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The interactive effects of microencapsulated essential oils-organic acids preparation (EOA) and non-starch polysaccharide (NSP) enzymes on intestinal health of broilers fed wheat-based diets remain poorly elucidated. This study aimed to investigate the effects of dietary supplementation with EOA alone and in combination with NSP enzymes on growth performance, slaughter characteristics, serum biochemical indexes and intestinal microenvironment of broilers fed wheat-based diets. A total of 360 one-day-old male Arbor Acres broilers were randomly allocated to five treatment groups for 42 days (n&#x2009;=&#x2009;6 replicates/treatment, 12 birds/replicate): the basal diet supplemented with 200&#x2009;mg/kg EOA (A), 400&#x2009;mg/kg EOA (B), 200&#x2009;mg/kg NSP enzymes (C), along with 200&#x2009;mg/kg NSP enzymes plus 200&#x2009;mg/kg EOA (D), and 200&#x2009;mg/kg NSP enzymes plus 400&#x2009;mg/kg EOA (E), respectively. Growth performance was monitored on d 1, 21, and 42; slaughter characteristics, serum biochemical indexes and jejunal digestive enzyme activities were assessed on d 42; and jejunal villus morphology on d 21 and 42 was measured using hematoxylin and eosin (HE) staining. Additionally, on d 42, jejunal gene expression was analyzed by qPCR, cecal short-chain fatty acids (SCFAs) content was determined using gas chromatography (GC), and cecal microbiota composition was characterized via 16S rRNA gene sequencing. Data were analyzed using one-way analysis of variance (ANOVA) followed by Duncan's multiple range test, and statistical significance was set at P < 0.05. Results showed that compared with the single enzymes-added group (group C), dietary addition of EOA alone and combined with NSP enzymes had no significant impacts on the growth performance, slaughter characteristics and serum biochemical indexes of broilers (P > 0.05). However, group D exhibited a 23% decrease in jejunal crypt depth and a 37% increase in villus height to crypt depth ratio (VH/CD) on d 21, and a 29% decrease in crypt depth with a 36% increase in VH/CD on d 42 compared with group C (P < 0.05). Single EOA supplementation significantly decreased jejunal trypsin activity, with 53% and 50% reductions in group A and group B, respectively, relative to group C (P = 0.035). For cecal SCFAs, group B showed a 69% decrease in isovaleric acid content (P = 0.012), while group D had a 73% increase in butyric acid content and a 34% increase in total SCFAs content compared with group C (P < 0.05). In group E, the jejunal mRNA expression of IFN-&#x3b3; was upregulated 2.0-fold, and the relative abundance of Bacteroides_fragilis in the cecum was reduced by 42% when compared with group C (P = 0.001 and P = 0.034, respectively). Collectively, these findings indicate that the combined application of NSP enzymes with low-dose EOA (200&#x2009;mg/kg) in wheat-based diets can optimize the intestinal microenvironment of broilers by reducing crypt depth, elevating the VH/CD ratio, and increasing the content of cecal butyric acid and total SCFAs, without compromising growth performance. In contrast, the combination of NSP enzymes with high-dose EOA (400&#x2009;mg/kg) triggers intestinal microbial dysbiosis and intestinal inflammatory responses in broilers. Therefore, high-dose EOA is not recommended for combined supplementation with NSP enzymes in wheat-based broiler diets under conventional conditions. With policies restricting antibiotic overuse becoming mainstream, farmers are turning to non-antibiotic feed additives to maintain poultry health. Based on this trend, this study evaluated the effects of supplementing wheat-based broiler diets with essential oils-organic acids mixture (EOA) alongside enzyme preparations. The results showed that combining a low dose of EOA with enzyme preparations effectively improved the intestinal microenvironment of poultry, outperforming the individual use of each component. However, surprisingly, high-dose supplementation exacerbated intestinal burden and worsened health conditions. These findings demonstrate that an optimal ratio of feed additives is required for maximum efficacy, whereas indiscriminate application can lead to either ineffective waste or adverse outcomes.

Pheochromocytoma is a rare neuroendocrine tumor that may present with atypical and potentially life-threatening cardiovascular manifestations due to catecholamine excess. Reverse Takotsubo cardiomyopathy, a distinct form of stress-induced cardiomyopathy, has been strongly associated with catecholamine crisis but remains underrecognized. The purpose of this report is to describe a rare case of pheochromocytoma-induced reverse Takotsubo cardiomyopathy complicated by acute severe mitral regurgitation and to emphasize the importance of early endocrine recognition. A 40-year-old woman presented with hypertensive emergency, acute chest pain, electrocardiographic changes suggestive of acute coronary syndrome, and markedly elevated cardiac biomarkers. Transthoracic echocardiography revealed reduced left ventricular ejection fraction with basal and mid-ventricular akinesis, apical hyperkinesis, and acute severe mitral regurgitation consistent with reverse Takotsubo cardiomyopathy. Emergency coronary angiography demonstrated normal coronary arteries. Recurrent stress-induced cardiomyopathy in a young patient without conventional cardiovascular risk factors, accompanied by autonomic symptoms, hyperglycemia, and lactic acidosis, raised suspicion of pheochromocytoma-related catecholamine crisis. Cross-sectional imaging identified a left adrenal mass and biochemical testing confirmed markedly elevated plasma metanephrines. After appropriate preoperative &#x3b1;-adrenergic blockade, laparoscopic adrenalectomy resulted in complete clinical and biochemical remission with full recovery of cardiac function. Pheochromocytoma should be considered in younger patients presenting with recurrent or atypical Takotsubo cardiomyopathy, particularly in the case of reverse pattern and when associated with acute mitral regurgitation or hypertensive emergency. Early endocrine diagnosis is critical as definitive surgical treatment leads to complete resolution and prevents recurrence of severe cardiovascular complications.

Sharing the most recent common ancestor, receptor-like kinases EXCESS MICROSPOROCYTES1 (EMS1) and BRASSINOSTEROID INSENSITIVE1 (BRI1) family members respectively perceive the peptide ligand TAPETUM DETERMINANT1 (TPD1) and the phytohormone brassinosteroids (BRs) to activate the same downstream BRI1 EMS SUPPRESSOR1 (BES1)/BRASSINAZOLE RESISTANT1 (BZR1) transcription factor family. Yet only their distinct canonical functions have been revealed. TPD1 specifically sustains tapetum development but is dispensable for global plant growth, whereas BRs regulate overall plant growth without impacting tapetum development. This generates a fundamental evolutionary conflict: gradual biochemical divergence with saltational biological diversification. Here, we identify an unrecognized redundant role of TPD1 and BR signaling in controlling early anther lobe formation. Simultaneous disruption of both pathways causes a lobeless anther defect, phenocopying the loss of the entire BES1/BZR1 family. Single-pathway disruption produces no such defect. Interestingly, we found that pathway specificity during tapetum development is caused by spatiotemporal ligand dynamics. The expression of DWF4 (encoding a rate-limiting BR biosynthetic enzyme) decreases sharply at the onset of tapetum development, while TPD1 expression remains stable. Consistently, exogenous BR application or the introduction of an active, ligand-independent BRI1 rescues tapetum defects in either the ems1 mutant or the dual-pathway-deficient mutant background. Our findings reconcile biochemical divergence and biological diversification with gradual evolution, likely stimulating study of the functional divergence of numerous other receptor-like kinases at multiple levels.

ADP-ribosylation (ADPr), long recognized as a canonical protein post-translational modification, has recently expanded to include targeting nucleic acids, uncovering a diverse landscape of noncanonical biological functions. Emerging evidence suggests that ADPr at the 5'-phosphate terminus of DNA is implicated in the DNA damage response, yet understanding its precise molecular function has been hampered by the lack of structurally defined chemical probes. Here, we report the stereoselective synthesis of deoxynucleotide-phospho-ADPr (dN-P-ADPr) probes, representing native fragments of terminal DNA-ADPr. Our strategy leverages a mild, stereocontrolled glycosylation to construct the challenging ribosyl-phosphate linkage, followed by P(III)-P(V) coupling to establish the pyrophosphate bridge. This robust toolkit enabled the systematic biochemical profiling of DNA-ADPr hydrolases across diverse kingdoms of life. Remarkably, using these newly developed probes, we uncover hydrolases across the diversity of life capable of reversing ADPr modifications at phosphorylated DNA ends. We further show that these enzymes exhibit an absolute preference for the native-like &#x3b1;-anomer, independent of the identity of the adjacent DNA nucleobase, suggesting that substrate recognition is governed primarily by the ADPr-phosphate linkages rather than the local nucleobase context. Together, these synthetic probes and biochemical insights provide an essential foundation for deciphering the biological landscape of noncanonical ADPr.

Due to production of some important biochemicals including secondary metabolites (SM), medicinal plants are of economic and health significance. However, medicinal plants are subjected to different types of stress including drought affecting their growth and biochemical properties including SM production. There is an increasing demand for cultivation of medicinal plants and subsequent production of SM as suitable alternatives for conventional pharmaceuticals. Additionally, although research has indicated drought stress may alter SM production in medicinal plants, affecting their health and economic values, the related mechanisms must be investigated in greater details. This review is about drought stress affecting the production of different types of SM (alkaloids, terpenoids and flavonoids), and so, plant response in drought stress as indicated by omics analyses. Moreover, role of elicitors including plant growth regulators such as plant hormones on SM production in drought stress conditions has also been reviewed. Plant stress tolerance (sensitive or tolerant) is an important factor determining the accumulation of SM and plant response in drought stress conditions. Accumulation of flavonoids including anthocyanins and flavonols may alleviate unfavorable effects of drought stress on plant, though the related mechanisms have yet to be indicated. Finding methods, which enhance tolerance of medicinal plants in stress conditions, and so, improve their quality and quantity, is of significance for innovation in the synthesis of therapeutic drugs. This indicates the applicability of this review including the present research gap. Proper level of drought stress may enhance SM production in medicinal plants, and so, their economic and health significance.

Secondary lymphedema, characterized by localized tissue swelling caused by lymphatic damage or dysfunction, remains a major clinical challenge that compromises quality of life. Current physical therapies provide only temporary relief, underscoring the need for effective regenerative strategies. Here, we report the fabrication of a micropatterned, small-diameter fibrous artificial lymphatic vessel incorporating hyaluronic acid (HA) via electrospinning to enhance lymphatic fluid transport. The engineered scaffold exhibits optimized mechanical properties and elicits favorable cellular responses through HA-mediated biochemical cues. Lymphatic endothelial cells (LEC) cultured on the scaffold show increased expression of lymphangiogenesis-related markers, including Prox1 and LYVE-1, accompanied by AKT activation and increased VEGF-C/VEGFR3-associated marker expression. The topographical features of the scaffold were also associated with altered YAP localization and increased lymphatic endothelial marker expression. In vivo implantation of the scaffold in a rat lymphedema model reduced ankle swelling and lymphatic retention across the surgically disrupted region toward an anatomically preserved drainage basin. Collectively, these findings suggest that HA-integrated fibrous lymphatic scaffolds represent a promising strategy for lymphedema treatment by synergistically engaging biochemical and biomechanical pathways associated with lymphatic repair and functional fluid transport.

Celiac disease (CeD) is an autoimmune enteropathy; nearly 60-80% of first-degree relatives (FDRs) of CeD patients carry HLA-DQ2/DQ8 haplotypes; however, only 7.5% of them develop enteropathy. This suggests the modulation of biochemical and molecular mechanisms that might help in maintaining intestinal integrity. Thus, the present study investigated the metabolome of FDRs to gain insight into biochemical mechanisms that might help in maintaining intestinal integrity. The metabolome of small intestinal mucosal biopsies, blood plasma and urine of serologically negative first-degree relatives (FDRs, n&#x202f;=&#x202f;50) was investigated using proton NMR spectroscopy and compared with CeD patients (n&#x202f;=&#x202f;64) and controls (disease controls, n&#x202f;=&#x202f;35 or healthy controls, n&#x202f;=&#x202f;32) using both univariate and multivariate statistical analyses. The metabolic profiles of FDRs of CeD patients differed significantly from both CeD patients and controls. Higher myo-inositol and fumarate in the mucosa of FDRs suggest the role of these metabolites in modulating the immune response and inflammation, which may protect intestinal integrity in FDRs. Elevated formate and tyrosine levels in the intestinal mucosa of FDRs, compared to both CeD patients and controls, suggested alterations in gut microbiota that may support intestinal homeostasis. Furthermore, significant changes in levels of branched-chain amino acids in FDRs compared to CeD patients indicated their increased utilization for enterocytes renewal, upregulation of tight junction proteins and modulating immune response to maintain villous architecture. Our data showed that FDRs exhibit a specific metabolic signature that may represent an adaptive response aimed at maintaining intestinal homeostasis and mucosal integrity despite genetic predisposition.

Ischemic stroke accounts for 87% of all stroke cases, and remains a leading cause of mortality and disability worldwide. Current reperfusion therapies are limited by narrow therapeutic windows, and cerebral ischemia-reperfusion injury (CIRI) remains a major clinical challenge. Ferroptosis, an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation, has been identified as a key pathological driver of CIRI. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has shown neuroprotective effects in ischemic stroke, but its underlying mechanism, especially the regulatory effect on ferroptosis via the TAK1-CREB1 signaling axis, remains unclear. To investigate the neuroprotective effect of DHA in ischemic stroke and its molecular mechanism related to the TAK1-CREB1 signaling pathway and ferroptosis regulation. Wild-type (WT) C57BL/6&#x202f;J mice and astrocyte-specific CREB1 conditional knockout (CREB1 CKO) mice were used to establish a photothrombotic stroke (PTs) model. Neurological function was evaluated by modified neurological severity score (mNSS), Bederson score, Garcia scale and hanging test. Cerebral infarct volume was measured by TTC staining. Cerebral blood flow (CBF) was detected by laser speckle contrast imaging. Histopathological changes were observed by HE and Nissl staining. Mitochondrial ultrastructure was examined by transmission electron microscopy (TEM). The levels of malondialdehyde (MDA), glutathione (GSH), NADPH/NADP+ ratio, ferrous iron (Fe2+) and total iron in brain tissue were detected by biochemical kits. The expression of ferroptosis-related proteins and CREB1 was detected by Western blot and immunofluorescence staining. DHA treatment dose-dependently improved neurological function, reduced infarct volume, restored CBF, and ameliorated histopathological damage in PTs mice. TEM revealed that DHA reversed ferroptosis-typical mitochondrial changes in ischemic brain tissue. Biochemically, DHA decreased MDA, Fe&#xb2;&#x207a;, and total iron, while increasing GSH and NADPH/NADP&#x207a; ratio. Mechanistically, DHA dose-dependently upregulated GPX4, xCT, and FTH1, and downregulated ACSL4. Notably, astrocyte-specific CREB1 knockout nearly completely abolished DHA's neuroprotective and anti-ferroptosis effects. DHA promotes neurological rehabilitation after ischemic stroke by targeting the astrocytic TAK1-CREB1 signaling pathway to inhibit ferroptosis. This study provides a novel theoretical basis and promising candidate drug for the clinical treatment of ischemic stroke.

To evaluate 68Ga-pentixafor PET/CT in the surgical management of primary aldosteronism (PA), with emphasis on its relationship with adrenal venous sampling (AVS), KCNJ5 mutation status, tracer uptake, and postoperative outcomes. This retrospective single-center cohort screened 929 consecutive patients with suspected PA from November 2021 to February 2025. The final cohort included 162 patients who underwent unilateral adrenalectomy and 6-month follow-up; 83 also underwent AVS. Patients treated before September 2024 followed an AVS-guided pathway, and those treated thereafter followed a PET/CT-guided pathway. Outcomes were assessed by PASO criteria. Firth logistic regression, overlap weighting, paired PET/CT-versus-AVS analysis, and genotype-stratified analyses were performed. Clinical and biochemical complete success did not differ significantly between the PET-guided and AVS-guided groups. Among patients with both tests, unilateral PET/CT showed high positive predictive value versus AVS (56/57, 98.2%), but 26 of 82 AVS-confirmed unilateral PA cases had negative or bilateral PET findings. All KCNJ5-mutated patients in the PET-status cohort were PET-positive, whereas 22 of 52 KCNJ5-nonmutated patients were PET-negative. KCNJ5 mutation and CT lesion size were independently associated with PET positivity. SUVmax LI was associated with biochemical complete success, including within KCNJ5-nonmutated patients. 68Ga-pentixafor PET/CT provides strong rule-in information when uptake is clearly unilateral. Negative or bilateral PET/CT, especially in small or KCNJ5-nonmutated lesions, should be interpreted cautiously and should not preclude AVS-based evaluation.

ObjectiveSuperselective adrenal arterial embolization with ethanol has demonstrated promising efficacy in patients with primary aldosteronism and lateralized aldosterone secretion. However, approximately 40% of patients have nonlateralized disease, defined as bilateral primary aldosteronism based on adrenal venous sampling.MethodsIn this prospective observational cohort study, 30 patients with primary aldosteronism underwent superselective adrenal arterial embolization, including 16 patients with unilateral primary aldosteronism and 14 patients with bilateral primary aldosteronism confirmed by adrenal venous sampling. Patients were stratified into the unilateral primary aldosteronism and bilateral primary aldosteronism groups. Blood pressure and biochemical parameters were assessed at 15-40&#x2005;h and at 1, 3, and 6 months after the procedure.ResultsPlasma aldosterone concentration, plasma renin activity, and the aldosterone-to-renin ratio improved significantly in both groups within 15-40&#x2005;h after superselective adrenal arterial embolization compared with baseline. At 6 months, the rates of complete or partial clinical and biochemical success were 85.7% and 92.9%, respectively, in the bilateral primary aldosteronism group compared with 81.3% and 87.5%, respectively, in the unilateral primary aldosteronism group. Significant reductions in serum sodium levels and microalbuminuria were observed in patients undergoing bilateral superselective adrenal arterial embolization. Body mass index also decreased significantly at 1, 3, and 6 months in both groups. No procedure-related complications were observed during a median follow-up of 6 months.ConclusionsBilateral superselective adrenal arterial embolization may represent a valuable adjunctive treatment strategy for patients with bilateral primary aldosteronism.

Polyethylene microplastics (PE-MPs) have recently emerged as ubiquitous environmental contaminants capable of penetrating biological systems and exerting toxic effects on vital organs. Experimental evidence indicates that oral exposure to PE-MPs induces biochemical, hepatic, and renal dysfunctions; however, dose-dependent metabolic and histopathological alterations following sub-acute exposure and subsequent recovery remain insufficiently characterized. Sixty male C57BL/6 mice were randomly allocated into four groups (n&#x202f;=&#x202f;15/group): control, 6&#x202f;&#xb5;g/mL, 60&#x202f;&#xb5;g/mL, and 600&#x202f;&#xb5;g/mL PE-MPs. Animals received daily oral gavage of PE-MPs suspended in distilled water for 15 days. After treatment, eight animals from each group were sacrificed, while the remaining animals were allowed 15 days recovery period. Liver and kidney tissues were examined histologically using hematoxylin and eosin (H&E) and histochemical by periodic acid-Schiff (PAS) staining. Meanwhile, detection of apoptosis stained with acridine orange and DNA damage by comet assay in blood tissue. Many histopathological alternations, apoptosis, and genotoxicity were prominent in both liver and kidney tissue. The severity of harmful alternation increased progressively with escalating polyethylene microplastics exposure. Sub-acute oral exposure to polyethylene microplastics induces dose-dependent in hepatic, renal, blood tissues toxicity in mice. Although partial recovery occurs after exposure cessation, the findings highlight the cumulative and potentially irreversible toxic effects of PE-MPs.

Like heterochromatin protein 1 (LHP1) is a conserved HP1-like chromatin protein in land plants and a major Polycomb-associated factor that recognizes H3K27me3 enriched euchromatic domains. Recent biochemical, genomic, and structural studies show that LHP1 acts as a modular chromatin scaffold whose regulatory output depends on local histone modifications, RNA interactions, transcriptional factors, and PRC1/PRC2-associated partners. In this review, we outline emerging roles of LHP1 in Polycomb-mediated repression, chromatin-state maintenance, transcriptional responsiveness, hormone signaling, stress responses, and TE-proximal gene regulation. We also examine the structural features and evolutionary diversification of LHP1 homologs across land plants and assess how duplicated LHP1 copies may contribute to species-specific developmental and stress-adaptive traits. Rather than presenting LHP1 as a universal master regulator, we emphasize its context-dependent functions and distinguish experimentally supported mechanisms from correlative or still unresolved models. Finally, we highlight future directions involving genome editing, epigenomic profiling, chromatin conformation analysis, and targeted epigenome engineering to clarify how LHP1 associated modules may be exploited for crop improvement and postharvest quality management.

SGLT2 inhibitors (SGLT2i) are extensively used in India for glycemic control, weight management and cardiorenal protection in individuals with type 2 diabetes (T2DM). SGLT2i promotes glucosuria, which may predispose these patients to asymptomatic bacteriuria (ASB). In this study, we assessed the prevalence, microbial spectrum, and risk factors of ASB in T2DM patients treated with and without SGLT2i at a tertiary centre in Northern India. This was a hospital-based, prospective observational study conducted at a tertiary care hospital in North India and included 150 adults with T2DM (75 on SGLT2i, 75 on other treatments). Midstream urine samples were collected for culture and sensitivity testing; ASB was defined as >&#x2009;10&#x2075; CFU/mL without UTI symptoms. Microbiological analysis, antibiotic susceptibility testing, and biochemical evaluation were performed. Total, ASB prevalence was 26.7%, and SGLT2i users had significantly higher rates than non-SGLT2i users (34.6% vs. 18.7%). Overall, Escherichia coli was the predominant organism (47.5%); non-Escherichia coli occurred exclusively in SGLT2i users (p&#x2009;<&#x2009;0.001). SGLT2i use was independently associated with ASB in logistic regression analysis (OR 2.23, 95% CI 1.03-4.83, p&#x2009;=&#x2009;0.043). The sensitivity to fluoroquinolones was about 45.0%, but it was 85% for Carbapenems. Age, sex, HbA1c, and eGFR were not independent predictors of ASB in regression analysis. Occurrence of ASB is common in patients with T2DM and is significantly more common among SGLT2i users. ASB in SGLT2i user have distinct microbial spectrum. Routine urine screening may be considered in SGLT2i users, even in the absence of symptoms.

Organophosphate flame retardants (OPFRs) are emerging pollutants that pose increasing health risks. The association between urinary metabolites of OPFRs (m-OPFRs) and lipid metabolism remains unclear. This study evaluated lipid metabolism disorders of OPFRs in a population-based observational study and C57BL/6 mice. Urinary m-OPFRs, serum lipid molecules, and biochemical biomarkers in serum were measured. Linear regression and quantile-based g-computation analyses assessed associations between m-OPFRs and lipid markers. Benchmark dose and 95% lower confidence limit (BMDL) for m-OPFRs were determined by Bayesian BMD analysis, and the health risk of internal exposure was further assessed by hazard quotient (HQ). Mediation analysis assessed whether lipid molecules mediated OPFRs-induced hepatotoxicity. Association analyses identified three m-OPFRs, including bis(1-chloro-2-propyl) phosphate (BCIPP), diphenyl phosphate (DPP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), which were significantly associated with the levels of docosahexaenoic acid, 18:0 choline phosphate (LysoPC (18:0)), and 18:0 phosphoethanolamine. The BMDLs of BCIPP, DPP, and BDCIPP were 1.320, 0.100, and 0.030 &#x3bc;g/L, respectively. BDCIPP showed the highest HQ (4.50), followed by BCIPP (2.30) and DPP (0.66), indicating that the non-cancer risk of BDCIPP should be of concern. TDCIPP exposure induced hepatotoxicity in mice. LysoPC (18:0) increased at early exposure and mediated 7.88-30.02% of hepatotoxicity (P < 0.05). In conclusion, TDCIPP may induce hepatic lipid toxicity.

Pramipexole (PPX), dopamine D2/D3 receptor agonist, exhibits neuroprotective effects in patients with restless legs syndrome and Parkinson's disease. The present study aimed to investigate the cellular and molecular mechanisms underlying PPX treatment in memory and cognitive impairments induced by sevoflurane anesthesia in the aged mice. Aged mice received 2-h daily exposures to 60% oxygen, either with or without 3% sevoflurane, for three consecutive days. For interventional evaluation, PPX was administered intraperitoneally 1&#x202f;h before sevoflurane exposure on three consecutive days. After the behavioral tests, hippocampal tissues were harvested from the mice for histochemical and biochemical examinations. Ex vivo electrophysiology was used to assess the activity of pyramidal neurons, while in vivo electrophysiology to evaluate changes in neural oscillations in the hippocampus of mice. PPX attenuated glial cell activation, reversed the downregulation of parvalbumin (PV) expression, rescued the reduction in the activity of PV interneuron and the imbalance of local neuronal excitatory/inhibitory, reversed the reduction in gamma oscillations, and ameliorated the downregulation of dopamine D2 receptors in the hippocampus after repeated sevoflurane exposure in aged mice. Our findings suggest that PPX confers neuroprotection, at least in part, by attenuating neuroinflammation and PV interneuron dysfunction via upregulation of hippocampal dopamine D2 receptors, thereby ameliorating memory and cognitive deficits.

Data about clinical implications of subclinical hypothyroidism (SH) in children are scanty, and the management of this condition is still challenging particularly for mild forms (TSH levels ranging between 4.5 and 10 mU/L). Aim of this study is to compare left ventricular (LV) geometry and function in SH children and matched euthyroid controls, and to evaluate the cardiac effects of L-thyroxine (L-T4) therapy. Thirty-six children (19 females), aged 8.3&#x2009;&#xb1;&#x2009;0.7 years, with persistent and idiopathic SH were enrolled in the study. Thirty-six euthyroid children comparable for sex, age and body mass index were enrolled as controls. Baseline echocardiography and biochemical assessment was performed in all subjects. Thereafter, SH children started L-T4 therapy. Both assessments were repeated after 2 years of therapy in patients and 2 year -follow-up in controls. The LV cavity size was comparable between SH and controls, at baseline, and increased similarly over time. LV systolic function was normal at baseline in both groups and remained comparable at end-study. With regard to diastolic function, SH children showed a significant prolongation of isovolumic relaxation time (IVRT) compared with controls (92.95&#x2009;&#xb1;&#x2009;3.74 vs 76.13&#x2009;&#xb1;&#x2009;2.75 msec, p&#x2009;=&#x2009;0.0006), with normal E/A and E/E' ratios in both populations, consistent with subclinical, mild diastolic dysfunction. After L-T4 therapy, IVRT significantly decreased (81.43&#x2009;&#xb1;&#x2009;4.28 msec p&#x2009;<&#x2009;0.05) becoming similar to controls (82.20&#x2009;&#xb1;&#x2009;2.14 msec). Long-lasting mild SH in children is associated with subtle abnormality of LV relaxation which improves with L-T4 therapy. Whether these subtle alterations may lead to significant clinical consequences require further investigation.