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Systemic transplantation of oxygen−glucose deprivation (OGD)-preconditioned primary microglia enhances neurological recovery in rodent stroke models, albeit the underlying mechanisms have not been sufficiently addressed. Herein, we analyzed whether or not extracellular vesicles (EVs) derived from such microglia are the biological mediators of these observations and which signaling pathways are involved in the process. Exposing bEnd.3 endothelial cells (ECs) and primary cortical neurons to OGD, the impact of EVs from OGD-preconditioned microglia on angiogenesis and neuronal apoptosis by the tube formation assay and TUNEL staining was assessed. Under these conditions, EV treatment stimulated both angiogenesis and tube formation in ECs and repressed neuronal cell injury. Characterizing microglia EVs by means of Western blot analysis and other techniques revealed these EVs to be rich in TGF-β1. The latter turned out to be a key compound for the therapeutic potential of microglia EVs, affecting the Smad2/3 pathway in both ECs and neurons. EV infusion in stroke mice confirmed the aforementioned in vitro results, demonstrating an activation of the TGF-β/Smad2/3 signaling pathway within the ischemic brain. Furthermore, enriched TGF-β1 in EVs secreted from OGD-preconditioned microglia stimulated M2 polarization of residing microglia within the ischemic cerebral environment, which may contribute to a regulation of an early inflammatory response in postischemic hemispheres. These observations are not only interesting from the mechanistic point of view but have an immediate therapeutic implication as well, since stroke mice treated with such EVs displayed a better functional recovery in the behavioral test analyses. Hence, the present findings suggest a new way of action of EVs derived from OGD-preconditioned microglia by regulating the TGF-β/Smad2/3 pathway in order to promote tissue regeneration and neurological recovery in stroke mice.

Inflammation triggers secondary brain damage after stroke. The meninges and other CNS border compartments serve as invasion sites for leukocyte influx into the brain thus promoting tissue damage after stroke. However, the post-ischemic immune response of border compartments compared to brain parenchyma remains poorly characterized. Here, we deeply characterize tissue-resident leukocytes in meninges and brain parenchyma and discover that leukocytes respond differently to stroke depending on their site of residence. We thereby discover a unique phenotype of myeloid cells exclusive to the brain after stroke. These stroke-associated myeloid cells partially resemble neurodegenerative disease-associated microglia. They are mainly of resident microglial origin, partially conserved in humans and exhibit a lipid-phagocytosing phenotype. Blocking markers specific for these cells partially ameliorates stroke outcome thus providing a potential therapeutic target. The injury-response of myeloid cells in the CNS is thus compartmentalized, adjusted to the type of injury and may represent a therapeutic target. How ischaemic stroke affects the brain borders is not fully understood. Here the authors show that a stroke-associated myeloid cell population occurs exclusively in brain parenchyma that shares features with neurodegenerative microglia and blockade of proteins on these cells can ameliorate stroke symptoms.

Phosphodiesterase 10A (PDE10A) hydrolyzes adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP). It is highly expressed in the striatum. Recent evidence implied that PDE10A may be involved in the inflammatory processes following injury, such as ischemic stroke. Its role in ischemic injury was unknown. Herein, we exposed mice to 90 or 30-min middle cerebral artery occlusion, followed by the delivery of the highly selective PDE10A inhibitor TAK-063 (0.3 mg/kg or 3 mg/kg) immediately after reperfusion. Animals were sacrificed after 24 or 72 h, respectively. Both TAK-063 doses enhanced neurological function, reduced infarct volume, increased neuronal survival, reduced brain edema, and increased blood–brain barrier integrity, alongside cerebral microcirculation improvements. Post-ischemic neuroprotection was associated with increased phosphorylation (i.e., activation) of pro-survival Akt, Erk-1/2, GSK-3α/β and anti-apoptotic Bcl-xL abundance, decreased phosphorylation of pro-survival mTOR, and HIF-1α, MMP-9 and pro-apoptotic Bax abundance. Interestingly, PDE10A inhibition reduced inflammatory cytokines/chemokines, including IFN-γ and TNF-α, analyzed by planar surface immunoassay. In addition, liquid chromatography-tandem mass spectrometry revealed 40 proteins were significantly altered by TAK-063. Our study established PDE10A as a target for ischemic stroke therapy.

Occurrence of stroke cases displays a time-of-day variation in human. However, the mechanism linking circadian rhythm to the internal response mechanisms against pathophysiological events after ischemic stroke remained largely unknown. To this end, temporal changes in the susceptibility to ischemia/reperfusion (I/R) injury were investigated in mice in which the ischemic stroke induced at four different Zeitgeber time points with 6-h intervals (ZT0, ZT6, ZT12, and ZT18). Besides infarct volume and brain swelling, neuronal survival, apoptosis, ischemia, and circadian rhythm related proteins were examined using immunohistochemistry, Western blot, planar surface immune assay, and liquid chromatography–mass spectrometry tools. Here, we present evidence that midnight (ZT18; 24:00) I/R injury in mice resulted in significantly improved infarct volume, brain swelling, neurological deficit score, neuronal survival, and decreased apoptotic cell death compared with ischemia induced at other time points, which were associated with increased expressions of circadian proteins Bmal1, PerI, and Clock proteins and survival kinases AKT and Erk-1/2. Moreover, ribosomal protein S6, mTOR, and Bad were also significantly increased, while the levels of PRAS40, negative regulator of AKT and mTOR, and phosphorylated p53 were decreased at this time point compared to ZT0 (06:00). Furthermore, detailed proteomic analysis revealed significantly decreased CSKP, HBB-1/2, and HBA levels, while increased GNAZ, NEGR1, IMPCT, and PDE1B at midnight as compared with early morning. Our results indicate that nighttime I/R injury results in less severe neuronal damage, with increased neuronal survival, increased levels of survival kinases and circadian clock proteins, and also alters the circadian-related proteins.

Objective: An effective pain control is important in early mobilization and returning to normal daily life following percutaneous nephrolithotomy (PCNL) operations. The use of an intraoperative local anaesthetic or postoperative analgesic has been reported for pain control in PCNL. Transmuscular quadratus block (QLB III) is a regional anaesthetic technique applied under ultrasound guidance. The aim of this study was to investigate the effectiveness of QLB III on postoperative pain in PCNL. Methods: This prospective, randomized, double-blinded study was carried out at the Dr Ersin Arslan Training and Research Hospital between December 2016 and March 2017. The QLB III block was administered to a total of 44 patients who had undergone elective PCNL under spinal anaesthesia. While half of the patients (Group S, n=22) received 0.2 cc kg-1 of 0.9% saline, the other half (Group Q, n=22) received 0.2 mL kg-1 of 0.0125 isobaric bupivacain with QLB III. For all patients, the pain level was measured using the visual analog scale (VAS), and the morphine consumptions through patient-controlled analgesia (PCA) were recorded at the postoperative 4, 8, 12, 24, and 48 hours. Results: The postoperative VAS was found to be statistically significantly higher at the 8th, 12th, and 24th hour in Group S (p<0.05). The postoperative morphine consumption was determined to be statistically significantly higher at the 4th, 8th, 12th, and 24th hour in Group S (p<0.05). Conclusion: The QLB III was observed to be effective in pain control and reducing morphine consumption during the postoperative 48 hours follow-up after PCNL.

Aim: To prepare two different kinds of wound care creams containing plant extracts and examine their effectiveness in comparison with a placebo cream and a commercial wound care cream, Madecassol®. Methods: The two cream formulations were developed using the same placebo cream (PC) as base cream. One formulation contained balsam of oriental sweet gum, or Levant storax, named as Levant Storax Cream (LSC); the other contained oil of Calendula, extract of St. John’s Wort, aescin (an extract of horse chestnut), and freeze-dried powder from Aloe vera (L.) Burm. f. leaf juice, designated as Complex Cream (CC). In the characterization of the creams, organoleptic properties, pH, viscosity, size distribution, and zeta potential of oil globules were measured. Furthermore, the stability of the creams was assessed under different environmental conditions. In vitro studies were performed by using an excisional wound model in rats to assess the potential of the creams for stimulating wound healing. The efficacy of LSC and CC was compared with a commercial reference cream, Madecassol® (M), and the placebo control. The study was also designed with a negative control group of rats that were not treated but handled the same way as the other treatment groups. The wound contraction rate, total skin thickness recovery, and results of histopathological parameter examinations were used to compare the effectiveness of the treatments. Results: The stability of formulated creams confirmed that they were stable for the duration of the study. In vivo studies showed that rats treated with LSC achieved the highest wound healing rates when compared with the other groups. A better response was recorded for the CC-treated population when compared to both control and placebo groups, but there was no significant difference seen in healing score between CC and M groups.

Background Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies. However, the chemotherapeutic use of cisplatin is limited by its serious side-effects such as nephrotoxicity and ototoxicity. Cisplatin chemotherapy induces a reduction in the antioxidant status, leading to a failure of the antioxidant defense against free-radical damage generated by antitumor drugs. Cisplatin-induced oxidative stress in the kidney was partially prevented by antioxidant treatments using superoxide dismutase, glutathione, selenium and flavonoids. Melatonin and its metabolites possess free-radical scavenging activity and it has been shown that they protect against cisplatin toxicity. However, the mechanism of the protective effects of melatonin against cisplatin-induced nephrotoxicity is still essentially unknown. We therefore designed this study to investigate the underlying mechanism of the protective effect of melatonin against cisplatin-induced renal damage in a rat nephrotoxicity model in vivo. Methods Twenty eight 8-week-old male Wistar rats were divided into four groups of control, melatonin treatment (4 mg/kg b.w i.p. for 10 days), cisplatin treatment (7 mg/kg b.w., i.p.) and melatonin and cisplatin combination treatment. Serum urea nitrogen (urea-N) and creatinine levels were measured. Histopathological changes were evaluated. In addition, we analyzed the expression levels of HO-1, Nrf2, NF-κB and AP-1 in Western blot analysis. Results Both serum creatinine and urea nitrogen increased significantly following cisplatin administration alone; these values decreased significantly with melatonin co-treatment of cisplatin-treated rats. Histological analysis showed that cisplatin caused damage in the proximal tubular cells in the kidneys of cisplatin-treated rats; these changes were reversed by melatonin co-treatment. Upon Western blot analysis, melatonin treatment increased Nrf2 accumulation in the nuclear fraction, and increased the expression of HO-1 in the cytosolic fraction as compared to the cisplatin-treated rats. Expressions of NF-κB p65 and AP-1 were increased significantly in the kidneys of rats treated with cisplatin compared with the expression in the kidneys from the control, melatonin-only-treated and melatonin co-treated rats. Conclusion Our present data suggest that melatonin attenuates cisplatin-induced nephrotoxicity possibly by modulating Nrf2/HO-1 signaling.

Microglia are critically involved in post‐stroke inflammation affecting neurological outcomes. Lipid droplet (LD) accumulation in microglia results in a dysfunctional and pro‐inflammatory state in the aged brain and worsens the outcome of neuroinflammatory and neurodegenerative diseases. However, the role of LD‐rich microglia (LDRM) under stroke conditions is unknown. Using in vitro and in vivo stroke models, herein accumulation patterns of microglial LD and their corresponding microglial inflammatory signaling cascades are studied. Interactions between temporal and spatial dynamics of lipid profiles and microglial phenotypes in different post‐stroke brain regions are found. Hence, microglia display enhanced levels of LD accumulation and elevated perilipin 2 (PLIN2) expression patterns when exposed to hypoxia or stroke. Such LDRM exhibit high levels of TNF‐α, IL‐6, and IL‐1β as well as a pro‐inflammatory phenotype and differentially expressed lipid metabolism‐related genes. These post‐ischemic alterations result in distinct lipid profiles with spatial and temporal dynamics, especially with regard to cholesteryl ester and triacylglycerol levels, further exacerbating post‐ischemic inflammation. The present study sheds new light on the dynamic changes of brain lipid profiles and aggregation patterns of LD in microglia exposed to ischemia, demonstrating a mutual mechanism between microglial phenotype and function, which contributes to progression of brain injury. The mechanisms underlying lipid metabolism and their impact on microglia in the context of stroke need further studies. Using an innovative in vitro and in vivo approach, this study observes dynamic changes in the lipid profile of the ischemic brain associated with microglial function. The study sheds new light on how lipid droplet accumulation and concomitant changes of lipidomic profiles modulate post‐ischemic inflammation, providing insights into potential therapeutic targets for reducing brain damage after stroke.

Melatonin has a role in the cell survival signaling pathways as a candidate for secondary stroke prevention. Therefore, in the present study, the coordination of ipsilateral and contralateral hemispheres to evaluate delayed post-acute effect of melatonin was examined on recovery of the cell survival and apoptosis after stroke. Melatonin was administered (4 mg/kg/day) intraperitoneally for 45 days, starting 3 days after 30 min of middle cerebral artery occlusion. The genes and proteins related to the cell survival and apoptosis were investigated by immunofluorescence, western blotting, and RT-PCR techniques after behavioral experiments. Melatonin produced delayed neurological recovery by improving motor coordination on grip strength and rotarod tests. This neurological recovery was also reflected by high level of NeuN positive cells and low level of TUNEL-positive cells suggesting enhanced neuronal survival and reduced apoptosis at the fifty-fifth day of stroke. The increase of NGF, Nrp1, c-jun; activation of AKT; and dephosphorylation of ERK and JNK at the fifty-fifth day showed that cell survival and apoptosis signaling molecules compete to contribute to the remodeling of brain. Furthermore, an increase in the CREB and Atf-1 expressions suggested the melatonin’s strong reformative effect on neuronal regeneration. The contralateral hemisphere was more active at the latter stages of the molecular and functional regeneration which provides a further proof of principle about melatonin’s action on the promotion of brain plasticity and recovery after stroke.

Testicular torsion (TT) is a urological emergency that results in ischemia/reperfusion (I/R) injury, leading to oxidative stress, cellular apoptosis, and impaired spermatogenesis. This study investigated the protective effects of the HMG-CoA reductase inhibitor rosuvastatin on TT-induced I/R injury and explored the underlying mechanisms. Male Balb/C mice ( n  = 28) were subjected to 720° testicular torsion for two hours, followed by 24 h of detorsion. Rosuvastatin was administered either acutely (post-torsion) or prophylactically (prior to injury). Histopathological evaluation, assessment of oxidative stress parameters, sperm motility and morphology analysis, and Western blot examination of survival and stress related signaling proteins (pAKT, pJNK1/2, pERK1/2, and Bcl-xL) were performed. Rosuvastatin treatment significantly reduced tissue damage decreased oxidative stress (as indicated by increased TAS and reduced TOS/OSI), and improved sperm motility and morphology. Both acute and prophylactic treatment regimens enhanced cell survival by increasing pAKT and Bcl-xL levels, reducing pERK1/2 activation, and modulating stress responsive JNK1/2 signaling. These findings suggest that rosuvastatin mitigates I/R induced testicular damage primarily through modulation of key intracellular pathways, particularly PI3K/AKT, and support its therapeutic potential in acute testicular injuries and related degenerative conditions.