemiparesis of the left side. An immediate MRI scan showed a circumscribed intracerebral hemorrhage in the right temporal lobe and a large new subdural hematoma on the right hemisphere with a midline shift to the left and incipient subfalcine and uncal herniation d. The epThe patient’s MRI and CT images obtained in the following days showed successful evacuation of the SDH, but progressive infarcts in the right MCA territory and bilaterally in the ACA territories f. The imDue to the poor prognosis and after consultation with the patient’s husband, a palliative therapy concept was pursued from day 24 onwards and she died on day 30 after the initial onset of symptoms.Due to pronounced stenoses of the cerebral vasculature leading to cerebral perfusion deficits the decision to attempt endovascular treatment was made in an interdisciplinary consensus between the Department of Neurology and the Department for Neuroradiology of the Clinic for Radiology at Muenster University Hospital.Diagnostic angiography of the cerebral arteries and vasospasmolysis was performed via an arterial transfemoral approach in general anesthesia.The following materials were used as standard for diagnostic angiography, PTA and vasospasmolysis:8F sheath, Flowgate balloon catheter + Vertebralis select catheter , Terumo standard wire , Rebar 18 microcatheter , Traxcess 14 microwire , 2 × 8 mm Neurospeed PTA Ballon Catheter .For vasospasmolysis, 2 mg Nimodipin in a total of 40 mL NaCl solution was applied over a period of 20 min for each respective cerebral vascular territory. The success of vasospasmolysis was verified with diagnostic angiography and repeated if necessary. In total, the patient received eight vasospasmolyses over the course of 12 days.No approval by the institutional review board was needed for this literature-based review.We conducted a systematic review of the medical literature to identify published cases of LNB-associated vasculitis and stroke using the online databases of MED-LINE/PubMed between introduction and July 2023.The search terms were “Lyme neuroborreliosis” OR “neuroborreliosis” OR “borrelio-sis” OR “Borrelia burgdorferi” and one of the following terms “cerebral vasculitis” OR “cerebral vasculopathy” OR “cerebral angiopathy” OR “stroke” OR “ischemia” OR “vasospasm” OR “vasospasmolysis” OR “spasmolysis” OR “stent”.Inclusion criteria were (1) diagnosis of LNB, (2) associated clinical and/or radiologic evidence of vasculitis and/or stroke, (3) excluded other causes of vasculitis and/or stroke, (4) neurointerventional therapeutic approach.Exclusion criteria were (1) reports on cases with LNB but without final vasculitis or stroke, (2) vasculitis and stroke due to other causes, (3) non-ischemic strokes, (4) unavailable full-text articles, (5) articles written in other languages than English see .We conducted a review of all articles that met our inclusion and exclusion criteria.Senior radiology residents with four years of experience in diagnostic neuroradiology independently screened titles and/or abstracts of the studies retrieved by using the aforementioned systematic search plan and extracted data from eligible studies into a standardized form. Discrepancies in the evaluation of the studies were resolved by consensus or by consultation with a senior reviewer.Initial search according to our search strategy showed a total of 190 studies.Thorough analysis of the available material of each article lead to the exclusion of 189 studies due to a missed topic or not meeting the inclusion criteria.Our search revealed one study that described acute cerebral ischemia due to large vessel occlusion caused by Lyme neuroborreliosis and treated with endovascular meth-ods.In this case report, Philipps et al.  report oCerebral imaging was conducted with non-contrast CT showing a hyperdense basilar artery, and MRI confirming basilar occlusion in ToF-angiography with concomitant bilateral pontomesencephalic diffusion restriction in DWI/ADC sequences indicating hyperacute stroke.Borrelia burgdorferi.Lumbar puncture before MRI revealed the diagnosis of Lyme neuroborreliosis with lymphocytic pleocytosis and elevated antibody index of IgG and IgM for The patient was administered to the angiography unit and received endovascular thrombectomy of the basilar occlusion with an aspiration catheter and Embotrap III stent-retriever together with intra-arterial thrombolysis with 5 mg alteplase.Antibiotic and anti-inflammatory treatment was started simultaneously after confirmation of diagnosis with cefotaxime IV (3 × 1.3 g) for 16 days and dexamethasone IV (4 mg)/prednisolone PO (30 mg). Furthermore, the patient received tirofiban IV off-label.Postinterventional imaging showed stable bilateral pontomesencephalic DWI/ADC and FLAIR lesions as well as subtotal reocclusion of the BA and stenosis of the left PCA, that improved gradually in the following weeks without further interventions.The patient developed well and was finally discharged with a pedNIHSS of 0, mRS 0 under medication with ASA 50 mg/d and prednisolone 15 mg/d .Lyme neuroborreliosis usually presents with the classic triad of meningitis, cranial neuritis and radiculoneuritis but may also have complicating courses including cerebral vessel vasculitis and consequent cerebral ischemia . LNB-assOur analysis of the available literature showed that in the majority of the reported cases, a primarily medicinal therapy concept was pursued, while additional neuroradiological interventions have only been reported in a singular case of LNB-associated vasculitis. It is known that neuroradiological interventions such as those presented here have been successfully carried out from the technical aspect in the past in the context of other underlying inflammatory diseases of the cerebral nervous system. In one case, Brisman et al.  reportedThe only study so far that describes endovascular treatment of LNB-associated stroke due to large vessel occlusion was conducted in a 6-year-old child with acute basilar occlusion who received intra-arterial thrombolysis and aspiration/stent-retriever-thrombectomy. In this case, presentation in the hyperacute phase of stroke in combination with quick diagnosis and immediate antibiotic and anti-inflammatory treatment together with fast interventional management led to a very good outcome . The litMoreover, bacterial meningitis has been associated with vasospasms of the cerebral arteries and furthermore with permanent neurological deficits and death . PatholoTo the best of our knowledge, the case presented here is the only report to date of interventional neuroradiological stent treatment in a case of pronounced vasospasms and stenoses of the cerebral vessels due to inflammation in the context of LNB.Neuroradiological intervention, especially in the setting of florid vasculitis, should always be carefully considered and discussed in detail on an interdisciplinary basis. In the case presented, the clinical symptoms and the vasospasms/persisting stenoses, which could not be treated by other means, forced the interventional steps to be taken. Further passive waiting considering the already manifest clinical symptoms would probably have led to a similarly negative clinical outcome due to the expected occurrence of further ischemia caused by vasospasms and the expected occlusion of the right middle cerebral artery in particular. It is possible that a further acceleration and change in drug therapy could have improved the patient’s outcome, but considering the rapid deterioration of the patient’s condition and the immediate need for neuroradiological intervention as the only short-term therapeutic option, this question remains unanswered.Furthermore, the respective improvement of the neurological symptoms following a total of eight vasospasmolyses, and especially after the first intervention, showed that these interventions were always able to improve the patient’s condition, even if only for a relatively short time.The initial therapeutic successes  show that endovascular therapy should always be considered after application of all conservative therapy options and may stabilize the patient’s status until the conservative therapies (antibiosis/anti-inflammation) take effect. Such endovascular therapies involve an increased risk, which is why stenting with consecutive antiplatelet therapy was only used as ultima ratio.However, the fact that the coated stent remained perfused even without antiplatelet therapy shows the potential of such modern stents.Nevertheless, such interventions for vasculitides of other etiologies are known and have been successfully performed. In the future, however, the option of neuroradiological intervention should always be discussed in the case of corresponding courses of disease.In summary, our study shows the potential of neuroradiological interventions as an ultima ratio alternative attempt in severe vasculitic courses of Lyme neuroborreliosis. Even though the therapy we performed, consisting of vasospasmolysis and stenting of the MCA, only led to short-term improvements in the patient’s symptoms, the performance of such interventions in similar cases of Lyme neuroborreliosis with concomitant vasculitis should not be ruled out per se.


Previous evidence shows that rapid changes occur in the brain following spinal cord injury (SCI). Here, we interrogated the expression of the neuropeptides pituitary adenylyl cyclase-activating peptide (PACAP), vasoactive intestinal peptides (VIP), and their binding receptors in the rat brain 24 h following SCI. Female Sprague-Dawley rats underwent thoracic laminectomy; half of the rats received a mild contusion injury at the level of the T10 vertebrate (SCI group); the other half underwent sham surgery (sham group). Twenty-four hours post-surgery, the hypothalamus, thalamus, amygdala, hippocampus , prefrontal cortex, and periaqueductal gray were collected. PACAP, VIP, PAC1, VPAC1, and VPAC2 mRNA and protein levels were measured by real-time quantitative polymerase chain reaction and Western blot. In SCI rats, PACAP expression was increased in the hypothalamus (104–141% vs sham) and amygdala (138–350%), but downregulated in the thalamus (35–95%) and periaqueductal gray (58–68%). VIP expression was increased only in the thalamus (175–385%), with a reduction in the amygdala (51–68%), hippocampus (40–75%), and periaqueductal gray (74–76%). The expression of the PAC1 receptor was the least disturbed by SCI, with decrease expression in the ventral hippocampus (63–68%) only. The expression levels of VPAC1 and VPAC2 receptors were globally reduced, with more prominent reductions of VPAC1 vs VPAC2 in the amygdala (21–70%) and ventral hippocampus (72–75%). In addition, VPAC1 downregulation also extended to the dorsal hippocampus (69–70%). These findings demonstrate that as early as 24 h post-SCI, there are region-specific disruptions of PACAP, VIP, and related receptor transcript and protein levels in supraspinal regions controlling higher cognitive functions. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two closely related neuropeptides with shared receptors that mediate a diverse range of neuroprotective functions within both the central and peripheral nervous systems Waschek .The activity of PACAP and VIP is mediated by three G-protein coupled receptors, PAC1, VPAC1, and VPAC2, which appear to regulate distinct biological functions  or sham surgery groups .All procedures were carried out with the approval of the University of Technology Sydney Animal Care and Ethics Committee (ETH13-0069), according to the guidelines set out by the National Health and Medical Research Council code of conduct for the use of animals in medical research. Twelve adult female rats  were acquired from Animal Resource Centre . Rats were housed in cages on a 12-h light-dark cycle with access to food and water ad libitum. Each cage was provided with environmental enrichment. Animals were randomly assigned to either mild contusion SCI group  buffer as previously described . Comparisons between two groups (sham vs SCI) were analyzed by unpaired Adcyap1 , the gene encoding PACAP peptide, and PACAP protein  was increased in the amygdala of animals that had received SCI, compared to sham controls . Conversely in the thalamus, we observed a significant reduction in the expression of the Adcyap1 gene  and protein levels in SCI vs sham controls  and protein  expression were significantly reduced in response to SCI, compared to sham controls  and protein  levels in the ventral portion of the hippocampus , in the SCI group; however, the decrease was not significant at the transcriptional level  and VIP protein  expression was seen in the thalamus of SCI animals  and expression of its protein product PAC1  were decreased in SCI animals, compared to sham controls  and VPAC1 protein expression . In the dorsal hippocampus, both mRNA  and protein  levels were reduced in SCI animals  and protein levels  . Vipr1 gene expression in the periaqueductal gray was not altered in response to SCI; however, we reported a broad distribution of results, reflecting individual variability in response across the sampled cohort of animals  Fig. e. Vipr1 p = 0.0115; 77% of the sham group; Fig. p = 0.0137; 83% of the sham group; SCI vs sham; Fig. Vipr2 gene expression in the periaqueductal gray of SCI animals (152% of the sham group; Fig. SCI animals demonstrated a downregulation of VPAC2 protein expression in the amygdala (*There are only limited studies addressing CNS changes 24 h following SCI, and these are almost exclusively focused on the local spinal effects and using experimental models of ischemic spinal injury (Li et al. The neuroprotective and immunomodulatory actions of PACAP and VIP are well established (Abad and Tan In the context of SCI, most studies have been focused on investigating molecular changes occurring at the site of injury—that is, within the spinal cord. Furthermore, the large bulk of investigations attempting to describe the contribution of this neuropeptides’ family have been restricted to PACAP and not VIP nor the receptors. Nonetheless, these studies have offered the opportunity to comprehend some of the beneficial properties of these neuropeptides in the injured CNS. For example, in a contusion model of SCI, heterozygous PACAP-KO mice displayed impaired motor function and greater neuronal cell death compared to wild-type mice (Tsuchikawa et al. VIP and VPAC receptors are linked to the peptide’s immunomodulatory functions, suggesting that the disruptions observed in their expression could be linked to inflammation. It is known that injuries to the spinal cord trigger pathological signaling cascades that result in microglial and astrocyte activation and, consequently, neuroinflammation (Li et al. Nonetheless, we demonstrated significant changes in neuropeptide expression in the amygdala and ventral hippocampus. This aligns with the fact that most SCI cases are traumatic experiences, caused by traffic accidents, violence, sports, and/or falls (Alizadeh et al. The pleiotropic nature of these peptides justifies the broad involvement of PACAP and VIP in several neuropathological processes, many of which may require several days to establish. Additionally, these studies should be performed with both male and female rats due to the known sexual dimorphism that exists in neurological pathologies. It has been shown that female rats benefit from their innate heightened immune activities, which facilitate spontaneous recovery from CNS injury (Hauben et al. Nardone et al. reported that SCI leads to a wide range of sensorimotor and autonomic nerve damage and this results in the rapid reorganization of supraspinal structures within hours of peripheral nerve damage (Nardone et al. We provide evidence that the expression of the neuropeptides, PACAP and VIP, along with their related receptors is altered 24 h after SCI in a region-specific manner (results are summarized in Table


Inward rectifier potassium channels (Kir channels) exist in a variety of cells and are involved in maintaining resting membrane potential and signal transduction in most cells, as well as connecting metabolism and membrane excitability of body cells. It is closely related to normal physiological functions of body and the occurrence and development of some diseases. Although the functional expression of Kir channels and their role in disease have been studied, they have not been fully elucidated. In this paper, the functional expression of Kir channels in vascular endothelial cells and smooth muscle cells and their changes in disease states were reviewed, especially the recent research progress of Kir channels in stem cells was introduced, in order to have a deeper understanding of Kir channels in vascular tissues and provide new ideas and directions for the treatment of related ion channel diseases.  As research on K+ channels continues to advance, an increasing number of ion channels have been discovered and thoroughly studied. Inward rectifier potassium channels (Kir channels) are a type of K+ channels that play a critical role in electrical signaling in cells. They are ion channels that allow the selective passage of K+ across the plasma membrane of a cell. These channels are referred to as “inward rectifiers” because they are highly selective for inward K+ currents, meaning they allow the flow of K+ ions into the cell but not out of the cell. These channels are responsible for maintaining the stability of the excitation and resting membrane potential (RP) of excitable tissue cells within living organisms, and are critical for the regulation in homeostasis, and signal transduction -1-naphthalenemethanamine Hydrochloride (ML133) has been found to selectively inhibit kir2.x channels and depolarize the membrane in a dose-dependent manner. The proper activation of Kir channels is dependent on the presence of phosphatidylinositol 4, 5-biphosphate (PIP2), which plays a critical role in regulating ion channels. This distinctive feature is further reinforced by the unique gating properties of Kir channels i) and Kir currents in freshly isolated RIRAs VSMCs, and the expression of Kir2.1 in RIRAs. They found that BaCl2 induced RIRAs contraction in a concentration-dependent manner and elevated [Ca2+]i levels. In both resting and stimulated RIRAs, cyclooxygenase inhibition and thromboxane-prostaglandin receptor (TP) antagonism inhibited BaCl2-induced RIRA contraction, while nitric oxide synthase inhibition and de-endothelialization enhanced RIRA contraction. Tykocki et al [Remarkably, Kir channels have also been identified in human bronchial SMCs , coronarki et al  conducteki et al .+ released from the endothelium increases Kir conductivity of SMCs, which promotes EDH. Researchers [Enhanced activity and expression of Kir channels in vascular tissues have been associated with various pathological conditions. Essential hypertension is often characterized by heightened vascular tone, which can be attributed to depolarization of VSMCs and shifts in the expression of ion channels that facilitate arterial constriction. Tajada et al  conducteearchers  studied + current in mouse epigastric SMCs increased with age, reinforcing the integral role that Kir channels play in regulating RP and vasomotor tension. This increase in Kir current in older mice may serve to compensate for functional alterations in the abdominal wall superior epigastric arteries caused by aging. Tajada et al. also observed an upsurge in functional expression of Kir channels in the resistance artery smooth muscle cells of older mice skeletal muscle. This adaptation in response to aging may contribute to maintaining vasomotor tone and regulating blood flow during exercise. Spasticity in cerebral vessels has been reported in patients following subarachnoid hemorrhage (SAH). Weyer et al [Functional adaptive enhancement of Kir channels has been observed in other cardiovascular disorders. A study by Park et al  in 2005 er et al  investig+ concentration. Sancho and his colleagues [+. This was attributed to deficient smooth muscle Kir channel function in the ability to promote vasodilation, as evidenced by a decrease in Kir2.1 mRNA and smooth muscle Kir current density in PAs under stress conditions. The authors proposed that glucocorticoid signaling pathways induced by stress played a role in impeding cerebrovascular Kir channel opening and consequently destroyed neurovascular coupling.However, decreased expression and dysfunction of Kir channels in disease states have also been reported. In a study conducted by Bastide et al , Kir challeagues  observedlleagues  revealedThe main findings in functional expression of Kir channels in VSMCs and their changes under pathological influences were summarized in + ion channels, including the Kir channels of the inward rectification family. These channels play a vital role in regulating vascular tone and controlling arterial blood pressure, and their electrophysiological properties, activation mechanisms and vascular wall expression are closely associated with these functions [2 effectively blocking Kir currents in these ECs. Conversely, no Kir currents were detected in VSMCs. An explanation for the apparent failure to detect current through Kir was that the channels were either very small or required agonist stimulation in order to be detected. The different K+ channel profiles reflect a real difference in the distribution of ion channels between SMCs and ECs of the mesenteric artery. In 2005, Fang et al [+ conductance of HAECs while Kir2.2 is the primary conductance. Climent et al [in situ” ECs. The results suggest that the ECs layer of a large artery is electrically coupled, and Kir channels play an important role in RP in in situ ECs. In 2011, Jang et al [2+ and 1 mM Cs+ and the inhibition resulted in endothelial cell depolarization. The study demonstrated that several subtypes of Kir channels, including Kir2.x, Kir3.x, Kir4.x, and Kir6.x, are present on endothelial cells. Furthermore, inhibition of Kir2.1 promoted the proliferation of EPCs. Multiple studies have indicated that capillary endothelial cells express Kir2.1 and Kir2.2, and may also express Kir2.3. William et al. have identified the presence of Kir2.1 protein on rat and mouse arteriole ECs, revealing it to be the fundamental Kir channel subunit expressed in both rat and mouse microvascular ECs [Studies have revealed that ECs exhibit a diverse range of Kunctions . In 2003unctions  conducteng et al  determinnt et al  investigng et al  discoverular ECs . Moreoveular ECs .+ concentration triggers the activation of Kir currents. These channels sense variations in extracellular K+ concentration, causing the membrane to become hyperpolarized and increasing the hyperpolarization created by other K+ channels and ion transporters. This amplification aids in regulating the Vm of ECs and other microvascular functions [+ ion concentration, impacting vasodilation. Inhibition or knockout of Kir channels can weaken endothelium-dependent vasodilation. To investigate the role of the Kir channel in the physiological response of ECs to blood flow, Ahn et al [Research indicates that an increase in extracellular Kunctions . The preunctions . Moreoveunctions  discoverhn et al  examined2+ and activation of IKCa/SKCa channels, leading researchers to suggest that Kir channels could be targeted for the treatment of endothelial dysfunction [Endothelial cells are tightly electrically coupled to their neighboring cells by gap junctions allowing ion channel-induced changes in Vm to be conducted for considerable distances along the endothelial cell tube that lines arterioles and forms capillaries. According to research, Kir channels in mouse mesenteric arteries are also capable of transmitting electrical signals to superior arterioles through cell-cell conduction and can participate in vasodilation . Numeroufunction . Recent function  summariz+ channel function, and that the effect of Kir channels on Vm in male endothelial cells was slightly lower than that in female cells. As individuals aged, the contribution of Kir channels in both sexes gradually declined, which was related to endothelial dysfunction [Previous research has demonstrated that EDH induces hyperpolarization and vasodilation, and can spread throughout the endothelium in mesenteric arteries of rats. However, this response is weakened in SHR rats, and the same effect can be elicited through inhibition of Kir channels . Althougfunction .+ channel subtypes are impaired in individuals with obesity and metabolic syndrome, leading to dysfunction of both smooth muscle and endothelium [in vitro, high cholesterol lipoprotein inhibits Kir currents [2 sensitive components were improved, and ROS was decreased in vitro. They suggested that early metabolic challenge leads to reduced Kir-mediated endothelium-dependent hyperpolarization. Subsequently, Fancher et al [The expression, function associated with impaired vasodilatation, and sensitivity of vascular Kothelium . It has othelium . This inothelium . Ahn et othelium  tested Ecurrents . Alaaeddcurrents  investiger et al  found th+ induced arterial dilation showed that oxidative stress and inflammation impaired the flow-activation of Kir, particularly the Kir2.1 channel. This impairment reduced vasodilation response, while inflammation induced overexpression of Kir2.1 in mice [2+ activated potassium channels (SKCa and IKCa) and Kir2.x channels during progressive AD pathology. Using newly isolated ECs of rat posterior cerebral artery, they determined that the function of SKCa/IKCa channels in male cerebral vascular ECs was enhanced by about 20% during the pathological process of AD, while that in females remained stable. Vascular Kir channels, which regulate cerebral blood flow and perfusion, were found to be interdependent with SKCa channel activation. However, the contribution of the Kir channel to Vm in AD decreased by about 50% compared to young age, which may be due to changes in membrane lipid and cholesterol content in the development of AD [The Kir channel plays a crucial role in regulating neurovascular vasodilation. These channels are responsible for regulating the resting state of cells and the distance that electrical signals travel along arterial walls in the brain’s circulation. However, the expression of Kir2.x channels has been found to be limited in the cerebral arteries of epileptic patients, which can negatively impact the resting tone and vasomotor response diffusion . In addi in mice . In theint of AD . Recent nt of AD .The main findings in functional expression of Kir channels in vascular ECs and their changes under pathological influences were summarized in Stem cells possess the remarkable ability to continuously grow and renew themselves, and are capable of developing into diverse types of mature tissue cells. Within the blood vessel wall, vascular resident stem cells exist within all three layers, contributing to the formation of blood vessels in normal physiological scenarios, while also playing a role in remodeling them during pathological conditions. The impact of some ion channels on stem cell function has been previously documented . Althoug2+ (100 μM) inhibited 91.2 ± 1.4% of the current, while Cs+ (1 mM) inhibited 76.1 ± 6.9% of the current. Furthermore, using DiBAC(3) – a fluorescent indicator of Vm – the researchers demonstrated that Ba2+ induced fluorescence enhancement of EPCs , which suggested depolarization of EPCs. In conducting functional experiments, they discovered that the presence of Ba2+ resulted in a dose-dependent decrease in the number of tubes formed by EPCs on Matrigel. Additionally, the proliferation of EPCs showed a corresponding dose-dependent increase, with specific inhibition of Kir2.1 achieved by small interfering RNA yielding further promotion of EPCs proliferation. These findings strongly suggest that multiple types of Kir may be expressed in EPCs, enabling them to regulate endothelial function and proliferation of ECs effectively. It has been reported that controlling the Kir channel of EPCs can regulate their endothelial function and proliferation. When Kir2.1 channels are inhibited, EPCs undergo depolarization, which induces autophagy and promotes differentiation into ECs. Conversely, the activation of Kir2.1 channels leads to EPCs hyperpolarization. In addition, the Akt/mTOR/Snail signaling pathway is activated to induce EPC transdifferentiation into mesenchymal cells, specifically pericytes, which can regulate and maintain stemness [In 2011, Jang et al  publishestemness . Researcstemness .−). This team identified corresponding ion channel genes and proteins in these cells, which were KCa3.1 for KCa, Kir2.1 for Kir and Clcn3 for Cl. The study sought to assess the impact of long-term in vitro culture on ion channels of human MSCs (hBM-MSCs). Specifically, the experiment involved culturing cells from eight patients with amyotrophic lateral sclerosis (ALS) for ten generations. Although all hBM-MSCs had multiple MSC markers, differences in the distribution of functional ion channels were observed across cells. Notably, four types of K+ currents were identified in the cells- noisy Ca2+ activated K+ current, transient outward K+ current, delayed rectifying K+ current, and Kir current. Besides, TTX-sensitive Na+ current was recorded during the experiments. Hinard et al [Although there is limited research on Kir in vascular stem cells, studies on other types of stem cells have provided insights into the potential roles and mechanisms of Kir in stem cell biology. In fact, bone marrow mesenchymal stem cells (MSCs) are believed to offer great potential as a cell source for cardiomyoplasty. According to research by Tao et al , who utird et al  have repBioelectrical signals play a crucial role in determining cellular behavior, with ion channels serving as the foundation of these signals. While there is some understanding of the relationship between functional vascular ion channel expression and vascular behavior, further exploration is needed. Kir channels, a type of ion channel responsible for maintaining the resting potential and signal transduction in most cells, are directly related to normal physiological functions of blood vessels and the development of certain diseases. Without the involvement of Kir channels, the ability of Kir to promote vasodilation in the circulatory system would be difficult to achieve. Different subtypes of Kir channels on VSMCs and ECs regulate vasomotor activity and blood flow supply. Advancements in understanding Kir channels are being made through various approaches such as analyzing their structure, studying their electrical activity using electrophysiological techniques, investigating their function using molecular biology techniques, and understanding their role in disease through the examination of specifically expressed subtypes in vascular tissues using transgenic animals. These findings have great potential to shed light on new treatment options for ion channel diseases and identify new targets for drug therapies.


This is a prime example when substantial energy metabolism is required at the level of the various cell types present in bone and in the bone marrow. This review Research Topic comprises a set of 6 manuscripts that all recognize in their own way the importance of energy metabolism within the skeleton.Following a fracture, an orchestrated sequence of events is initiated Metabolic bone diseases including obesity, diabetes, and osteoporosis are associated with increased risk of bone fractures caused by impaired bone remodeling and function of bone marrow stromal cells (BMSCs) with different underlying mechanisms. These different diseases share features including hyperglycemia and hyperlipidemia defining their pathology, but with different consequences on the skeletal system. Utilization of nutrients by BMSCs has been shown to affect differentiation potential, cell metabolism and bone marrow microenvironment.Arponen et al. investigated the role of different glucose transporters (GLUT1-GLUT4) in osteoblast differentiation and metabolism using primary female rat BMSCs. This study showed that GLUT1 and GLUT4 are downregulated in osteoblast differentiation, while GLUT3 was not changed during differentiation and GLUT2 was not detected in rat osteoblasts. Using siRNA screening and RNA seq analysis, the authors reported that modulation of GLUT4 expression had a major effect on proliferation and osteoblast differentiation, while GLUT3 mainly influenced cell proliferation. The authors suggested that the glucose transporters are differently involved at various stages of osteoblast differentiation and their functional cooperation is important for the physiological role of osteoblasts.Shen et al. investigated the role of exogenous proline for osteolineage cells in adult mice through specific deletion of the System A transporter SNAT2 (encoded by Slc38a2) and found that Slc38a2-conditional knockout mice exhibit a significant decrease in trabecular, but not cortical, bone mass. As a mechanism, they proposed that SLC38A2 is necessary for proline and alanine uptake, which in turn is required for proliferation and differentiation of skeletal progenitor cells although the exact metabolic fate of proline and alanine is still unknown. Together, this study clearly demonstrates the importance of SLC38A2-mediated proline and alanine uptake for osteoblast function. Intriguingly, SLC38A2 expression was not only observed in osteolineage cells, but also in growth plate and articular chondrocytes. Whether and how proline uptake regulates their function during bone development, or whether proline metabolism is altered during pathologies such as osteoarthritis are interesting questions that warrant further investigation.Bone takes up a considerable amount of postprandial glucose and fatty acids, and these nutrients have been recently shown to fuel specific metabolic pathways in osteoblasts that regulate their function. Certain amino acids, such as glutamine or proline, complement the action of glucose and fatty acids during endochondral ossification, but their roles in the maintenance of postnatal bone mass remain less well understood. In this Research Topic, Kushwaha et al. examined the requirement for mitochondrial fatty acid β-oxidation by osteoclasts by disrupting the expression of the gene encoding carnitine palmitoyltransferase-2 (Cpt2) in lysozyme-2+ myeloid progenitors that give rise to osteoclasts. Fatty acid oxidation increased during in vitro osteoclast differentiation while progenitor cells deficient for Cpt2 failed to form large, multi-nucleated, tartrate-resistant acid phosphatase + osteoclasts. Importantly and in line with these data, female mice deficient for Cpt2 in osteoclasts exhibited a high bone mass phenotype due secondary to reduced osteoclast numbers and activity. These data highlight a key role for fatty acid catabolism in osteoclast maturation and function.The metabolic requirements of osteoclast-driven bone resorption have yet to receive the same level of attention that osteoblastic bone formation has received. In this Research Topic, Lecka-Czernik et al. assessed the role of PPARα in osteocytes by comparing osteocyte-specific and global PPARα knockout mice. It was shown that osteocyte-derived PPARα is vital for the bioenergetics and mitochondrial stress control in these cells and it is up to 40% responsible for the global energy metabolism mediated through PPARα. The contribution of osteocytes to a high energy phenotype typically found in young mice reverts to a low energy and obese phenotype during aging, a phenotype that is shared between the local and global knockout mouse. In contrast, the enlarged bone phenotype and effects on BMSCs and hematopoietic stem cell differentiation following global PPARα deficiency is not observed in the osteocyte-specific model, except increased bone marrow adipose tissue. Apparently, PPARα in osteocytes contributes to systemic energy metabolism by controlling marrow adiposity and peripheral fat metabolism.Osteocytes are the most numerous bone cell type in the skeleton and involved in mechanotransduction and subsequent communication with other osteoblast and osteoclast to orchestrate bone formation and resorption, respectively. Given the established involvement of PPARγ as a master regulator of energy metabolism in bone, Zhang et al. used a drug-repurposing approach to prioritize small molecules employing the connectivity map (CMap). Having selected a set of potential anti-adipogenic compounds, subsequent BMSC-derived adipocyte cultures and transcriptomic profile generation revealed the small molecules emetine and kinetin riboside to potently inhibit adipogenesis. This proof-of-concept study demonstrates that CMap can be used to identify repurposable drugs capable of inhibiting the function of marrow adipocytes.Aging, obesity, diabetes and anorexia nervosa are all associated with increased adipogenesis in the bone marrow. In an attempt to identify novel compounds that may counteract enhanced marrow adiposity, Thapa et al. reported an interesting overview on the endocrine metabolic regulation on the skeletal system in osteoporosis, with a focus on post-menopausal women. This review focused on the prevalence and different stages of osteoporosis including sexual dimorphism, as higher prevalence in women is caused by loss of the protective role of estrogen. Estrogen levels are key in moderating bone remodeling, keeping a balance between the function of osteoblasts and osteoclasts. This view also interestingly points out the possible role of sex hormones in regulating bioenergetics of BMSCs, which might contribute to manifestation of bone pathology and bone loss induced by osteoporosis. This review provides a perspective focused on the role of gonadal hormones regulating bone cell metabolic potential.The review by within the skeleton and discover mechanisms underlying the pathways involved. Ultimately, this should lead to the development of treatment modalities for metabolic bone diseases, such as osteoporosis, obesity and diabetes.Collectively, the studies within this Research Topic illustrate the need to further study energy metabolism