Obesity, characterized by excess lipid accumulation, has emerged as a leading public health problem. Excessive, adipocyte-induced lipid accumulation raises the risk of metabolic disorders. ...Adipose-derived stem cells (ASCs) are mesenchymal stem cells (MSCs) that can be obtained from abundant adipose tissue. High fat mass could be caused by an increase in the size (hypertrophy) and number (hyperplasia) of adipocytes. Reactive oxygen species (ROS) are involved in the adipogenic differentiation of human adipose-derived stem cells (hASCs). Lowering the level of ROS is important to blocking or retarding the adipogenic differentiation of hASCs. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a transcription factor that mediates various antioxidant enzymes and regulates cellular ROS levels. Neohesperidin dihydrochalcone (NHDC), widely used as artificial sweetener, has been shown to have significant free radical scavenging activity. In the present study, (
)-3-(4-chlorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (CTP), a novel NHDC analogue, was synthesized and examined to determine whether it could inhibit adipogenic differentiation. The inhibition of adipogenic differentiation in hASCs was tested using NHDC and CTP. In the CTP group, reduced Oil Red O staining was observed compared with the differentiation group. CTP treatment also downregulated the expression of PPAR-γ and C/EBP-α, adipogenic differentiation markers in hASCs, compared to the adipogenic differentiation group. The expression of FAS and SREBP-1 decreased in the CTP group, along with the fluorescent intensity (amount) of ROS. Expression of the Nrf2 protein was slightly decreased in the differentiation group. Meanwhile, in both the NHDC and CTP groups, Nrf2 expression was restored to the level of the control group. Moreover, the expression of HO-1 and NQO-1 increased significantly in the CTP group. Taken together, these results suggest that CTP treatment suppresses the adipogenic differentiation of hASCs by decreasing intracellular ROS, possibly through activation of the Nrf2 cytoprotective pathway. Thus, the use of bioactive substances such as CTP, which activates Nrf2 to reduce the cellular level of ROS and inhibit the adipogenic differentiation of hASCs, could be a new strategy for overcoming obesity.
YM155 is a clinically evaluated anticancer with a fused naphthoquinone-imidazolium scaffold. In this study, we demonstrated that based on weak or cryptic antibacterial activity of YM155 against ...methicillin-resistant
(MRSA) (MIC of 50 μg/ml), some congeneric compounds with short alkyl chains (e.g., c5 with a hexyl chain) at the N3 position of the scaffold, displayed more potent antibacterial activity against MRSA (MIC of 3.13 μg/ml), which is in a clinically achievable range. Their antibacterial activity was evident against Gram-negative bacteria, only in the presence of the outer membrane-permeabilizing agent, polymyxin B. The antibacterial efficacy of c5 was confirmed using the
systemic infection model. We also characterized five spontaneous c5-resistant MRSA mutants that carry mutations in the
gene, for quinone metabolism and respiratory electron transfer, and subsequently exhibited reduced respiration activity. The antibacterial activity of c5 was compromised either by an antioxidant,
-acetylcysteine, or in an anaerobic condition. These suggest that the antibacterial mechanism of c5 involves the generation of reactive oxygen species (ROS), presumably during respiratory electron transport. This study provides an insight into "drug redirecting," through a chemical modification, based on an ROS-generating pharmacophore.
Despite numerous reports on the beneficial effects of catechin or epicatechin contained in tea and cacao extract on human health, a conclusive and precise molecular mechanism has not been elucidated. ...Metabolism of chemical compounds in gut microbiota recently gained significant attention, and extensive studies have been devoted in this field. In conjunction with these results, our group focused on the anti-inflammatory effects of both enantiomers of DHPV (5-(3',4'-dihydroxyphenyl)-γ-valerolactone), produced in the intestine by microbiota metabolism, on IEC-6 cells. Divergent and efficient enantioselective synthesis of (
)- and (
)-DHPV was efficiently achieved by cross-metathesis and Sharpless asymmetric dihydroxylation as a key reaction for four steps in 16% and 14% overall yields, respectively. The anti-inflammatory effects of two enantiomers were tested on IEC-6 cells, and we found that (
)-DHPV was more active than (
)-DHPV. This result implicates that the metabolite produced in the gut has beneficial effects on IEC-6 cells of rat intestines, and the chirality of the metabolite is important for its anti-inflammatory activity. This also provided information for the future discovery of novel small molecular therapeutics for the treatment of inflammatory bowel disease.
α-Vinyl or α-acetylenyl azacycles were easily synthesized from 7- to 9-membered lactams and 6- to 9-membered lactams via
,
-acetal trimethylsilyl (TMS) ethers. Organocopper and organostannane ...reagents afforded reasonable yields for the respective
-acyliminium ion vinylation and acetylenylation intermediates generated from
,
-acetal TMS ethers in the presence of a Lewis acid.
Despite great potential for regenerative medicine, the high tumorigenic potential of human pluripotent stem cells (hPSCs) to form undesirable teratoma is an important technical hurdle preventing safe ...cell therapy. Various small molecules that induce the complete elimination of undifferentiated hPSCs, referred to as "stemotoxics," have been developed to facilitate tumor-free cell therapy, including the Survivin inhibitor YM155. In the present work, based on the chemical structure of YM155, total 26 analogs were synthesized and tested for stemotoxic activity toward human embryonic stem cells (hESCs) and induced PSCs (iPSCs). We found that a hydrogen bond acceptor in the pyrazine ring of YM155 derivatives is critical for stemotoxic activity, which is completely lost in hESCs lacking
, which encodes a solute carrier protein. These results suggest that hydrogen bonding interactions between the nitrogens of the pyrazine ring and the SLC35F2 protein are critical for entry of YM155 into hPSCs, and hence stemotoxic activity.
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Brain derived neurotrophic factor (BDNF) promotes maturation of dopaminergic (DAergic) neurons in the midbrain and positively regulates their maintenance and outgrowth. Therefore, ...understanding the mechanisms regulating the BDNF signaling pathway in DAergic neurons may help discover potential therapeutic strategies for neuropsychological disorders associated with dysregulation of DAergic neurotransmission. Because estrogen‐related receptor gamma (ERRγ) is highly expressed in both the fetal nervous system and adult brains during DAergic neuronal differentiation, and it is involved in regulating the DAergic neuronal phenotype, we asked in this study whether ERRγ ligand regulates BDNF signaling and subsequent DAergic neuronal phenotype. Based on the X-ray crystal structures of the ligand binding domain of ERRγ, we designed and synthesized the ERRγ agonist, (E)-4-hydroxy-N'-(4-(phenylethynyl)benzylidene)benzohydrazide (HPB2) (Kd value, 8.35 μmol/L). HPB2 increased BDNF mRNA and protein levels, and enhanced the expression of the BDNF receptor tropomyosin receptor kinase B (TrkB) in human neuroblastoma SH-SY5Y, differentiated Lund human mesencephalic (LUHMES) cells, and primary ventral mesencephalic (VM) neurons. HPB2-induced upregulation of BDNF was attenuated by GSK5182, an antagonist of ERRγ, and siRNA-mediated ERRγ silencing. HPB2-induced activation of extracellular-signal-regulated kinase (ERK) and phosphorylation of cAMP-response element binding protein (CREB) was responsible for BDNF upregulation in SH-SY5Y cells. HPB2 enhanced the DAergic neuronal phenotype, namely upregulation of tyrosine hydroxylase (TH) and DA transporter (DAT) with neurite outgrowth, both in SH-SY5Y and primary VM neurons, which was interfered by the inhibition of BDNF-TrkB signaling, ERRγ knockdown, or blockade of ERK activation. HPB2 also upregulated BDNF and TH in the striatum and induced neurite elongation in the substantia nigra of mice brain. In conclusion, ERRγ activation regulated BDNF expression and the subsequent DAergic neuronal phenotype in neuronal cells. Our results might provide new insights into the mechanism underlying the regulation of BDNF expression, leading to novel therapeutic strategies for neuropsychological disorders associated with DAergic dysregulation.
This study aimed to compare radiographic outcomes of adult spinal deformity (ASD) surgery with or without 2-level prophylactic vertebroplasty (PVP) at the uppermost instrumented vertebra (UIV) and ...the vertebra 1 level proximal to the UIV.
This retrospective 1:2 matched-cohort comparative study enrolled 2 groups of patients undergoing ASD surgery, including 28 patients with PVP (PVP group) and 56 patients without PVP (non-PVP group), in 3 institutes between 2012 and 2015. The primary outcome measure was the incidence of proximal junctional kyphosis (PJK), proximal junctional failure (PJF), and proximal junctional fracture (PJFX). The secondary outcome measure were radiologic outcomes between PVP segments and non-PVP segments.
Between the PVP group and non-PVP group, no significant differences were found in the incidence of PJK (13 46.4% vs. 26 46.4%; P = 1.000), PJF (11 39.3% vs. 18 32.1%; P = 0.516), and PJFX (11 39.3% vs. 18 32.1%; P = 0.516). The number of the PJFX segments was 16 and 33 in PVP segments and non-PVP segments, respectively. Until revision surgery or final follow-up, the PJFX had progressed in 24 non-PVP segments (82.7%), but not in PVP segments. The PJFX progression in all PVP segments stopped near the PVP mass at the final follow-up. Reoperation as a result of PJFX was performed in 1 patient (3.6%) and 8 patients (14.3%) in the PVP and non-PVP groups, respectively.
PVP at UIV and vertebra 1 level proximal to the UIV cannot prevent PJK, PJF, and PJFX; however, it plays a positive role by delaying their progression. Furthermore, PVP tends to lower the reoperation rate after PJFX in ASD surgery.
Background: Chronic spinal subdural hematomas are extremely rare with only 28 cases reported in the literature. Nevertheless, they should be considered among the differential diagnoses for spinal ...intradural/extramedullary lesions.
Case Report: A 65-year-old male presented with progressive back pain and right S1 radiculopathy. Magnetic resonance imaging scan revealed a right-sided posterolateral intradural/extramedullary lesion at the L5-S1 level. It was hyperintense on T1 and hypointense on T2-weighted images; on the short TI inversion recovery sequence it was hyperintense. The lesion was excised through a right L5 hemilaminectomy, and the patient was neurologically intact postoperatively. Histopathology revealed a chronic subdural hematoma.
Conclusion: Chronic spinal subdural hematoma can mimic intradural extramedullary spinal tumors even in the absence of trauma and/or coagulopathies.
The development of the electronic tongue (e-tongue) significantly relies on the monitoring of taste-inducing molecules and ions in solutions. One of the five primary flavors, sourness, has a direct ...correlation with pH measurement, making it essential for food assessment. However, real-time food evaluation is constrained by the high cost and limited portability of conventional taste sensors. Ti3C2 MXene is remarkable in the field of two-dimensional (2D) materials for its abundance of functional groups and metallic conductivity. These characteristics contribute to its enormous potential as a material for the fabrication of taste sensors with high sensitivity. This study presents the fabrication and application of reliable and reversible pH sensors based on 2D Ti3C2 MXene for the first time. By integrating a microfluidic channel with interdigitated electrodes (IDEs) and a Nafion layer, the sensors exhibit high selectivity for real-time detection of hydronium ions with the MXene channel. Differentiating soft drinks and evaluating the fermentation of Kimchi are demonstrated. Our work on a low-cost, high-performance MXene-based sensor will pave the way for the future of e-tongue development.
•The reliable measurements of ions are effectively conducted by microfluidic channel.•MXene-based pH sensor exhibits high selectivity and sensitivity to pH variation.•The real-time pH monitoring was demonstrated by high performance MXene-based pH sensor.
We have investigated strong optical nonlinearity of monolayer MoS2(1–x)Se2x across the exciton resonance, which is directly tunable by Se doping. The quality of monolayer alloys prepared by chemical ...vapor deposition is verified by atomic force microscopy, Raman spectroscopy, and photoluminescence analysis. The crystal symmetry of all of our alloys is essentially D 3h , as confirmed by polarization-dependent second-harmonic generation (SHG). The spectral structure of the exciton resonance is sampled by wavelength-dependent SHG (λ = 1000–1800 nm), where the SHG resonance red-shifts in accordance with the corresponding optical gap. Surprisingly, the effect of compositional variation turns out to be much more dramatic owing to the unexpected increase of B-exciton-induced SHG, which indeed dominates over the A-exciton resonance for x ≥ 0.3. The overall effect is therefore stronger and broader SHG resonance where the latter arises from different degrees of red-shift for the two exciton states. We report the corresponding absolute SHG dispersion of monolayer alloys, χ(2), as a function of Se doping. We believe that our finding is a critical step toward engineering highly efficient nonlinear optical van der Waals materials working in a broader performance range.
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