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Background: Full-cohort and sibling-comparison designs have yielded inconsistent results about the impacts of caesarean delivery on offspring health outcomes, with the effect estimates from the latter being more likely directed towards the null value. We hypothesized that the seemingly conservative results obtained from the sibling-comparison design might be attributed to inadequate adjustment for non-shared confounders between siblings, particularly maternal age at delivery. Methods: A systematic review and meta-analysis was first conducted. PubMed, Embase, and the Web of Science were searched from database inception to April 6, 2022. Included studies (1) examined the association of caesarean delivery, whether elective or emergency, with offspring health outcomes; (2) simultaneously conducted full-cohort and sibling-comparison analyses; and (3) reported adjusted effect estimates with 95% confidence intervals (95% CIs). No language restrictions were applied. Data were extracted by 2 reviewers independently. Three-level meta-analytic models were used to calculate the pooled odds ratios (ORs) and 95% CIs for caesarean versus vaginal delivery on multiple offspring health outcomes separately for full-cohort and sibling-comparison designs. Subgroup analyses were performed based on the method of adjustment for maternal age at delivery. A simulation study was then conducted. The simulated datasets were generated with some key parameters derived from the meta-analysis. Results: Eighteen studies involving 21,854,828 individuals were included. The outcomes assessed included mental and behavioral disorders; endocrine, nutritional and metabolic diseases; asthma; cardiorespiratory fitness; and multiple sclerosis. The overall pooled OR for estimates from the full-cohort design was 1.14 (95% CI: 1.11 to 1.17), higher than that for estimates from the sibling-comparison design (OR = 1.08; 95% CI: 1.02 to 1.14). Stratified analyses showed that estimates from the sibling-comparison design varied considerably across studies using different methods to adjust for maternal age at delivery in multivariate analyses, while those from the full-cohort design were rather stable: in studies that did not adjust maternal age at delivery, the pooled OR of full-cohort vs. sibling-comparison design was 1.10 (95% CI: 0.99 to 1.22) vs. 1.06 (95% CI: 0.85 to 1.31), in studies adjusting it as a categorical variable, 1.15 (95% CI: 1.11 to 1.19) vs. 1.07 (95% CI: 1.00 to 1.15), and in studies adjusting it as a continuous variable, 1.12 (95% CI: 1.05 to 1.19) vs. 1.12 (95% CI: 0.98 to 1.29). The severe underestimation bias related to the inadequate adjustment of maternal age at delivery in sibling-comparison analyses was fully replicated in the simulation study. Conclusions: Sibling-comparison analyses may underestimate the association of caesarean delivery with multiple offspring health outcomes due to inadequate adjustment of non-shared confounders, such as maternal age at delivery. Thus, we should be cautious when interpreting the seemingly conservative results of sibling-comparison analyses in delivery-related studies. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction in brain endothelial cells contributes to vasogenic cerebral edema and increased mortality after various neurological diseases. The postsynaptic density protein Homer1 plays an important role in neuronal synaptic activity and is extensively involved in neurological disorders. The present study investigated the role of Homer1 in modulating cell survival using an in vitro endothelial dysfunction model in murine brain endothelial cells (mBECs). Treatment with tert-butyl hydroperoxide (t-BHP) induced a dose-dependent toxicity in mBECs, with no effects on Homer1 expression and distribution. Knockdown of Homer1 using specific siRNA significantly alleviated lactate dehydrogenase (LDH) release, increased cell viability, and ultimately decreased apoptosis after t-BHP treatment. Moreover, Homer1 knockdown attenuated t-BHP-induced ROS generation, lipid peroxidation and mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential (MMP), ATP synthesis collapse and mitochondrial swelling. The results of Ca 2+ imaging showed that Homer1 was involved in inositol trisphosphate receptors (IP 3 R)- and ryanodine receptor (RyR)-mediated intracellular Ca 2+ release, and also mediated t-BHP-induced Ca 2+ release from the endoplasmic reticulum (ER). In addition, knockdown of Homer1 significantly prevented activation of ER stress markers induced by t-BHP exposure. All these results showed that Homer1 is involved in t-BHP-induced endothelial dysfunction in mBECs, and may be an ideal candidate for searching gene intervention strategy for preventing endothelial oxidative stress in vitro. [ABSTRACT FROM AUTHOR]

In this study, a novel low-alloyed Mg–2Sn–2Bi-0.2Mn (wt.%) alloy is designed and extruded successfully at 523 K. Microstructural analysis reveals that a bimodal-sized grain structure is obtained due to the abnormal dynamic recrystallized (DRXed) grain growth. The results indicate that the studied alloy exhibits a good balance between strength and ductility with a tensile yield strength (TYS) of 299.7 MPa, an ultimate tensile strength (UTS) of 382.6 MPa, and an elongation (EL) of 21.2%. Besides, the underlying strengthening mechanism and ductility enhancement are analyzed and discussed in terms of bimodal-sized grain structure. • An extruded Mg–2Sn–2Bi-0.2Mn alloy with bimodal-sized grain structure was developed. • Abnormal DRXed grain growth yields the bimodal-sized grain structure. • Bimodal-sized grain structure results in high strength-ductility synergy. [ABSTRACT FROM AUTHOR]

Abstract: The stratigraphy, age, depositional environment and correlation of the collision-related variegated sandstone and conglomerate beds exposed along the southern side of the Gangdise Mountains to the north of the Yarlung Zangbo suture in the Xigaze region, Xizang (Tibet) have been much debated. Generally referred to as the Dagzhuka Formation, these beds of great thickness have, until recently, not been reported to contain any convincing fossils. Two distinctly different palynological assemblages, indicating Late Cretaceous and Oligocene–Early Miocene ages respectively, have now been recovered from lithologically distinguishable units of the sedimentary succession at Qiabulin to the west of the town of Xigaze. This means that instead of one stratigraphic unit, as has been generally accepted hitherto, at least two are represented. As a result, the Dagzhuga Formation is considered here to refer only to the Cenozoic deposits and the Qiabulin Formation, previously regarded as a synonym, is resurrected to accommodate the Cretaceous beds. These two formations were juxtaposed by tectonic movements. Our finding indicates that the stratigraphic successions on the southern Laurasian continental margin of Xizang reflect changes from a deep forearc basin through shallow littoral environments to a mountainous landscape during the Late Cretaceous and early Cenozoic. This interpretation compares well with those documented from the Gamba and Tingri districts to the south of the Yarlung Zangbo suture. [Copyright &y& Elsevier]

Purpose: To systematically assess the evidence of efficacy and safety of the use of ketamine and esketamine for patients with treatment-resistant depression (TRD) with suicidal ideation (SI). Methods: We independently searched for clinical trials from inception to January 2023 using electronic databases, e.g., PubMed and EMBASE. A systematic review and meta-analysis were performed to assess SI scores of depression rating scales, which were regarded as the outcomes. Results: A total of five independent double-blind, placebo controlled randomized clinical trials (RCTs) are eligible for inclusion. Four of the studies used ketamine as an intervention and one used esketamine as an intervention. Three hundred ninety-one patients with TRD were included (the intervention group with ketamine or esketamine is 246, and the control group is 145). No statistically significant interaction between the subscales of suicide ideation (SMD = − 0.66, 95% CI (− 1.61, 0.29); Z = 1.36, P = 0.17) and antidepressant effects (SMD = − 0.99, 95% CI (− 2.33, 0.34); Z = 1.46, P = 0.15) based on the results of ketamine and esketamine, compared with placebo groups. Conclusion: This meta-analysis suggested that esketamine and ketamine have failed to reduce suicidal ideation in patients with TRD. Further studies are desirable to confirm the effects of ketamine and esketamine in TRD patients. [ABSTRACT FROM AUTHOR]

The roots and rhizomes of Bergenia purpurascens (Hook. f. et Thomson) Engl. , was used as a sunscreen to protect against ultraviolet rays in Tibet of China historically, but its skin whitening constituents and pharmacological effects of this plant remained unknown. To investigate the anti-melanogenesis effect of B. purpurascens in vitro and in vivo , and then explore the preliminary mechanism. An ultraviolet B (UVB)-induced skin injury model of mice was used to verify the ameliorative effect of B. purpurascens extract (BPE) on ultraviolet damage. Then, alpha-melanocyte stimulating hormone (α-MSH)-induced murine melanoma cell line (B16F10) melanin generation model was further adopted to approval the effects of BPE and its bioactive compound, cuscutin, in vitro. Moreover, α-MSH stimulated melanogenesis model in zebrafish was employed to confirm the anti-pigmentation effect of cuscutin. Then, proteins expressions associated with melanin production were observed using western blotting assay to explore preliminary mechanism. BPE inhibited UVB-induced mice injury and restored skin barrier function observably in vivo. BPE and cuscutin suppressed the overproduction of melanin in α-MSH induced B16F10 significantly, in which cuscutin exhibited better effect than well-known whitening agent α-arbutin at same 10 μg/mL concentration. Moreover, the pigmentation of zebrafish embryo was decreased by cuscutin. Finally, cuscutin showed significant downregulation of expressions of tyrosinase (TYR) and tyrosinase related protein-1 (TRP-1), TRP-2 and microphthalmia-associated transcription factor (MITF) in the melanogenic signaling pathway. B. purpurascens extract and its major bioactive constituent, cuscutin, showed potent anti-melanogenesis and skin-whitening effect by targeting TYR and TRP-2 proteins for the first time, which supported its traditional use. [Display omitted] • B. purpurascens could effectively treat skin damage induced by UVB and inhibit the generation of melanin. • Cuscutin is responsible for the effect through inhibiting the expressions of tyrosinase and tyrosinase-related protein 2. • B. purpurascens , as a source of new natural ingredient for skincare, presented the whitening potential. [ABSTRACT FROM AUTHOR]

Paeoniflorin, a bioactive compound extracted from the traditional Chinese herb, Paeonia lactiflora Pall, has been demonstrated to possess efficient antidepressant activity in previous studies. Our systematic review and meta-analysis aimed to assess the effectiveness of paeoniflorin in relieving depressive-like behaviors in animal models. We searched for in vivo studies on the antidepressant effects of paeoniflorin in rodents using electronic databases from their inception to April 2021. The measurements of animal behavioral tests, including the sucrose consumption, forced swimming, tail suspension, and open field tests, were regarded as the outcomes. Fourteen studies involving 416 animals met the inclusion criteria and were included in the meta-analysis. Statistical analysis revealed remarkable differences between the paeoniflorin and control groups. Furthermore, the paeoniflorin group showed great efficiency in improving depressive-like symptoms of animals in the sucrose consumption, forced swimming, tail suspension, and open field tests. Our meta-analysis demonstrates that paeoniflorin can significantly improve depressive-like symptoms in animals and suggests that it can be a potential therapy for patients with depression in the future. [Display omitted] [ABSTRACT FROM AUTHOR]

Kai-Xin-San (KXS, or Happy Feeling Powder), a typical Chinese herbal prescription, is frequently used for treating depression by the multi-level and multi-target mechanism. To systematically investigate the efficacy and safety of KXS on depression in preclinic trials. We independently searched for preclinical animal studies of KXS on depression from inception to June 28, 2022, using electronic databases, e.g., PUBMED. The measurements were performed to assess the outcomes of behavioral tests. This systematic review and meta-analysis included twenty-four studies and 608 animals. A remarkable effect of KXS in depression behavioral tests, including sucrose consumption test (SMD: 2.36, 95% CI: (1.81, 2.90); Z = 8.49, P < 0.00001)., forced swimming test (MD = -60.52, 95% CI: (-89.04, -31.99); Z = 4.16, P < 0.0001), rearing times (MD=4.48, 95% CI: (3.39, 5.57); Z = 8.05, P < 0.00001) and crossing times (MD = -33.7, 95% CI: (25.74, 41.67); Z = 8.29, P < 0.00001) in the open field test, showing KXS's excellent efficiency in improving depressive-like symptoms of animals. Our meta-analysis showed KXS remarkably relieved animals' depressive-like symptoms, providing evidence that KXS can be a promising drug candidate for depression treatment. [Display omitted] • Kai-Xin-San is a traditional Chinese medicine for treating depression widely. • This meta-ananysis assessed the efficacy and safty of Kai-Xin-San for depression. • Kai-Xin-San remarkably improved rodents's depressive symptoms in the behavior tests. [ABSTRACT FROM AUTHOR]

The infinite dilution activity coefficient (γ i ∞) is one of important thermodynamic parameters. In this study, new sets of experimental γ i ∞ data of 30 organic solutes in the ionic liquid 1-ethyl-2,3-dimethylimidazolium thiocyanate ([EDMIM][SCN]) have been measured in the temperature range of 353.15–383.15 K. The infinite dilution partial molar excess enthalpy (H ¯ i E , ∞) was determined from the temperature dependence of the ln γ i ∞ value, and Gibbs free energy (G ¯ i E , ∞) and entropy (T r e f S ¯ i E , ∞ ) of various solutes in [EDMIM][SCN] were calculated from the γ i ∞ value at a reference temperature T r e f = 298.15 K. The density of [EDMIM][SCN] as a function of temperature at pressure p = 101.33 kPa were measured and gas-liquid partition coefficients (K L) were determined. The interaction between the solute and the IL was quantified using the linear free energy relationship (LFER) model. Moreover, the Hildebrand's solubility parameter of [EDMIM][SCN] was obtained by the regular solution theory (RST) combined with the Flory equation by Kikic et al. modification. At 358.15 K, the selectivity (S i j ∞) for cyclohexane(i)/benzene (j), and capacity factor (k j ∞) at infinite dilution of benzene have been gotten. The results were analyzed in comparison with literature data of the ILs with [SCN]−. [Display omitted] [ABSTRACT FROM AUTHOR]

Highlights • DJ-1 knockdown resulted in mitochondrial dysfunction. • loss of DJ-1 suppressed Akt pathway, and reduced nuclear translocation of Nrf2. • DJ-1 deficiency led to an obvious increase in the ROS level, and then activated JNK signaling. Abstract Deletions or some mutations in the gene encoding the multifunctional protein, DJ-1, have been considered to be linked with autosomal recessive early onset Parkinson's disease (PD). Current emerging evidence suggests that DJ-1 is involved in the protection against oxidative stress-induced mitochondrial damage. However, the exact molecular mechanisms underlying this are not completely clear. The aim of this study was to investigate the effects of DJ-1 on the Akt pathway, nuclear factor erythroid 2-related factor (Nrf2), and c-Jun N-terminal kinase (JNK) with regard to modulating mitochondrial function. Here we showed that knockdown of DJ-1 resulted in mitochondrial dysfunction, including a decrease in active mitochondrial mass, complex I deficits, and inhibition of cellular adenosine 5′-triphosphate (ATP) content in the dopaminergic neuron-like cells PC12 and SH-SY5Y. Additionally, loss of DJ-1 impaired Akt signaling, and reduced nuclear translocation of Nrf2, thereby inhibiting activity of Nrf2-regulated downstream antioxidant enzymes such as heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. Moreover, DJ-1 knockdown also led to a significant increase in the mitochondrial reactive oxygen species, and then promoted the activation of JNK pathways. Furthermore, oxidative stress and mitochondrial dysfunction induced by knockdown of DJ-1 were blocked by a JNK inhibitor, which confirmed the important role of JNK activation in mitochondrial dysfunction. In conclusion, the present study indicates that DJ-1 knockdown leads to mitochondrial dysfunction in dopaminergic neuron-like cells, at least in part, through suppressing the Akt/GSK3β pathway and impairing the oxidative stress response, as well as through the subsequent increased JNK activation in dopaminergic neuron-like cells. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Da-Bu-Yin-Wan (DBYW), a historically traditional Chinese medicine formula, was originally defined over 600 years ago. In recent decades, DBYW was clinically employed to treat Parkinson's disease (PD). Aim of the study To explore the underlying mechanism of DBYW on mitochondrial function, we investigated the effect of DBYW on mitochondrial function from the perspectives of DJ-1 and Akt signaling. Materials and methods Human derived neuroblastoma SH-SY5Y cells were transiently transfected with the plasmid pcDNA3-Flag-DJ-1 aimed to overexpress the DJ-1 protein. Transfected cells were treated with 1-methyl-4-phenylpyridinium (MPP + ), a PD-related mitochondrial complex I inhibitor, in the absence and presence of DBYW. The cell viability was assessed by Cell Counting Kit-8 assay. The protein expressions of DJ-1 and Akt signaling were examined by western blotting. The mitochondrial mass was evaluated by confocal fluorescence microscopy. The mitochondrial complex I activity and cellular ATP content were measured by commercial kits. Results Transfection with pcDNA3-Flag-DJ-1 decreased the MPP + -induced toxicity and overexpressed the DJ-1. In DJ-1 overexpressed cells, the mitochondrial mass was raised, mitochondrial complex I activity was improved, and cellular ATP content was increased. In addition, overexpression of DJ-1 augmented the Akt phosphorylation on threonine 308 and serine 473. Moreover, DBYW promoted the above effects in DJ-1 expressed cells. Conclusions These data suggest that DJ-1 protects the mitochondrial function by medicating Akt phosphorylation in MPP + -treated SH-SY5Y cells. Moreover, DBYW enhances the protective effect of DJ-1 medicated Akt phosphorylation on mitochondrial function. [ABSTRACT FROM AUTHOR]

DJ-1/PARK7, the Parkinson's disease-related protein, plays an important role in mitochondrial function. However, the mechanisms by which DJ-1 affects mitochondrial function are not fully understood. Akt is a promoter of neuron survival and is partly involved in the neurodegenerative process. This research aimed at investigating a possible relationship between DJ-1 and Akt signalling in regulating mitochondrial function in the dopaminergic neuron-like cells SH-SY5Y and PC-12. Overexpression of DJ-1 was firstly validated at both the transcriptional and translational levels after transit transfection with plasmid pcDNA3-Flag-DJ-1. Confocal fluorescence microscopy demonstrated that overexpression of DJ-1 increased the mitochondrial mass, but did not disrupt the mitochondrial morphology. In addition, mitochondrial complex I activity was raised in DJ-1-overexpressing cells, and this rise occurred with an increase in cellular adenosine 50-triphosphate content. Moreover, immunoblotting demonstrated that the levels of phosphoinositide 3-kinase and the total Akt were not altered in DJ-1-overexpressing cells, and nor was the Akt phosphorylation on serine 473 changed. By contrast, Akt phosphorylation on threonine 308 was significantly augmented by overexpression of DJ-1, and the expression of glycogen synthase kinase-3beta, a downstream effector of Akt, was suppressed. In summary, these results suggest that overexpression of DJ-1 improves the mitochondrial function, at least in part, through a mechanism involving Akt phosphorylation on threonine 308. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Da-Bu-Yin-Wan (DBYW) and Qian-Zheng-San (QZS), two traditional Chinese herbal formulas, were clinically employed to treat Parkinson''s disease (PD) for decades. Aim of the study: Our previous studies demonstrated neuroprotective effects of DBYW and QZS on mitochondrial function in mice model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In present research, we aimed to investigate the possible neuroprotective mechanisms of DBYW and QZS. Materials and methods: The effects of DBYW and QZS on the behavioral changes (pole test), expression of tyrosine hydroxylase (TH) of substantia nigra by immunohistochemistry, monoaminergic contents and activity of striatum by high performance liquid chromatography, neuronal ultrastructure changes by transmission electron microscopy, mitochondrial DNA (mtDNA) damage by long-extension polymerase chain reaction (PCR), and mRNA expression of mitochondrial subunit NADH dehydrogenase 1(ND1) by qualitative real-time PCR were investigated. Results: Present study demonstrated that DBYW and QZS not only ameliorated the behavior induced by the administration of MPTP and synergistically prevented the decreasing of TH expression, but also increased monoaminergic contents and activity, improved the ultrastructural changes, decreased the mtDNA damage, and synergistically up-regulated the expression of ND1 in mRNA level. Conclusions: These results suggest that DBYW and QZS possess anti-parkinsonism and neuroprotective properties. [Copyright &y& Elsevier]

Parkinson's disease (PD) is the prevalent neurodegenerative disorder characterized by the degeneration of the nigrostriatal neurons. Dynamin-related protein 1 (Drp1) is a key regulator mediating mitochondrial fission and affecting mitophagy in neurons. It has been reported that the inhibition of Drp1 may be beneficial to PD. However, the role of Drp1 and mitophagy in PD remains elusive. Therefore, in this research, we investigated the role of Drp1 and the underlying mechanisms in the mice model of PD. We used the dynasore, a GTPase inhibitor, to inhibit the expression of Drp1. We found that inhibition of Drp1 could ameliorate the motor deficits and the expression of tyrosine hydroxylase in the mice of the PD model. But Drp1 inhibition did not affect mitochondria number and morphological parameters. Moreover, suppression of Drp1 up-regulated the mitochondrial expressions of PINK1 and Parkin while not affected the expressions of NIX and BNIP3. Conclusively, our findings suggest that the inhibition of Drp1 ameliorated the mitochondrial ultrastructure at least via regulating PINK1 and Parkin in the mice of the PD model. This study also implicates that inhibition of Drp1 might impact mitophagy and recover mitochondrial homeostasis in PD. [ABSTRACT FROM AUTHOR]

Nine undescribed polyacetylated 18-norspirostanol saponins, trilliumosides A‒J, were obtained after a guidance based on a molecular networking strategy from the rhizomes of Trillium tschonoskii. Their structures were established by analysis of comprehensive spectroscopic data and chemical methods after their isolation in pure form. All isolated saponins were evaluated for their cytotoxicities against five selected human cancer cell lines (Huh7,A549,MCF-7,HepG2, and MOLT-4) and anti-inflammatory effects on a lipopolysaccharide (LPS)-stimulated NO production model in RAW264.7 macrophages. Trilliumoside D showed significant cytotoxicity against MOLT-4 cell lines with an IC 50 value of 1.0 ± 0.1 μM, whereas trilliumosides H and I displayed remarkable anti-inflammatory effects on NO production with inhibitory rates of 56.3 ± 1.5 and 56.2 ± 2.2% at the concentration of 1.0 μM, respectively. Image 1 • Molecular networking was used to capture 18-norspirostanol saponins form Trillium tschonoskii. • Nine undescribed polyacetylated 18-norspirostanol saponins were obtained. • Their structures were characterized by spectroscopic data and chemical methods. • Trilliumoside D was the most cytotoxic against MOLT-4 cells with an IC 50 value of 1.0 ± 0.1 μM. [ABSTRACT FROM AUTHOR]