Apoptotic vesicles (apoVs) derived from fibroblast-converted hepatocyte-like cells effectively ameliorate liver fibrosis.

Liver fibrosis is a serious global health issue for which effective treatment remains elusive. Chemical-induced hepatocyte-like cells (ciHeps) have emerged as an appealing source for cell transplantation therapy, although they present several challenges such as the risk of lung thromboembolism or hemorrhage. Apoptotic vesicles (apoVs), small membrane vesicles generated during the apoptosis process, have gained attention for their role in regulating various physiological and pathological processes. In this study, we generated ciHep-derived apoVs (ciHep-apoVs) and investigated their therapeutic potential in alleviating liver fibrosis. Our findings revealed that ciHep-apoVs induced the transformation of macrophages into an anti-inflammatory phenotype, effectively suppressed the activity of activated hepatic stellate cells (aHSCs), and enhanced the survival of hepatocytes. When intravenously administered to mice with liver fibrosis, ciHep-apoVs were primarily engulfed by macrophages and myofibroblasts, leading to a reduction in liver inflammation and fibrosis. Proteomic and miRNA analyses showed that ciHep-apoVs were enriched in various functional molecules that modulate crucial cellular processes, including metabolism, signaling transduction, and ECM-receptor interactions. ciHep-apoVs effectively suppressed aHSCs activity through the synergistic inhibition of glycolysis, the PI3K/AKT/mTOR pathway, and epithelial-to-mesenchymal transition (EMT) cascades. These findings highlight the potential of ciHep-apoVs as multifunctional nanotherapeutics for liver fibrosis and provide insights into the treatment of other liver diseases and fibrosis in other organs.

Post-synthetic Rhodium (III) Complexes in Covalent Organic Frameworks for Photothermal Heterogeneous C-H Activation.

Although photocatalytic C-H activation has been realized by using heterogeneous catalysts, most of them require high-temperature conditions to provide the energy required for C-H bond breakage. The catalysts with photothermal conversion properties can catalyze this reaction efficiently at room temperature, but so far, these catalysts have been rarely developed. Here, we construct bifunctional catalysts Rh-COF-316 and -318 to combine photosensitive covalent organic frameworks (COFs) and transition-metal catalytic moiety using a post-synthetic approach. The Rh-COF enable the heterogeneous C-H activation reaction by photothermal conversion for the first time, and exhibit excellent yields (up to 98 %) and broad scope of substrates in [4+2] annulation at room temperature, while maintaining the high stability and recyclability. Significantly, this work is the highest yield reported so far in porous materials catalyzing C(sp2)-C(sp2) formation at room temperature. The excellent performances can be attributed to the COF-316, which enhances the photothermal effect (ΔT=50.9 °C), thus accelerating C-H bond activation and the exchange of catalyst with substrates.

Muscone and (+)-Borneol Cooperatively Strengthen CREB Induction of Claudin 5 in IL-1ß-Induced Endothelium Injury.

Claudin 5 is one of the major proteins of tight junctions and is responsible for cerebrovascular integrity and BBB function. Muscone and (+)-borneol is the major ingredient of moschus and borneolum, respectively, with antioxidative and anti-inflammatory activities. This study investigated whether muscone and (+)-borneol combination protected claudin 5 by targeting ROS-mediated IL-1ß accumulation. Muscone and (+)-borneol reduced cerebral infarct volume and cerebrovascular leakage with claudin 5 protection in mice after stroke, largely due to inhibiting ROS accumulation and inflammatory infiltrate of microglia. Muscone reduced ROS and then blocked the CaN/Erk1/2 pathway to decrease IL-1ß release, while (+)-borneol removed mitochondrial ROS and attenuated the SDH/Hif-1α pathway to inhibit IL-1ß transcription, thereby jointly reducing IL-1ß production. Accumulated IL-1ß disrupted cAMP/CREB activation and attenuated transcriptional regulation of claudin 5. Muscone and (+)-borneol combination cooperatively protected BBB function by blocking IL-1ß-mediated cAMP/CREB/claudin 5 cascades. Mutation of Ser133 site of CREB or knockdown of claudin 5 weakened the effects of muscone and (+)-borneol on upregulation of TEER value and downregulation of FITC-dextran permeability, suggesting that targeting CREB/claudin 5 was an important strategy to protect vascular integrity. This study provided ideas for the studies of synergistic protection against ischemic brain injury about the active ingredients of traditional Chinese medicines (TCMs).

Hydroxysafflor Yellow A Blocks HIF-1α Induction of NOX2 and Protects ZO-1 Protein in Cerebral Microvascular Endothelium.

Zonula occludens-1 (ZO-1) is a tight junction protein in the cerebrovascular endothelium, responsible for blood-brain barrier function. Hydroxysafflor yellow A (HSYA) is a major ingredient of safflower (Carthamus tinctorius L.) with antioxidative activity. This study investigated whether HSYA protected ZO-1 by targeting ROS-generating NADPH oxidases (NOXs). HSYA administration reduced cerebral vascular leakage with ZO-1 protection in mice after photothrombotic stroke, largely due to suppression of ROS-associated inflammation. In LPS-stimulated brain microvascular endothelial cells, HSYA increased the ratio of NAD+/NADH to restore Sirt1 induction, which bound to Von Hippel-Lindau to promote HIF-1αdegradation. NOX2 was the predominant isoform of NOXs in endothelial cells and HIF-1α transcriptionally upregulated p47phox and Nox2 subunits for the assembly of the NOX2 complex, but the signaling cascades were blocked by HSYA via HIF-1α inactivation. When oxidate stress impaired ZO-1 protein, HSYA attenuated carbonyl modification and prevented ZO-1 protein from 20S proteasomal degradation, eventually protecting endothelial integrity. In microvascular ZO-1 deficient mice, we further confirmed that HSYA protected cerebrovascular integrity and attenuated ischemic injury in a manner that was dependent on ZO-1 protection. HSYA blocked HIF-1α/NOX2 signaling cascades to protect ZO-1 stability, suggestive of a potential therapeutic strategy against ischemic brain injury.

Small Molecule-Induced Differentiation As a Potential Therapy for Liver Cancer.

Despite the efficacy demonstrated by immunotherapy recently, liver cancer still remains one of the deadliest cancers, mainly due to heterogeneity of this disease. Continuous exploration of new therapeutics is therefore necessary. Chemical-induced cell differentiation can serve as a promising approach, with its ability to consistently remodel gene expression profile and alter cell fate. Inspired by advances in stem cell and reprogramming field, here it is reported that a small molecule cocktail (SMC) consisted of: SB431542 (TGFß inhibitor), CHIR99021 (GSK3ß inhibitor), BIX01294 (H3K9 methyltransferase/G9a inhibitor), and all-trans retinoic acid (ATRA), can induce differentiation of liver cancer cells including cell lines, primary cancer cells, cancer stem cells, and drug resistant cells. Treated cells lose malignant characteristics and regain hepatocyte phenotype instead. When applied in vivo, SMC induces wide range of tissue necrosis or fibrosis within the tumors, while remaining tissues begin to express hepatic nuclear factor 4α (HNF4α), the hepatic nuclear marker. SMC also leads to tumor abrogation in orthotopic xenograft models and life span extension of animals. The powerful differentiation induction of SMC is exerted through modulation of Akt/mTOR/HIF1α signaling and metabolic reprogramming, as well as suppressing Snail and enhancing HNF4α expression. Together, these results highlight that chemical-induced differentiation has the potential to effectively treat liver cancer disregard of heterogeneity.

A systematic review of pharmacological activities, toxicological mechanisms and pharmacokinetic studies on Aconitum alkaloids.

The tubers and roots of Aconitum (Ranunculaceae) are widely used as heart medicine or analgesic agents for the treatment of coronary heart disease, chronic heart failure, rheumatoid arthritis and neuropathic pain since ancient times. As a type of natural products mainly extracted from Aconitum plants, Aconitum alkaloids have complex chemical structures and exert remarkable biological activity, which are mainly responsible for significant effects of Aconitum plants. The present review is to summarize the progress of the pharmacological, toxicological, and pharmacokinetic studies of Aconitum alkaloids, so as to provide evidence for better clinical application. Research data concerning pharmacological, toxicological and pharmacokinetic studies of Aconitum alkaloids were collected from different scientific databases (PubMed, CNKI, Google Scholar, Baidu Scholar, and Web of Science) using the phrase Aconitum alkaloids, as well as generic synonyms. Aconitum alkaloids are both bioactive compounds and toxic ingredients in Aconitum plants. They produce a wide range of pharmacological activities, including protecting the cardiovascular system, nervous system, and immune system and anti-cancer effects. Notably, Aconitum alkaloids also exert strong cardiac toxicity, neurotoxicity and liver toxicity, which are supported by clinical studies. Finally, pharmacokinetic studies indicated that cytochrome P450 proteins (CYPs) and efflux transporters (ETs) are closely related to the low bioavailability of Aconitum alkaloids and play an important role in their metabolism and detoxification in vivo.

Psiguadiols A-J, Rearranged Meroterpenoids as Potent PTP1B Inhibitors from Psidium guajava.

Psiguadiols A-J (1-10), new meroterpenoids with rearranged skeletons, were isolated from the leaves of Psidium guajava. Compounds 1-3 represent the first examples of 6,8-diformyl-5,7-dihydroxy-4-phenylchromane-coupled sesquiterpenoids with an unprecedented C-8-spiro-fused 6/6/9/4 tetracyclic ring system. Compounds 4 and 5 represent two unusual scaffolds featuring 1ß,6ß- and 3α,5α-epoxy rings, respectively. The combination of spectroscopic data analyses, comparison of experimental and calculated ECD data, and single-crystal X-ray diffraction data of 1, 6, and 8 allowed for the assignment of the structures. A putative biosynthetic pathway for 1-10 is discussed. Compounds 1, 7, and 8 exhibited inhibitory activities against PTP1B with IC50 values of 4.7, 6.2, and 9.2 µM, respectively. In addition, molecular docking was performed to investigate the mechanism of action.

Phloroglucinols with Immunosuppressive Activities from the Fruits of Eucalyptus globulus.

Five new phloroglucinol derivatives, eucalyptins C-G (1-5), together with 13 known analogues (6-18) were isolated from the fruits of Eucalyptus globulus. The structures and absolute configurations of 1-5 were established by means of spectroscopic data analysis, computational calculation methods, and single-crystal X-ray diffraction. Compounds 1-18 were investigated for their immunosuppressive effects in vitro, and 1, 2, 6, and 7 displayed moderate inhibitory activities with IC50 values of 11.8, 10.2, 18.2, and 19.1 µM, respectively. The stimulation index (SI) of 1 was 64.2 and was compared to that of cyclosporine A (SI = 149.57). Further study demonstrated that 1 exhibited an immunosuppressive effect through inducing apoptosis and inhibiting cytokine secretion.

Atropisomeric meroterpenoids with rare triketone-phloroglucinol-terpene hybrids from Baeckea frutescens.

Baefrutones A-F (1-6), six new meroterpenoids with rare triketone-phloroglucinol-monoterpene/sesquiterpene frameworks, together with their biosynthetically related intermediate (±)-baeckenon B (7), were isolated from the aerial part of Baeckea frutescens under the guidance of HPLC-Q/TOF-MS2 investigation. Compounds 1-4 represent the first examples of natural meroterpenoids existing as four pairs of inseparable diastereomeric atropisomers (2 : 1, 1H NMR integration) caused by the restricted rotation around the C-6-C-7-C-1' bonds arising from the intramolecular hydrogen bond between C-1 carbonyl and 2'-OH. The discovery of these architectures not only largely enriched the chemodiversity of the meroterpenoid and atropisomer library, but also might be exciting and challenging for asymmetric organic synthesis. Their structures and absolute configurations were established by extensive spectroscopic analysis, X-ray diffraction, and ECD calculations. Compounds 5 and 6 were biomimetically synthesized from 7 and ß-caryophyllene via a regioselective oxidative hetero-Diels-Alder reaction, thus providing access to the construction of the 6/6/9/4 tetracyclic ring system. The anti-inflammatory activities of these meroterpenoids were also discussed.

[Expression of heme oxygenase-1 and inducible nitric oxide synthase in the lungs of hyperoxia-exposed preterm rats].

OBJECTIVE: To study the expression and the role of heme oxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) in preterm rats with hyperoxia-induced lung injuries. METHODS: Sixty-four three-day-old preterm Sprague-Dawley rats were randomly assigned to a hyperoxia group (90% oxygen exposure) and a control group (room air exposure), with 32 rats in each group. After 3 days or 7 days of exposure, the lung activity of HO-1 and nitric oxide (NO) contents in bronchoalveolar lavage fluid (BALF), pulmonary histopathologic changes, and the cellular distribution and expression of HO-1 and iNOS in the lungs were measured. RESULTS: After 3 days and 7 days of exposure, the hyperoxia group showed acute lung injuries characterized by the presence of hyperaemia, red cell extravasation and inflammatory infiltration. The NO contents in BALF and the iNOS expression in the lungs increased significantly in the hyperoxia group compared with those in the control group 3 and 7 days after exposure. The expression of HO-1 in macrophages in the lungs increased significantly in the hyperoxia group compared with that in the control group 3 and 7 days after exposure. The NO contents in BALF and the iNOS and HO-1 expression in the lungs increased significantly 7 days after hyperoxia exposure compared with 3 days after hyperoxia exposure. CONCLUSIONS: iNOS and HO-1 levels in the lungs increase in preterm rats with hyperoxia-induced lung injuries, suggesting that iNOS and HO-1 may play roles in hyperoxia-induced pulmonary injuries.

A weighted multi-scale morphological gradient filter for rolling element bearing fault detection.

This paper presents a novel signal processing scheme, named the weighted multi-scale morphological gradient filter (WMMG), for rolling element bearing fault detection. The WMMG can depress the noise at large scale and preserve the impulsive shape details at small scale. Both a simulated signal and vibration signals from a bearing test rig are employed to evaluate the performance of the proposed technique. The traditional envelope analysis and a multi-scale enveloping spectrogram algorithm combining continuous wavelet transform and envelope analysis (WT-EA) are also studied and compared with the presented WMMG. Experimental results have demonstrated the effectiveness of the WMMG to extract the impulsive components from the raw vibration signal with strong background noise. We also investigated the classification performance on identifying bearing faults based on the WMMG and statistical parameters with varied noise levels. Application results reveal that the WMMG achieves the same or better performance as EA and WT-EA. Meanwhile, the WMMG requires low computation cost and is very suitable for on-line condition monitoring of bearing operating states.

[Oil atomic spectrometric feature selection by Parzen window based vague sets theory].

Large quantity and ambiguity of oil atomic spectrometric information greatly affects the applicable efficiency and accuracy in fault diagnosis. A novel method for choosing less and effective spectrometric features is presented. Based on gearbox test bed, we simulated the normal wear state and two typical faults to acquire the lubricant samples. The three wear states are regarded as three vague sets, and spectrometric feature values are vague values on vague sets. Based on similarity between vague values, mean vague sensibility (MVS) is defined to describe the sensitive degree of spectrometric feature to wear state. Besides, the membership degrees of vague sets greatly depend on human experience. The probability density distribution of spectrometric data of three wear states was estimated with Parzen window. Combined with Bayesian formula, the range of vague sets membership was calculated. Experimental results verify that the proposed method is of efficient help in choosing high fault-sensitive features from so many spectrometric features.

[Research on oil atomic spectrometric data semi-supervised fuzzy C-means clustering based on Parzen window].

A Parzen window based semi-supervised fuzzy c-means (PSFCM) clustering algorithm was presented. The initial clustering centers of fuzzy c-means (FCM) were determined with training samples. The membership iteration of FCM was redefined after the membership degrees of testing samples relatively to each state were calculated using Parzen window. Two typical faults of gear box were simulated through the gear box bed in order to acquire the lubricant samples. Concentration of Fe, Si and B, which were the representative elements, was selected as the three-dimensional feature vectors to be analyzed with FCM and PSFCM clustering methods. The clustering results were that the correct ratio of FCM was 48.9%, while that of PSFCM was 97.4% because of integrating with supervised information. Experimental results also indicated that it can reduce the dependence of the experience and lots of faults data to introduce PSFCM into oil atomic spectrometric analysis. It was of great help in improving the wear faults diagnosis ratio.

[Research on monitoring mechanical wear state based on oil spectrum multi-dimensional time series model].

A new method using oil atomic spectrometric analysis technology to monitor the mechanical wear state was proposed. Multi-dimensional time series model of oil atomic spectrometric data of running-in period was treated as the standard model. Residues remained after new data were processed by the standard model. The residues variance matrix was selected as the features of the corresponding wear state. Then, high dimensional feature vectors were reduced through the principal component analysis and the first three principal components were extracted to represent the wear state. Euclidean distance was computed for feature vectors to classify the testing samples. Thus, the mechanical wear state was identified correctly. The wear state of a specified track vehicle engine was effectively identified, which verified the validity of the proposed method. Experimental results showed that introducing the multi-dimensional time series model to oil spectrometric analysis can fuse the spectrum data and improve the accuracy of monitoring mechanical wear state.

Induction of neuronal and myelin-related gene expression by IL-6-receptor/IL-6: a study on embryonic dorsal root ganglia cells and isolated Schwann cells.

The conditional knockdown of the Interleukin-6 (IL-6) family signal transducer (gp130) causes peripheral nerve demyelination and degeneration. In the present work, we investigated the effect of gp130 signaling on peripheral nerves and Schwann cells (SC). We stimulated gp130 signaling with IL6RIL6, a fusion molecule of IL-6 and IL-6R, in rat embryonic day 14 dorsal root ganglia (DRG) cell cultures. In neurons, IL6RIL6 strongly increased the axonal network. In SC, IL6RIL6 favored the appearance of elongated more mature cells versus stellar shaped cells. Gene expression profiling showed an increased expression of neuronal and glial-specific genes. mRNAs related to SC function, including myelin-specific genes, were increased by IL6RIL6 treatment of DRG cells, or of purified SCs isolated from rat sciatic nerve. In IL6RIL6-treated cells, immunostaining showed a strong nuclear signal for Krox-20, a transcription factor essential for differentiation of the SC lineage. On the contrary, we observed that IL6RIL6 inhibited the genes related to TGF-beta family as well as the production of smooth muscle actin.

Increased myelinating capacity of embryonic stem cell derived oligodendrocyte precursors after treatment by interleukin-6/soluble interleukin-6 receptor fusion protein.

Neurosphere cells (NSc) derived from embryonic stem cells have characteristics of neural stem cells and can differentiate into oligodendrocyte precursors. Culture of NSc with IL6RIL6 chimera (soluble interleukin-6 receptor fused to interleukin-6) enhances their differentiation into oligodendrocytes with longer and more numerous branches and with peripheral accumulation of myelin basic protein (MBP) in myelin membranes indicating maturation. Gene expression profiling reveals that one of the proteins strongly induced by IL6RIL6 is a regulator of microtubule dynamics, stathmin-like 2 (SCG10/Stmn2), and gene silencing shows that Stmn2 plays an important role in the development of the mature oligodendrocyte morphology. IL6RIL6 acts as an effective stimulator of the myelinating function of ES cell-derived oligodendrocyte precursors, as observed upon transplantation of the IL6RIL6- pretreated cells into brain slices of MBP-deficient shiverer mice.

Effect of leonurine on the activity of creatine kinase.

The effects of leonurine (1) on the activity of creatine kinase (CK) have been studied. The results show that leonurine inhibits enzyme activity in concentration- and time-dependent manners (at 0.75 and 1.51 mmol from 12 to 72 h). There are two mechanisms for the inhibition process. Compound 1 first acts as a non-competitive inhibitor and then as an irreversible inhibitor. Changes of CK were not found in 10% SDS-PAGE, but the amount of dimeric CK decreased in 10% non-SDS gel. The results suggest that 1 can inhibit CK activity by degrading its dimeric structure.