Search Results (774)

Sodium tanshinone IIA sulfonate (STS) injection is clinically used to protect against cerebral ischemia–reperfusion injury (CIRI). This study aimed to establish physiologically based pharmacokinetic–pharmacodynamic (PBPK–PD) models for normal and CIRI rats and to quantitatively characterize the time–concentration–effect relationship, as well as disease-specific mechanistic differences. A middle cerebral artery occlusion rat model was established. STS was administered via the tail vein, and blood samples were collected at serial time points. High-performance liquid chromatography and enzyme-linked immunosorbent assay were used to quantify plasma STS concentrations and inflammatory markers, respectively, whereas equilibrium dialysis was performed to determine protein binding. PK-Sim and Python were used to establish a PBPK model, which was subsequently extrapolated to humans to construct PBPK–PD models. The results showed that plasma STS concentrations were consistently higher in the model rats than in normal rats. STS significantly reduced inflammatory levels in model rats, with a delayed onset of pharmacological effect. Human PBPK model simulations indicated that STS is rapidly eliminated in healthy individuals, while its elimination is reduced under pathological conditions. This study provides a robust modeling framework and methodological reference for dose optimization and prediction of clinical efficacy of STS in the treatment of CIRI. Full article

Background: Anterior cranial fossa dural arteriovenous fistulas (ACF DAVFs) usually receive ethmoidal dural supply. Pial arterial supply has been described in intracranial DAVFs, including ACF DAVFs, but a dominant orbitofrontal pial feeder can create diagnostic overlap with mixed pial-dural arteriovenous malformation and make endovascular treatment hazardous. Case Presentation: A 75-year-old man with atrial fibrillation presented with right middle cerebral artery occlusion and underwent intravenous thrombolysis followed by mechanical thrombectomy. During right internal carotid angiography, transient arterial-phase opacification of a contralateral frontal draining vein through the anterior communicating artery prompted post-recanalization angiography. A high-grade left ACF DAVF was diagnosed, with dominant supply from the left orbitofrontal artery, minor anterior ethmoidal supply, two venous drainage routes, cortical venous reflux, and a varix. Although the DAVF was incidental to the ischemic presentation, it was considered to require treatment because of high-risk angioarchitecture, including Borden type III/Cognard type IV drainage, cortical venous reflux, and venous ectasia. No intraparenchymal nidus or normal venous-phase use of the refluxing veins was identified. Because pial transarterial access and complete transvenous closure were considered unsafe or uncertain, microsurgical draining-vein disconnection was performed. Postoperative angiography confirmed complete obliteration. Conclusions: In this case, microsurgical disconnection achieved angiographic cure, and the patient was transferred for rehabilitation with a modified Rankin Scale score of 1. The central diagnostic and therapeutic issue in pial-feeder-dominant ACF DAVF is not rarity alone, but angiographic differentiation from mixed pial-dural arteriovenous malformation and assessment of whether the shunt can be closed without compromising normal pial arteries or venous outflow. The thrombectomy angiogram provided the route to diagnosis, whereas pial arterial dominance and divided venous drainage determined the curative strategy. Full article

Pterostilbene (Pts), a small molecule stilbenoid and a dimethyl analogue of the star molecule resveratrol, exerts significant blood–brain barrier protection on cerebral ischemia-reperfusion injury and has received extensive attention. This study performed structural optimizations on Pts to obtain a series of derivatives and investigated their anti-ischemic activities both in vitro and in vivo, aiming to identify candidates with high safety and improved efficacy compared with Pts. The ADMET method was used to predict the drug-likeness of a series of Pts derivatives, and in vitro MTT cell viability analysis was conducted on neuroblastoma cells (SH-SY5Y) and brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation/reperfusion (OGD/R) injury. On the basis of the cytotoxicity results, four derivatives (NO. 1, NO. 3, NO. 5, and NO. 7) were selected for subsequent in vitro and in vivo biological activities evaluation. These compounds exhibited significantly higher TI values (18.29–30.61) in OGD/R-injured hBMECs compared with Pts (7.63) and effectively suppressed apoptosis, promoted cell migration, and enhanced tube formation capacity. In vivo, NO. 3 (5 mg/kg, ip., 7 d) demonstrated superior efficacy compared to Pts in improving cerebral blood flow, reducing infarction volume, enhancing neurological function, and modulating serum biomarker levels in middle cerebral artery occlusion/reperfusion (MCAO/R) rats, whereas NO. 1 and NO. 7 showed comparable efficacy to Pts. The acute intraperitoneal toxicity of NO. 3 was conducted and showed that the LD₅₀ of NO. 3 was estimated to be more than 300 mg/kg. In this study, the rational design and comprehensive evaluation of Pts derivatives were reported. Compound NO. 3 demonstrated superior pharmacological efficacy to Pts both in vitro and in vivo, and it may be a promising therapeutic candidate for ischemic stroke intervention. Full article

Objective: To investigate whether gestational diabetes mellitus (GDM), including insulin-treated GDM, affects cerebroplacental ratio (CPR) values in monochorionic diamniotic (MCDA) twin pregnancies. Methods: This retrospective single-center cohort study included a total of 262 MCDA twin pregnancies managed at a tertiary referral center, comprising pregnancies without GDM (n = 120), with diet-controlled GDM (n = 80), and with insulin-treated GDM (n = 62). Doppler ultrasound examinations were performed at three gestational time points between 24 and 36 weeks of gestation. CPR, umbilical artery pulsatility index (UA-PI), and middle cerebral artery pulsatility index (MCA-PI) were compared longitudinally between groups. Doppler indices were compared between groups without adjustment for baseline differences such as BMI and parity Results: Maternal body mass index was significantly higher in pregnancies complicated by GDM, particularly in those requiring insulin therapy (p < 0.001). Estimated fetal weight was higher in the insulin-treated GDM group at mid-gestation (28–32 weeks; p = 0.01). However, CPR values remained within normal ranges throughout all screening points across all three groups. No relevant differences in UA-PI, MCA-PI, gestational age at delivery, Apgar scores, or umbilical cord pH were observed between groups. Conclusions: In MCDA twin pregnancies, gestational diabetes—regardless of insulin treatment—does not appear to significantly influence cerebroplacental ratio values throughout gestation. No statistically significant differences in CPR values were observed between groups. No statistically significant differences in CPR values were detected between groups. However, given the exploratory design and lack of adjustment for confounders, subtle effects cannot be excluded. The clinical utility of CPR in this population requires further investigation. Full article

Calycosin-7-O-β-D-glucoside (CG), a bioactive compound extracted from the traditional Chinese herb Astragalus (AR), exhibits diverse biological activities, including anti-oxidative and anti-inflammatory effects, and has shown protective properties in ischemia–reperfusion (I/R) injury. While previous studies have demonstrated that CG mitigates I/R injury primarily through its anti-oxidative and anti-inflammatory actions, its potential role in promoting neuroregeneration—a critical process for stroke recovery—remains unclear, and the underlying mechanisms have yet to be elucidated. In this study, an ischemic stroke model was established in rats via middle cerebral artery occlusion (MCAO). Seven days after CG treatment, cerebral infarct volume was assessed using triphenyltetrazolium chloride (TTC) staining, while neurological function was evaluated through behavioral tests. Nissl staining and Bielschowsky silver staining were employed to examine neuronal damage and axonal loss, and immunofluorescence was used to assess axonal regeneration. The expression of key proteins in the Rho/ROCK signaling pathway was analyzed by Western blotting (WB) and quantitative real-time PCR (qRT-PCR). CG treatment significantly reduced infarct volume, promoted axonal regeneration, improved neurological outcomes, and modulated the expression of RGMa, Rho, ROCK, and CRMP2. Collectively, these findings provide the first evidence that CG facilitates axonal regeneration and neurological recovery after cerebral ischemia, at least in part by inhibiting activation of the Rho/ROCK pathway, highlighting its potential as a therapeutic agent for ischemic stroke. Full article

Inflammation plays a key role in the pathogenesis of many diseases, including cardiovascular disease and ischemic stroke. However, despite the existence of known inflammatory genes, the question of estimating their total number and the possibility of discovering new ones remains open. This study sought and analyzed genes involved in inflammation among genes related to cardiovascular disease and ischemic stroke. Human genes associated with ischemic stroke (N = 1177) and cardiovascular disease (N = 1756) were retrieved from the DisGeNET platform. Inflammatory and immune response genes were obtained from the Gene Ontology, NCBI, and Reactome databases. An additional list of 140 inflammatory genes was compiled based on our previously obtained data on the differential gene expression in a rat brain under transient middle cerebral artery occlusion. Genes that occurred simultaneously in both the inflammatory gene lists and gene lists of diseases were selected and considered. The resulting combined gene list included 1285 inflammatory genes. The NFKB1 and RELA genes demonstrated the highest frequencies across the various inflammatory gene selection resources we examined. Using a combination of experimental and bioinformatics approaches, a representative list of inflammatory genes important for the pathogenesis of ischemic stroke was compiled. The identified genes may be crucial for the development of anti-inflammatory therapeutic strategies for this disease. Full article

Background: Dysplasia or absence of anterior communicating artery (ACoA) is a common variation in the circle of Willis (COW) anomaly, and it may elevate the risks of cerebrovascular diseases. We aimed at investigating the association of ACoA dysplasia/absence with plaque imaging features of middle cerebral artery (MCA) atherosclerosis. Methods: We analyzed the prospective data from a vessel wall imaging cohort of adult patients suffering from acute ischemic stroke or transient ischemic attack due to intracranial atherosclerosis (2014 to 2020). Patients demonstrating MCA atherosclerotic plaques were included. The ACoA dysplasia/absence and other incomplete COW configurations were identified on magnetic resonance angiography. The MCA plaques were evaluated through high-resolution vessel wall imaging. Results: Of the 107 patients with MCA atherosclerosis, 29.9% showed ACoA dysplasia/absence. The patients with ACoA dysplasia/absence were more likely to have concomitant dysplasia/absence of anterior cerebral artery (71.9% vs. 18.7%, p < 0.001). For the 158 MCA plaques identified, those with ACoA dysplasia/absence exhibited a significantly higher prevalence of symptomatic status (58.7% vs. 31.3%, p = 0.001) and non-positive remodeling (58.7% vs. 26.8%, p < 0.001) than those without this variant. Regression analyses further demonstrated the robust association of ACoA dysplasia/absence with symptomatic status (odds ratio, 5.158; 95% confidence interval, 1.744–15.254; p = 0.003) and non-positive remodeling (odds ratio, 6.92; 95% confidence interval, 2.396–19.982; p < 0.001) of MCA atherosclerosis. Conclusions: As a common variation among patients with MCA atherosclerosis, ACoA dysplasia/absence may elevate the possibility to develop symptomatic MCA atherosclerosis, which showed non-positive remodeling. Stroke risk stratification based on the ACoA morphology needs further validation. Full article

Objective: To evaluate and compare fetal arterial and venous Doppler parameters in early-onset (EO) and late-onset (LO) fetal growth restriction (FGR), and to assess their performance within the study cohort and their association with composite adverse neonatal outcome (CANO). Methods: This prospective observational cohort study included 184 singleton pregnancies between 24 and 37 weeks of gestation, comprising 91 FGR cases and 93 appropriate-for-gestational-age controls. FGR was defined according to Delphi consensus criteria and classified as EO-FGR (<32 weeks) or LO-FGR (≥32 weeks). All fetuses underwent standardized Doppler assessment of the umbilical artery (UA), middle cerebral artery (MCA), uterine artery (UtA), and ductus venosus (DV). The cerebroplacental ratio (CPR) was calculated. Multivariable logistic regression models were constructed separately for EO-FGR and LO-FGR. Classification performance was evaluated using receiver operating characteristic analysis. CANO was defined as at least one of the following: 5-min Apgar score <7, respiratory distress syndrome, neonatal intensive care unit admission, or preterm birth. Results: In both EO-FGR and LO-FGR, UA PI values were significantly higher, whereas MCA PI and CPR were significantly lower than in controls. CPR demonstrated the highest discriminative performance among arterial parameters in both subgroups. DV Doppler indices were not significantly different in EO-FGR. In LO-FGR, DV S-wave and v-wave velocities were independently associated with FGR. No significant associations were observed between Doppler parameters and CANO in subgroup analyses. Conclusions: Arterial Doppler parameters, particularly CPR, showed consistent alterations in both EO- and LO-FGR. The contribution of venous Doppler parameters differed according to clinical subtype, with additional value observed in LO-FGR. Full article

Backgroud and Objectives: To evaluate conventional Doppler indices and the novel middle cerebral artery (MCA) diastolic deceleration area (DDA) in pregnancies complicated by gestational diabetes mellitus (GDM), and to explore their associations with perinatal outcomes. Prospective case–control study conducted at a tertiary referral perinatology center. Materials and Methods: The study included 83 women with GDM and 92 healthy controls. Standard fetal biometric and Doppler parameters—umbilical artery, MCA, ductus venosus, cerebroplacental ratio, and umbilicocerebral ratio—were assessed, alongside calculation of MCA DDA. Perinatal outcomes were recorded. Results: Most conventional Doppler indices did not differ between groups, except for lower MCA dicrotic notch velocity and higher ductus venosus time-averaged maximum velocity in the GDM group. MCA DDA values did not differ significantly between GDM and control groups (6.67 [5.02–8.20] vs. 7.05 [5.21–8.39] cm·s, p = 0.444) and showed no difference between insulin- and diet-controlled subgroups (p > 0.05). MCA DDA showed significant correlations with gestational age, MCA peak systolic velocity, and birth weight. However, after adjustment for potential confounders, gestational age remained the only independent determinant of MCA DDA. The multivariable analysis evaluating composite adverse neonatal outcomes was limited by the small number of adverse events (n = 14). Conclusions: MCA DDA did not differ between GDM and control pregnancies and primarily reflected gestational age-related physiological variation rather than diabetes specific hemodynamic changes. However, its relationship with adverse neonatal outcomes remains uncertain and requires further investigation in larger prospective studies. Full article

Objective: To evaluate fetal pulmonary artery hemodynamics (PAAT, PAET, PATET) in pregnancies complicated by intrahepatic cholestasis of pregnancy (ICP) and to investigate their association with the aspartate aminotransferase-to-platelet ratio index (APRI). Methods: In this prospective study, 64 ICP cases and 64 healthy pregnancies are included. Doppler measurements of the fetal main pulmonary artery, umbilical artery (UAPI), and middle cerebral artery (MCAPI) were performed by a single operator, and all biochemical analyses were conducted in the same laboratory. APRI was calculated using the standard formula. Results: Doppler evaluation demonstrated significantly higher PAAT, PAET, PATET, UAPI, and MCAPI values in the ICP group (all p < 0.05). AST, ALT, and APRI levels were markedly elevated in ICP pregnancies (all p < 0.001). No significant correlation was observed between PATET and APRI (p = 0.368) or fasting bile acid levels (FBA) (p = 0.116), whereas APRI showed a weak positive correlation with FBA (r = 0.308; p = 0.013). Doppler parameters and APRI values did not differ significantly according to cholestasis severity (10–39/≥40/≥100 μmol/L; all p > 0.05). Conclusions: In ICP, fetal pulmonary artery Doppler indices (PAAT, PAET, PATET) and fetoplacental Doppler parameters are increased; the elevation in PATET is consistent with lower—rather than higher—fetal pulmonary vascular resistance, potentially reflecting accelerated fetal lung maturation or a hemodynamic adaptation to ICP-related physiological perturbations. Despite elevated APRI levels, these biochemical changes do not parallel fetal hemodynamic indicators. These findings suggest that fetal hemodynamic effects in ICP may be independent of biochemical disease severity. PATET is best conceptualized as a hemodynamic monitoring variable complementing bile acid assessment in fetal surveillance, not as a standalone screening or prognostic tool. Full article

Objective: Cerebral ischemia–reperfusion (I/R) injury constitutes a pivotal pathological driver in cerebrovascular disorders such as stroke, yet effective therapeutic interventions remain scarce. This study explored whether hydrogen sulfide (H₂S) mitigates endothelial cell damage in the cerebral vasculature during I/R by modulating nicotinamide phosphoribosyltransferase (NAMPT) activity and its S-sulfhydration status, consequently restoring mitochondrial integrity and energetic homeostasis. Methods: Primary cerebrovascular endothelial cells (ECs) were subjected to hypoxia/reoxygenation (H/R) conditions in vitro, while rats experienced middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo. The H₂S donor sodium hydrosulfide (NaHS) was administered, and outcomes were evaluated through Western blot analysis, S-sulfhydration assays, mitochondrial functional tests, autophagy profiling, and neurobehavioral assessments. The contributions of NAMPT and S-sulfhydration were validated using FK866 and dithiothreitol (DTT), respectively. LC-MS/MS was employed to identify candidate S-sulfhydration sites on NAMPT triggered by H₂S. Results: In cellular models, NaHS substantially boosted NAMPT enzymatic activity, elevated NAD⁺ and ATP levels, and enhanced cell survival. These protective benefits were nullified upon NAMPT inhibition with FK866 or reversal of S-sulfhydration via DTT. In animal studies, NaHS treatment significantly diminished infarct volume and ameliorated neurological deficits in MCAO/R rats; however, pretreatment with FK866 or DTT attenuated these benefits. Mechanistic investigations revealed that NaHS promoted S-sulfhydration of NAMPT, thereby activating autophagy of dysfunctional mitochondria. LC-MS/MS analysis confirmed enhanced S-sulfhydration at Cys39 and Cys397 residues of NAMPT following H₂S exposure. Conclusions: H₂S exerts neuroprotection against cerebral I/R injury in rats through S-sulfhydration-mediated activation of NAMPT, which improves mitochondrial performance and stimulates autophagy in cerebrovascular ECs. Full article

Early-onset infection caused by Streptococcus agalactiae (Group B Streptococcus, GBS) may occur during gestation or delivery and can lead to severe neonatal sepsis, meningitis, or pneumonia. Discordant GBS infections in twin gestations are rare. We report a fatal case of early-onset GBS infection in dichorionic–diamniotic twins conceived via IVF and delivered by caesarean section at 32 weeks’ gestation due to discordant fetal growth and abnormal Doppler indices in Twin A (Umbilical Artery PI = 1.4; Middle Cerebral Artery PI = 1.5). Twin A had Apgar scores of 3, 5, and 5 and rapidly developed tachycardia, respiratory distress, and systemic infection, while Twin B, with Apgar scores of 7, 8, and 9, remained clinically stable. Both infants were admitted to the NICU and underwent routine blood, urine, and cerebrospinal fluid testing. Despite the prompt initiation of parenteral ceftriaxone and respiratory support, Twin A deteriorated rapidly and died within 28 h. GBS was isolated from Twin A’s blood culture, and maternal placental tissue and high vaginal samples collected before antibiotic administration also grew GBS, with all isolates demonstrating identical antimicrobial resistance profiles. Molecular analysis revealed matching rib1 and alp2/3 gene patterns in isolates from the mother and Twin A. Maternal anovaginal immunochromatography at delivery was positive, whereas screening cultures obtained at 29 weeks’ gestation were negative. This case highlights the limitations of culture-based GBS screening in high-risk pregnancies and preterm deliveries and underscores the potential value of molecular assays and point-of-care testing to improve detection of S. agalactiae throughout pregnancy and the peripartum period. Emerging preventive strategies, including modulation of the genital microbiome and maternal vaccination aligned with WHO recommendations, may further reduce the burden of neonatal GBS disease. Full article

Neuronal ferroptosis is a key contributor to secondary brain injury following cerebral ischemia, yet the metabolic mechanisms governing this process remain poorly understood. Enriched environment (EE) is a housing paradigm that provides enhanced sensory, cognitive, and social stimulation through complex physical surroundings and increased opportunities for voluntary activity. Our preliminary data indicate that EE confers cerebroprotection against ischemia-induced ferroptosis; however, whether this effect is associated with glycogen metabolic regulation and the underlying molecular pathways has not been elucidated. This study aimed to determine whether EE may influence ferroptosis-associated pathways, potentially via Sirtuin 1 (SIRT1)/protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β)-related mechanisms of glycogen metabolism. Using a mouse model of middle cerebral artery occlusion (MCAO) and an oxygen–glucose deprivation/reoxygenation (OGD/R) cellular model, we performed behavioral assessments, molecular and biochemical analyses, and pharmacological interventions to elucidate mechanistic pathways. EE was associated with improved neurological outcomes and reduced infarct volume after ischemia. Mechanistically, EE appeared to activate the SIRT1/AKT pathway and increase the inhibitory phosphorylation of GSK3β and relieving its suppressive effect on glycogen synthase, which may underlie the observed increase in glycogen levels within ischemic brain tissue. Pharmacological inhibition of SIRT1 largely diminished these metabolic and neuroprotective benefits. Consistently, at the cellular level, SIRT1 overexpression contributed to the restoration of glycogen metabolism and robustly attenuated ferroptosis under ischemic conditions. Collectively, these findings suggest that EE may attenuate ferroptosis-related pathways possibly involving SIRT1/AKT/GSK3β-dependent glycogen metabolic remodeling, providing a novel metabolic perspective on EE-induced cerebroprotection and highlighting SIRT1-centered regulation of glycogen metabolism as a potential therapeutic target for ischemic stroke. Full article

Background: Temporary arterial occlusion (TAO) is a key adjunct in microsurgical clipping of middle cerebral artery (MCA) aneurysms, but its safe duration and impact on perioperative ischemia—particularly in subarachnoid hemorrhage (SAH)—remain uncertain. Methods: A retrospective cohort of 245 patients undergoing microsurgical clipping of MCA aneurysms (154 incidental, 91 SAH) at a tertiary neurovascular center (2010–2020) was analyzed. TAO use, cumulative duration (>5, >8, >10, >15 min), number of applications, and occlusion site were extracted alongside clinical, radiographic, and outcome data. The primary endpoint was perioperative ischemia within 48 h; secondary endpoints included clinically relevant cerebral vasospasm (CVS), intraoperative rupture, and functional outcome (mRS) at discharge and 6 months. Multivariable logistic and ordinal regression models adjusted for demographic, aneurysmal, and treatment covariates. Results: TAO was used in 134 cases (54.7%; mean total duration 10.4 ± 8.7 min). In the overall cohort, TAO (presence or duration) was not independently associated with perioperative ischemia or CVS. In the SAH subgroup, cumulative TAO > 5 min conferred an approximately sixfold higher odds of ischemia (p = 0.012; OR 6.33), whereas no threshold was significant in incidental aneurysms. Female sex, M2 location, SAH at admission, and initial GCS < 9 independently predicted ischemia; female sex, higher ASA grade, larger size, irregular morphology, and SAH predicted CVS. SAH and aneurysm wall calcification were associated with worse 6-month mRS. Conclusions: TAO appears safe in elective clipping of incidental MCA aneurysms when applied judiciously, but cumulative durations beyond 5 min substantially increase ischemia risk in SAH patients. TAO management should therefore be individualized by rupture status, neurological grade, and aneurysm morphology rather than a single universal time limit. Full article

The kidney and the brain share similarities in terms of structure and haemodynamic regime. The aim of the study was to assess a potential correlation of vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor-1 (sFlt-1), and placental growth factor (PlGF) with biomarkers of podocyte damage, proximal tubular (PT) dysfunction, and endothelial dysfunction, as well as with cerebral vessels haemodynamic indices in neurologic asymptomatic type 2 DM patients. A cohort of 212 patients diagnosed with type 2 DM and 49 age- and gender-matched healthy controls were enrolled in the study. Parameters studied were urinary albumin/creatinine ratio (UACR), biomarkers of podocyte damage (synaptopodin, podocalyxin), PT dysfunction (kidney injury molecule-1-KIM-1, N-acetyl-β-(D)-glucosaminidase-NAG), endothelial dysfunction (P-selectin), VEGF, sFlt-1, and PlGF. The cerebrovascular hemodynamic indices evaluated were intima–media thickness (IMT) in the common carotid arteries (CCAs), the pulsatility index (PI), and the resistivity index (RI) in the internal carotid arteries (ICAs) and middle cerebral arteries (MCAs). Cerebrovascular reactivity (CVR) was assessed by the breath-holding index (BHI). In multivariable regression analysis, serum VEGF correlated directly with UACR, synaptopodin, NAG, serum P-selectin; serum sFlt-1 correlated directly with UACR, synaptopodin, podocalyxin, NAG, KIM-1; serum PlGF correlated negatively with eGFR and directly with UACR, synaptopodin, KIM-1. IMT-CCA correlated indirectly with eGFR and directly with UACR, serum P-selectin, and serum sFlt-1. The PI-ICAs correlated negatively with eGFR and positively with UACR, synaptopodin, serum P-selectin, and serum sFlt-1. The PI-MCAs correlated indirectly with eGFR and directly with synaptopodin, serum P-selectin, and serum sFlt-1. The RI-ICAs had a negative correlation with eGFR and a positive one with UACR, synaptopodin, NAG, KIM-1, urinary sFlt-1, and serum PlGF. The RI-MCAs displayed an indirect correlation with eGFR and a direct correlation with NAG, KIM-1, and serum sFlt-1. The BHT correlated directly with eGFR and negatively with serum P-selectin and serum PlGF. The study shows a significant association of VEGF, sFlt-1, and PlGF with biomarkers of podocyte injury, PT dysfunction, and endothelial dysfunction in early stages of DKD. These pro-angiogenic and anti-angiogenic factors correlated with cerebrovascular haemodynamic indices in neurologic asymptomatic type 2 DM, even in the normoalbuminuric stage of diabetic kidney disease. Full article