Unilateral biportal endoscopy vs. open decompression for lumbar epidural lipomatosis-cohort study using a prospective registry.

Objective: This study aimed to compare the outcomes of unilateral biportal endoscopy, unilateral laminectomy bilateral decompression (UBE-ULBD), and open lumbar decompression (OLD) in patients with lumbar epidural lipomatosis (LEL). Methods: This prospective observational study was conducted from March 2019 to May 2022 and encompassed 33 patients with LEL who underwent lumbar decompression. The study included 15 cases of UBE-ULBD decompression and 18 cases of open decompression, which were followed up for 1 year. The baseline characteristics, initial clinical manifestations, and surgical details [including estimated blood loss (EBL) and preoperative complications] of all patients were recorded. Radiographic evaluation included the cross-sectional area (CSA) of the thecal sac and paraspinal muscles on MRI. Clinical results were analyzed using the Short Form-36 Score (SF-36), the Numeric Pain Rating Scale (NRS) for lumbar and leg pain, creatine kinase, the Roland and Morris Disability Questionnaire (RMDQ), and the Oswestry Disability Index (ODI). Results: The dural sac CSA increased considerably at the 1-year postoperative follow-up in both groups (p < 0.001). The operative duration in the OLD group (48.2 ± 7.2 min) was shorter than that in the UBE-ULBD group (67.7 ± 6.3 min, p < 0.001). The OLD group (97.2 ± 19.8 mL) was associated with more EBL than the UBE-ULBD group (40.6 ± 13.6 mL, p < 0.001). The duration of hospitalization in the OLD group (5.4 ± 1.3 days) was significantly longer compared with the UBE-ULBD group (3.5 ± 1.2 days, p < 0.01). The SF-36, NRS, RMDQ, and ODI scores improved in both groups postoperatively (p < 0.001). Serum creatine kinase values in the UBE-ULBD group (101.7 ± 15.5) were significantly lower than those in the OLD group (330.8 ± 28.1 U/L) 1 day after surgery (p < 0.001). The degree of paraspinal muscle atrophy in the UBE-ULBD group (4.81 ± 1.94) was significantly lower than that in the OLD group (12.15 ± 6.99) at 1 year (p < 0.001). Conclusion: UBE-ULBD and OLD demonstrated comparable clinical outcomes in treating LEL. However, UBE-ULBD surgery was associated with shorter hospital stays, lower rates of incision infection, lighter paravertebral muscle injury, and lower EBL than OLD surgery. Consequently, UBE-ULBD can be recommended in patients with LEL if conservative treatment fails.

Structural and pharmacological characterization of a medium-chain fatty acid receptor GPR84 in common carp (Cyprinus carpio).

The medium-chain fatty acid receptor GPR84, a member of the G protein-coupled receptor family, is mainly expressed in macrophages and microglia, and is involved in the regulation of inflammatory responses and retinal development in mammals and amphibians. However, structure, tissue distribution, and pharmacology of this receptor have rarely been reported in fish. In this study, we cloned the coding sequence (CDS) of common carp GPR84 (ccGPR84), examined its tissue distribution, and explored its cellular signaling function. The results showed that the CDS of ccGPR84 is 1191 bp and encodes a putative protein with 396 amino acids. Phylogenetic and chromosomal synteny analyses revealed that ccGPR84 was evolutionarily conserved with Cyprinids. Real-time quantitative PCR (qPCR) indicated that ccGPR84 was predominantly expressed in the intestine and spleen. Luciferase reporter assay demonstrated that nonanoic acid, capric acid (decanoic acid), undecanoic acid and lauric acid could inhibit cAMP signaling pathway and activate MAPK/ERK signaling pathway, while the potencies of these four fatty acids on the two signaling pathways were different. Lauric acid has the highest inhibitory potency on cAMP signaling pathway, followed by undecanoic acid, nonanoic acid, and capric acid. While for MAPK/ERK signaling pathway, nonanoic acid has the highest activation potency, followed by undecanoic acid, capric acid, and lauric acid. These findings lay the foundation for revealing the roles of different medium-chain fatty acids in the inflammatory response of common carp.

In vitro and in vivo anticancer activity of novel Rh(III) and Pd(II) complexes with pyrazolopyrimidine derivatives.

Six pyrazolopyrimidine rhodium(III) or palladium(II) complexes, [Rh(L1)(H2O)Cl3] (1), [Rh(L2)(CH3OH)Cl3] (2), [Rh(L3)(H2O)Cl3] (3), [Rh2(L4)Cl6]·CH3OH (4), [Rh(L5)(CH3CN)Cl3]·0.5CH3CN (5), and [Pd(L5)Cl2] (6), were synthesized and characterized. These complexes showed high cytotoxicity against six tested cancer cell lines. Most of the complexes showed higher cytotoxicity to T-24 cells in vitro than cisplatin. Mechanism studies indicated that complexes 5 and 6 induced G2/M phase cell cycle arrest through DNA damage, and induced apoptosis via endoplasmic reticulum stress response. In addition, complex 5 also induced cell apoptosis via mitochondrial dysfunction. Complexes 5 and 6 showed low in vivo toxicity and high tumor growth inhibitory activity in mouse tumor models. The inhibitory effect of rhodium complex 5 on tumor growth in vivo was more pronounced than that of palladium complex 6.

Rhodium(III)-Picolinamide Complexes Act as Anticancer and Antimetastasis Agents via Inducing Apoptosis and Autophagy.

As a continuation of our endeavors in discovering metal-based drugs with cytotoxic and antimetastatic activities, herein, we reported the syntheses of 11 new rhodium(III)-picolinamide complexes and the exploration of their potential anticancer activities. These Rh(III) complexes showed high antiproliferative activity against the tested cancer cell lines in vitro. The mechanism study indicated that Rh1 ([Rh(3a)(CH3CN)Cl2]) and Rh2 ([Rh(3b)(CH3CN)Cl2]) inhibited cell proliferation by multiple modes of action via cell cycle arrest, apoptosis, and autophagy and inhibited cell metastasis via FAK-regulated integrin ß1-mediated suppression of EGFR expression. Furthermore, Rh1 and Rh2 significantly inhibited bladder cancer growth and breast cancer metastasis in a xenograft model. These rhodium(III) complexes could be developed as potential anticancer agents with antitumor growth and antimetastasis activity.

Decompression via unilateral biportal endoscopy for severe degenerative lumbar spinal stenosis: A comparative study with decompression via open discectomy.

Background: Previous studies have shown that the Unilateral Biportal Endoscopy is an effective and safety surgery for sufficient decompression of degenerative lumbar spinal stenosis. However, data are lacking in terms of its benefits when compared with conventional open lumbar discectomy (OLD), especially in patients with severe degenerative lumbar spinal stenosis (DLSS). Aim: To compare the clini cal outcomes of two types decompressive surgery: unilateral biportal endoscopy-unilateral laminectomy bilateral decompression (UBE-ULBD) and conventional open lumbar discectomy (OLD) in severe degenerative lumbar spinal stenosis (DLSS). Methods: We retrospectively analyzed patients who underwent UBE-ULBD (n = 50, operated at 50 levels; UBE-ULBD group) and conventional open lumbar discectomy (n = 59, operated at 47 levels; OLD group) between February 2019 and July 2021. All patients were diagnosed with severe stenosis based on the Schizas classification (Grade C or D) on MRI. We compared radiographic and clinical outcome scores [including the visual analog scale (VAS), Oswestry Disability Index (ODI), and Zurich Claudication Questionnaire (ZCQ)] between the 2 groups at 1 year of follow-up. The radiographic evaluation included the cross-sectional area (CSA) of the thecal sac and paraspinal muscles on MRI. Fasting blood was drawn before and 1 and 7 days after the operation to detect creatine kinase (CK). Surgical data perioperative complications were also investigated. Results: The baseline demographic data of the 2 groups were comparable, including VAS, ODI and ZCQ scores, the cross-sectional area of the thecal sac and paraspinal muscles and creatine kinase levels. The dural sac CSA significantly increased post -operatively in both groups, which confirmed they benefited from comparable decompressive effects. The operative duration in the OLD group was less than the UBE-ULBD group (43.9 ± 5.6 min vs. 74.2 ± 9.3 min, p < 0.05). The OLD group was associated with more estimated blood loss than the UBE-ULBD group (111.2 ± 25.0 ml vs. 41.5 ± 22.2 ml, P < 0.05). The length of hospital stay (HS) was significantly longer in the OLD group than in the UBE-ULBD group (6.8 ± 1.6 vs. 4.0 ± 1.4 days, P < 0.05). The VAS, ODI, and ZCQ scores improved in both groups after the operation. Serum creatine kinase values in the UBE-ULBD group were significantly lower than in the OLD group at 1 day after surgery (108. 1 ± 11.9 vs. 347.0 ± 19.5 U/L, P < 0.05). The degree of paraspinal muscle atrophy in the UBE-ULBD group was significantly lower than in the OLD group at 1 year (4.50 ± 0.60 vs. 11.42 ± 0.87, P < 0.05). Conclusions: UBE-ULBD and conventional OLD demonstrate comparable short-term clinical outcomes in treating severe DLSS. However, UBE-ULBD surgery was associated with a shorter hospital stay, less EBL and paravertebral muscle injury than OLD surgery.

Digital Subtraction Angiography-Guided Percutaneous Kyphoplasty in Treatment of Multi-Segmental Osteoporotic Vertebral Compression Fracture: A retrospective single-Center study.

Purpose: This study aimed to explore the effectiveness and safety of digital subtractionangiography (DSA)-guided percutaneous kyphoplasty (PKP) in treating multi-segmental osteoporotic vertebral compression fracture (OVCF). Methods: We retrospectively reviewed 68 patients with multi-segmental OVCF who had unilateral PKP surgeries using DSA and C arm guiding at our hospital between October 2016 and June 2020 and were followed for at least two years. All patients were divided into two groups: DSA guidance (n = 31) and C-arm guidance (n=37). In addition, we collected the clinical and radiological evaluation results during postoperative and last follow-up periods. Results: Our findings revealed that the DSA guidance group required lesser time for channel establishment and surgery than the C-arm guidance group at P < 0.05. The incidences of bone cement leakage, fluoroscopy times, and radiation dose of the DSA guidance group were significantly lesser than the C-arm guidance group (P < 0.05). Compared to the C-arm guidance group, the deviation of puncture in the DSA guidance group was significantly lower, the puncture angle in the DSA guidance group was significantly larger, and better bone cement distribution was obtained (P < 0.05). Compared to preoperative data, the VAS score, median vertebral height, and Cobb angle were significantly improved one day after surgery and the final follow-up in both groups (P < 0.05). However, the VAS score, the median vertebral height, average length of stay, and Cobb angle were not significantly different between the two groups (P > 0.05). Conclusion: DSA-guided PKP in treating multi-segmental OVCF can shorten the operation time, improve puncture accuracy, reduce the times and dose of fluoroscopy, reduce the leakage of bone cement, and achieve better cement distribution.

Molecular cloning, tissue distribution, and pharmacologic function of melanocortin-3 receptor in common carp (Cyprinus carpio).

Melanocortin-3 receptor (MC3R) not only regulates energy homeostasis in animals, but also is an important regulator of inflammation. As one of the most widely farmed freshwater fish, common carp has attracted great interest for its feeding and inflammation regulation. In this study, we cloned the coding sequence (CDS) of common carp Mc3r (ccMc3r), examined its tissue expression profile, and investigated the function of this receptor in mediating downstream signaling pathways. The results showed that the CDS of ccMc3r was 975 bp, encoding a putative protein of 324 amino acids. Homology, phylogeny, and chromosomal synteny analyses revealed that ccMc3r is evolutionarily close to the orthologs of cyprinids. Quantitative real-time PCR (qPCR) indicated that ccMc3r was highly expressed in the brain and intestine. The luciferase reporter systems showed that four ligands, ACTH (1-24), α-MSH, ß-MSH, and NDP-MSH, were able to activate the cAMP and MAPK/ERK signaling pathways downstream of ccMc3r with different potencies. For the cAMP signaling pathway, ACTH (1-24) had the highest activation potency; while for the MAPK/ERK signaling pathway, ß-MSH had the greatest activation effect. In addition, we found that the four agonists were able to inhibit TNF-α-induced NF-κB signaling in approximately the same order of potency as cAMP signaling activation. This study may facilitate future studies on the role of Mc3r in common carp feed efficiency and immune regulation.

Molecular characterization and functional exploration of GPR84 in Chinese Giant Salamander (Andrias davidianus).

The G protein-coupled receptor 84 (GPR84) is a putative medium-chain fatty acids (MCFAs) receptor involved in immune regulation and other metabolic processes. Most available studies focused on the GPR84 characterization from mammals, neglecting vital information that could be obtained from other levels of life, such as amphibians, necessary for an apt evolutionary understanding of the orphan GPR84. Hence, this study molecularly characterized and functionally explored the GPR84 from the Chinese Giant Salamander (Andrias davidianus). Therefore, we report that the Chinese Giant Salamander (CGS), one of the world's largest amphibians, expresses a GPR84 protein having 376 amino acids, with about 70% homologous to other amphibians and around 50% to human GPR84. Investigating the relative localized expression of gpr84 mRNA in CGS using quantitative PCR revealed the highest expression in the kidney and liver. Furthermore, four medium-chain fatty acids (MCFAs) at micromolar levels activated CGS-GPR84 transfected and expressed in HEK293 cells. In HEK293 cells, four different concentrations of MCFAs inhibited forskolin-induced cAMP accumulation and resulted in a dose-dependent increase in extracellular signal-regulated kinases 1 and 2 (ERK1/2). Interestingly, MCFAs activation of GPR84 concomitantly led to the upregulation of inflammatory mediators such as Nuclear Factor Kappa B (NF-κB) and IL-6. Conclusively, this study successfully elucidated the intriguing molecular and functional properties of CGS GPR84, particularly as an immune modulator, and has positioned the findings within the existing body of knowledge for a better overall understanding of GPR84, especially in amphibians.

Role of the mucin-like glycoprotein FCGBP in mucosal immunity and cancer.

IgGFc-binding protein (FCGBP) is a mucin first detected in the intestinal epithelium. It plays an important role in innate mucosal epithelial defense, tumor metastasis, and tumor immunity. FCGBP forms disulfide-linked heterodimers with mucin-2 and members of the trefoil factor family. These formed complexes inhibit bacterial attachment to mucosal surfaces, affect the motility of pathogens, and support their clearance. Altered FCGBP expression levels may be important in the pathologic processes of Crohn's disease and ulcerative colitis. FCGBP is also involved in regulating the infiltration of immune cells into tumor microenvironments. Thus, the molecule is a valuable marker of tumor prognosis. This review summarizes the functional relevance and role of FCGBP in immune responses and disease development, and highlights the potential role in diagnosis and predicting tumor prognosis.

Arene-Ruthenium(II)/Osmium(II) Complexes Potentiate the Anticancer Efficacy of Metformin via Glucose Metabolism Reprogramming.

Targeting metabolic reprogramming to treat cancer could increase overall survival and reduce side effects. Here, we put forward a strategy using arene-ruthenium(II)/osmium(II) complexes to potentiate the anticancer effect of metformin (Met.) via glucose metabolism reprogramming. Complexes 1-6 with oxoglaucine derivatives as ligands were synthesized and their anti-tumor activities were tested under hypoglycemia. Results indicated that 2 and 5 potentiated the anticancer effects of Met. under hypoglycemia, exhibiting lower toxicity, slower blood glucose decline and inhibition of early tumor liver metastasis. Combination of 5 with Met. could be used as a new strategy to treat cancer under hypoglycemia through glucose metabolism reprogramming.

One-pot synthesis of oxoaporphines as potent antitumor agents and investigation of their mechanisms of actions.

An efficient one-pot reaction for the synthesis of oxoaporphine alkaloids has been developed. Twenty-three compounds of oxoaporphine alkaloids were prepared and assessed for their antitumor activities. Most compounds inhibited the growth of T-24 tumor cells in vitro. Particularly, 4B displayed the most potent activity with an IC50 value of 0.5 µM, which was 19-fold more potent than the parent compound 4. The substitution at C3-position of oxoaporphine core by -NO2 significantly enhanced the anticancer activity. Mechanism studies indicated that 4 and 4B induced cell cycle arrest at G2/M phase; in contrast, 4V induced cell cycle arrest at the S phase. Increase of mitochondrial ROS/Ca2+ and decrease of MMP, accompanied by activation of caspase-3/9, were observed in T-24 cells after exposure to compounds 4, 4B and 4V, suggesting that the mitochondrial pathway was involved in the induced apoptosis. Moreover, compound 4B effectively inhibited tumor growth in a mouse xenograft model bearing T-24.

Ru(III) complexes with pyrazolopyrimidines as anticancer agents: bioactivities and the underlying mechanisms.

Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(Ln)(H2O)Cl3] (1-3, n = 1-3) were prepared and characterized. These Ru(III) compounds show strong cytotoxicity against six cancer cell lines and low toxicity to normal human liver cells. Particularly, they exhibited stronger cytotoxicity to SK-OV-3 cells than cisplatin. Mechanism studies revealed that complex 1 inhibited tumor cell invasion and suppressed cell proliferation, induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca2+), and reduced mitochondrial membrane potential (ΔΨ). It also activated the caspase cascade, accompanied with upregulation of cytochrome c, Bax, p53, Apaf-1 and downregulation of Bcl-2. Moreover, complex 1 caused cell cycle arrest at S phase by inhibiting the expression of CDC 25, cyclin A2 and CDK 2 proteins, and induced DNA damage by interacting with DNA and inhibiting the topoisomerase I enzyme. Complex 1 exhibited efficient in vivo anticancer activity in a model of SK-OV-3 tumor xenograft.

Imprinted lncRNA Dio3os preprograms intergenerational brown fat development and obesity resistance.

Maternal obesity (MO) predisposes offspring to obesity and metabolic disorders but little is known about the contribution of offspring brown adipose tissue (BAT). We find that MO impairs fetal BAT development, which persistently suppresses BAT thermogenesis and primes female offspring to metabolic dysfunction. In fetal BAT, MO enhances expression of Dio3, which encodes deiodinase 3 (D3) to catabolize triiodothyronine (T3), while a maternally imprinted long noncoding RNA, Dio3 antisense RNA (Dio3os), is inhibited, leading to intracellular T3 deficiency and suppression of BAT development. Gain and loss of function shows Dio3os reduces D3 content and enhances BAT thermogenesis, rendering female offspring resistant to high fat diet-induced obesity. Attributing to Dio3os inactivation, its promoter has higher DNA methylation in obese dam oocytes which persists in fetal and adult BAT, uncovering an oocyte origin of intergenerational obesity. Overall, our data uncover key features of Dio3os activation in BAT to prevent intergenerational obesity and metabolic dysfunctions.

[Unilateral vertebroplasty and kyphoplasty by digital subtraction angiography for the treatment of osteoporotic vertebral compression fractures].

OBJECTIVE: To explore the methods and efficacy of unilateral extra-pedicle precision puncture percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty(PKP) by digital subtraction angiography (DSA) for the treatment of osteoporotic vertebral compression fractures (OVCFs). METHODS: The clinical data of 68 patients with osteoporotic vertebral compression fractures treated from August 2015 to December 2018 were retrospectively analyzed. There were 20 males and 48 females, aged 56 to 90(73.5±8.0) years, 40 cases of double segments, 28 cases of three segments, a total of 168 vertebrae. All the patients were performed PVP orPKP through unilateral extra pedicle precision puncture under the guidance of DSA. The vertebrae were distributed in T1-T6(29 vertebrae), T6-T12(89 vertebrae), and L1-L5(50 vertebrae). Whether the puncture needle tip reached the midline of vertebral body was observed during operation, the leakage rate of bone cement was recorded after operation. The height of anterior edge and middle of the fractured vertebral body were measured after operation. Visual analogue scale (VAS) and the Oswestry Disability Index (ODI) were used to assess pain and lumbar function before operation, 3 days after operation and final follow-up time. RESULTS: All the punctures were successful in 68 patients. All the puncture needles reached the midline of vertebral body, and the bone cement was well dispersed in the vertebral body with symmetrical distribution. The operation time was 35 to 60 (41.6±3.2) minutes, and there was no puncture complications. The injection volume of bone cement was 3 to 5 (3.6±0.5) ml in each vertebra. There were 8 cases of bone cement leakage, with a leakage rate of 11.76%. All 68 patients were followed up from 12 to 27 (14.3±3.5) months in the study. VAS score and ODI at 3 days after surgery and at final follow-up time were significantly improved (P<0.05). The height of the anterior edge and the middle of vertebral body at 3 days after operation and at final were significantly recovered (P<0.05). CONCLUSION: PVP or PKP under the guidance of DSA via a unilateral extrapedicular approach with precision puncture can effectively relieve pain, restore vertebral body height and spinal function, which is a safe, fast and effective method in the treatment of osteoporotic vertebral compression fractures.

Is It Necessary to Approach the Severe Osteoporotic Vertebral Biconcave-Shaped Fracture Bilaterally During the Process of PKP?

PURPOSE: The goal of this study was to explore the outcomes of unilateral and bilateral approach percutaneous kyphoplasty (PKP) using CT-guidance in the treatment of severe osteoporotic single-level vertebral biconcave-shaped fracture. METHODS: We retrospectively reviewed 89 patients with severe osteoporotic single-level vertebral biconcave-shaped fracture who had undergone unilateral and bilateral PKP surgeries using CT-guidance at our hospital between June 2013 and June 2019, and followed for at least 1 year. All patients were divided into unilateral (the transverse process-pedicle approach, n = 49) and bilateral (the pedicle approach, n = 40) groups. We collected the clinical and radiological evaluation results during postoperative and last follow-up periods. RESULTS: Our findings revealed that the surgery time for the unilateral group was significantly shorter than that of the bilateral group at P < 0.05. The amount of bone cement and radiation exposure of the unilateral group were significantly lesser than that of the bilateral group (P < 0.05). Relative to preoperative data, the values of the VAS score and Oswestry disability index (ODI) were significantly improved at 1 day after surgery and the last follow-up in the two groups (P < 0.05). Notably, the median height of vertebra at 1 day after surgery and the last follow-up in the unilateral group was significantly restored than that of preoperative data (P < 0.05). However, the median height of vertebra at the same time intervals in the bilateral group showed no significant change compared with preoperative data (P > 0.05). Furthermore, the rate of bone cement leakage and incidence of adjacent-level vertebra fracture were not significantly different in the two groups (P > 0.05). Finally, both groups can obtain an asymmetrical distribution of bone cement in the vertebra. CONCLUSION: Compared to the bilateral PKP, unilateral PKP using CT-guidance in the treatment of the sOVBFs exhibits significantly shorter operation time, lesser radiation dose, and complications. Moreover, unilateral PKP can restore the median height of the vertebral body and eventually obtain a symmetrical distribution of bone cement in the vertebra.

Embryonic exposure to hyper glucocorticoids suppresses brown fat development and thermogenesis via REDD1.

Maternal stress during pregnancy is prevailing worldwide, which exposes fetuses to intrauterine hyper glucocorticoids (GC), programming offspring to obesity and metabolic diseases. Despite the importance of brown adipose tissue (BAT) in maintaining long-term metabolic health, impacts of prenatal hyper GC on postnatal BAT thermogenesis and underlying regulations remain poorly defined. Pregnant mice were administrated with synthetic GC dexamethasone (DEX) at levels comparable to fetal GC exposure of stressed mothers. Prenatal GC exposure dose-dependently reduced BAT thermogenic activity, contributing to lower body temperature and higher mortality of neonates; such difference was abolished under thermoneutrality, underscoring BAT deficiency was the major contributor to adverse changes in postnatal thermogenesis due to excessive GC. Prenatal GC exposure highly activated Redd1 expression and reduced Ppargc1a transcription from the alternative promoter (Ppargc1a-AP) in neonatal BAT. During brown adipocyte differentiation, ectopic Redd1 expression reduced Ppargc1a-AP expression and mitochondrial biogenesis; and the inhibitory effects of GC on mitochondrial biogenesis and Ppargc1a-AP expression were blocked by Redd1 ablation. Redd1 reduced protein kinase A phosphorylation and suppressed cyclic adenosine monophosphate (cAMP) -responsive element-binding protein (CREB) binding to the cAMP regulatory element (CRE) in Ppargc1a-AP promoter, leading to Ppargc1a-AP inactivation. In summary, excessive maternal GC exposure during pregnancy dysregulates Redd1-Ppargc1a-AP axis, which impairs fetal BAT development, hampering postnatal thermogenic adaptation and metabolic health of offspring.

Synthesis, structural characterization and antitumor activity of six rare earth metal complexes with 8-hydroxyquinoline derivatives.

The rare earth metal Gd(III), Yb(III), Lu(III), Eu(III), Tb(III) and Ho(III) complexes 1-6 with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (H-L) as ligands were synthesized. The in vitro cytotoxicity assay indicated that the cytotoxicity of 1 was equivalent to cisplatin and higher than that of H-L and other complexes towards T24 tumor cells. The mechanism study indicated that 1 caused significant up-regulation of the proteins p27, p21 and p53 in T24 cells and cell cycle arrest in G2 phase. In addition, 1 induced effective T24 cells apoptosis via mitochondrial dysfunction pathway, which was indicated by changes in mitochondrial membrane potential (Δψ), reactive oxygen species (ROS), intracellular Ca2+ and the mitochondria-related proteins (including cytochrome C (Cyt C), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated x (Bax) and apoptotic protease activating factor-1 (Apaf-1)). Moreover, 1 could activate caspase-3/8/9 in T24 cells. Therefore, complex 1 is a promising and potent anticancer drug candidate.

Excessive Glucocorticoids During Pregnancy Impair Fetal Brown Fat Development and Predispose Offspring to Metabolic Dysfunctions.

Maternal stress during pregnancy exposes fetuses to hyperglucocorticoids, which increases the risk of metabolic dysfunctions in offspring. Despite being a key tissue for maintaining metabolic health, the impacts of maternal excessive glucocorticoids (GC) on fetal brown adipose tissue (BAT) development and its long-term thermogenesis and energy expenditure remain unexamined. For testing, pregnant mice were administered dexamethasone (DEX), a synthetic GC, in the last trimester of gestation, when BAT development is the most active. DEX offspring had glucose, insulin resistance, and adiposity and also displayed cold sensitivity following cold exposure. In BAT of DEX offspring, Ppargc1a expression was suppressed, together with reduced mitochondrial density, and the brown progenitor cells sorted from offspring BAT demonstrated attenuated brown adipogenic capacity. Increased DNA methylation in Ppargc1a promoter had a fetal origin; elevated DNA methylation was also detected in neonatal BAT and brown progenitors. Mechanistically, fetal GC exposure increased GC receptor/DNMT3b complex in binding to the Ppargc1a promoter, potentially driving its de novo DNA methylation and transcriptional silencing, which impaired fetal BAT development. In summary, maternal GC exposure during pregnancy increases DNA methylation in the Ppargc1a promoter, which epigenetically impairs BAT thermogenesis and energy expenditure, predisposing offspring to metabolic dysfunctions.

Syntheses, Crystal Structures, and Antitumor Activities of Copper(II) and Nickel(II) Complexes with 2-((2-(Pyridin-2-yl)hydrazono)methyl)quinolin-8-ol.

Two transition metal complexes with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (L), [Cu(L)Cl2]2 (1) and [Ni(L)Cl2]·CH2Cl2 (2), were synthesized and fully characterized. Complex 1 exhibited high in vitro antitumor activity against SK-OV-3, MGC80-3 and HeLa cells with IC50 values of 3.69 ± 0.16, 2.60 ± 0.17, and 3.62 ± 0.12 µM, respectively. In addition, complex 1 caused cell arrest in the S phase, which led to the down-regulation of Cdc25 A, Cyclin B, Cyclin A, and CDK2, and the up-regulation of p27, p21, and p53 proteins in MGC80-3 cells. Complex 1 induced MGC80-3 cell apoptosis via a mitochondrial dysfunction pathway, as shown by the significantly decreased level of bcl-2 protein and the loss of Δψ, as well as increased levels of reactive oxygen species (ROS), intracellular Ca2+, cytochrome C, apaf-1, caspase-3, and caspase-9 proteins in MGC80-3 cells.

Maternal obesity induces epigenetic modifications to facilitate Zfp423 expression and enhance adipogenic differentiation in fetal mice.

Maternal obesity (MO) predisposes offspring to obesity and type 2 diabetes despite poorly defined mechanisms. Zfp423 is the key transcription factor committing cells to the adipogenic lineage, with exceptionally dense CpG sites in its promoter. We hypothesized that MO enhances adipogenic differentiation during fetal development through inducing epigenetic changes in the Zfp423 promoter and elevating its expression. Female mice were subjected to a control (Con) or obesogenic (OB) diet for 2 months, mated, and maintained on their diets during pregnancy. Fetal tissue was harvested at embryonic day 14.5 (E14.5), when the early adipogenic commitment is initiated. The Zfp423 expression was 3.6-fold higher and DNA methylation in the Zfp423 promoter was lower in OB compared with Con. Correspondingly, repressive histone methylation (H3K27me3) was lower in the Zfp423 promoter of OB fetal tissue, accompanied by reduced binding of enhancer of zeste 2 (EZH2). Gain- and loss-of-function analysis showed that Zfp423 regulates early adipogenic differentiation in fetal progenitor cells. In summary, MO enhanced Zfp423 expression and adipogenic differentiation during fetal development, at least partially through reducing DNA methylation in the Zfp423 promoter, which is expected to durably elevate adipogenic differentiation of progenitor cells in adult tissue, programming adiposity and metabolic dysfunction later in life.