Micromechanical origin of heat transfer to granular flow.

Heat transfer across a granular flow is comprised of two resistances in series : near the wall and within the bulk particle bed, neither of which is well understood due to the lack of experimental probes to separate their respective contribution. Here, we use a frequency modulated photothermal technique to separately quantify the thermal resistances in the near-wall and the bulk bed regions of particles in flowing states. Compared to the stationary state, the flowing leads to a higher near-wall resistance and a lower thermal conductivity of bulk beds. Coupled with discrete element method simulation, we show that the near-wall resistance can be explained by particle diffusion in granular flows.

Ceramic-to-metal bonding using rare-earth containing Sn-Bi solder.

With the increasing miniaturization and power of optoelectronic devices, direct bonding of optical substrates like semiconductors and ceramics to metal heat sinks using low melting-point solder has gained significant interest. In this study, we demonstrated the bonding of glass to copper using Sn-58 wt% Bi solder (SB solder) doped with a small amount of rare earth (RE) elements. The RE elements act as active agents that facilitate the bonding to glasses without glass metallization. By optimizing the bonding parameters, such as reflow temperature and time, and employing an inert gas atmosphere to prevent solder or RE oxidation, we successfully achieved the highest shear strength in glass-copper solder joints using SB-RE solder, without the need for ultrasonic-assisted soldering (UAS). These results demonstrate the potential of using RE-containing solder for bonding unmetallized glass and ceramics in optoelectronic devices with metals at low soldering temperatures (< 200 °C). Furthermore, analysis of the shear strength and failure morphology of solder joints revealed only small degradation, primarily originating from the bulk solder region rather than the solder-glass interface, after both thermal aging (100 h) and cycling tests (100 cycles). The establishment of low-melting point RE-containing solders opens the possibility of direct jointing ceramic optoelectronic substrates to metal heat sinks for more efficient heat dissipation. In the meantime, our work also suggests that further optimization studies are necessary to explore its performance under more extreme working conditions.

Adipose-targeted triiodothyronine therapy counteracts obesity-related metabolic complications and atherosclerosis with negligible side effects.

Thyroid hormone (TH) is a thermogenic activator with anti-obesity potential. However, systemic TH administration has no obvious clinical benefits on weight reduction. Herein we selectively delivered triiodothyronine (T3) to adipose tissues by encapsulating T3 in liposomes modified with an adipose homing peptide (PLT3). Systemic T3 administration failed to promote thermogenesis in brown and white adipose tissues (WAT) due to a feedback suppression of sympathetic innervation. PLT3 therapy effectively obviated this feedback suppression on adrenergic inputs, and potently induced browning and thermogenesis of WAT, leading to alleviation of obesity, glucose intolerance, insulin resistance, and fatty liver in obese mice. Furthermore, PLT3 was much more effective than systemic T3 therapy in reducing hypercholesterolemia and atherosclerosis in apoE-deficient mice. These findings uncover WAT as a viable target mediating the therapeutic benefits of TH and provide a safe and efficient therapeutic strategy for obesity and its complications by delivering TH to adipose tissue.

Probing the Phase Transition during the Formation of Lithium Lanthanum Zirconium Oxide Solid Electrolyte.

Lithium lanthanum zirconium oxide (LLZO) has long been considered as a promising solid electrolyte for all-solid-state lithium (Li) metal batteries because of its interfacial stability when coupled with a Li metal anode. However, the cubic phase of LLZO (c-LLZO) with a higher Li-ion conductivity has a complex atomic structure and is subject to complicated phase transition during its processing and working conditions, which remain largely elusive. Here, we reveal the phase transition process during the formation of c-LLZO nanotubes through detailed microscopic characterization by scanning and transmission electron microscopy as well as X-ray diffraction. We find four typical stages during the formation of c-LLZO along with several intermediate phases including lanthanum (La)-rich cubic lanthanum zirconium oxide (La-rich c-LZO), c-LZO, and La-rich c-LLZO. We also reveal the role of m-Li2CO3 and h-Li2O2 as the "phase mediator".

Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2.

Adipose tissue macrophage (ATM) inflammation is involved with meta-inflammation and pathology of metabolic complications. Here we report that in adipocytes, elevated lactate production, previously regarded as the waste product of glycolysis, serves as a danger signal to promote ATM polarization to an inflammatory state in the context of obesity. Adipocyte-selective deletion of lactate dehydrogenase A (Ldha), the enzyme converting pyruvate to lactate, protects mice from obesity-associated glucose intolerance and insulin resistance, accompanied by a lower percentage of inflammatory ATM and reduced production of pro-inflammatory cytokines such as interleukin 1ß (IL-1ß). Mechanistically, lactate, at its physiological concentration, fosters the activation of inflammatory macrophages by directly binding to the catalytic domain of prolyl hydroxylase domain-containing 2 (PHD2) in a competitive manner with α-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1α). Lactate-induced IL-1ß was abolished in PHD2-deficient macrophages. Human adipose lactate level is positively linked with local inflammatory features and insulin resistance index independent of the body mass index (BMI). Our study shows a critical function of adipocyte-derived lactate in promoting the pro-inflammatory microenvironment in adipose and identifies PHD2 as a direct sensor of lactate, which functions to connect chronic inflammation and energy metabolism.

Hepatic CPT1A Facilitates Liver-Adipose Cross-Talk via Induction of FGF21 in Mice.

BACKGROUND & AIMS: Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Cpt1a knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism. APPROACH & RESULTS: Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. CONCLUSIONS: Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.

Hepatic CPT1A Facilitates Liver-Adipose Cross-Talk via Induction of FGF21 in Mice.

BACKGROUND & AIMS: Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Cpt1a knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism. APPROACH & RESULTS: Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. CONCLUSIONS: Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.

Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation.

Persistent, unresolved inflammation in adipose tissue is a major contributor to obesity-associated metabolic complications. However, the molecular links between lipid-overloaded adipocytes and inflammatory immune cells in obese adipose tissues remain elusive. Here we identified adipocyte-secreted microRNA-34a (miR-34a) as a key mediator through its paracrine actions on adipose-resident macrophages. The expression of miR-34a in adipose tissues was progressively increased with the development of dietary obesity. Adipose-selective or adipocyte-specific miR-34a-KO mice were resistant to obesity-induced glucose intolerance, insulin resistance, and systemic inflammation, and this was accompanied by a significant shift in polarization of adipose-resident macrophages from proinflammatory M1 to antiinflammatory M2 phenotype. Mechanistically, mature adipocyte-secreted exosomes transported miR-34a into macrophages, thereby suppressing M2 polarization by repressing the expression of Krüppel-like factor 4 (Klf4). The suppressive effects of miR-34a on M2 polarization and its stimulation of inflammatory responses were reversed by ectopic expression of Klf4 in both bone marrow-derived macrophages and adipose depots of obese mice. Furthermore, increased miR-34a expression in visceral fat of overweight/obese subjects correlated negatively with reduced Klf4 expression, but positively with the parameters of insulin resistance and metabolic inflammation. In summary, miR-34a was a key component of adipocyte-secreted exosomal vesicles that transmitted the signal of nutrient overload to the adipose-resident macrophages for exacerbation of obesity-induced systemic inflammation and metabolic dysregulation.

Reproductive toxicity of brazilein in ICR mice.

Brazilein is an active small molecular compound extracted from Caesalpinia sappan L. with favorable pharmacological properties on immune system, cardiovascular system, and nervous system. C. sappan has been used as a traditional medicine in China for hundreds of years for various diseases. However, the general reproductive toxicity of brazilein is still unknown. The purpose of the present study was to thoroughly evaluate the general reproductive toxicity of brazilein in ICR mice to support the future drug development and modernization of this potent traditional Chinese medicine. The results showed that, although no apparent toxicity on the reproducibility of the male was observed, brazilein might cause considerable risks to the fetuses and females as indicated by the ratios of dead fetuses and reabsorptions. In conclusion, our results from the present study provided some useful insights about the safety profile of brazilein, suggesting that brazilein should be used with caution in pregnant women.

A Photo-Triggered Traceless Staudinger-Bertozzi Ligation Reaction.

The use of light to control the course of a chemical/biochemical reaction is an attractive idea because of its ease of administration with high precision and fine spatial resolution. Staudinger ligation is one of the commonly adopted conjugation processes that involve a spontaneous reaction between azides and arylphosphines to form iminophosphoranes, which further hydrolyze to give stable amides. We designed an anthracenylmethyl diphenylphosphinothioester (1) that showed promising Staudinger ligation reactivity upon photo-excitation. Broadband photolysis at 360-400 nm in aqueous organic solvents induced heterolytic cleavage of its anthracenylmethyl-phosphorus bond, releasing a diphenylphosphinothioester (2) as an efficient traceless Staudinger-Bertozzi ligation reagent. The quantum yield of such a photo-induced heterolytic bond-cleavage at the optimal wavelength of photolysis (376 nm) at room temperature is ≥0.07. This work demonstrated the feasibility of photocaging arylphosphines to realize the photo-triggering of the Staudinger ligation reaction.

The FGF21-adiponectin axis in controlling energy and vascular homeostasis.

Whole-body energy metabolism and cardiovascular homeostasis are tightly controlled processes that involve highly coordinated crosstalk among distal organs. This is mainly achieved by a large number of hormones released from each organ. Among them, fibroblast growth factor 21 (FGF21) and adiponectin have recently gained considerable attention, since both of them possess multiple profound protective effects against a myriad of cardio-metabolic disorders. Despite their distinct structures and production sites, these two hormones share striking functional similarity. This dichotomy is recently reconciled by the demonstration of the FGF21-adiponectin axis. In adipocytes, both transcription and secretion of adiponectin are strongly induced by FGF21, which is partially dependent on PPARγ activity. Furthermore, the glucose-lowering, lipid-clearing, and anti-atherosclerotic functions of FGF21 are diminished in adiponectin-null mice, suggesting that adiponectin serves as an obligatory mediator of FGF21-elicited metabolic and vascular benefits. However, in both animals and human subjects with obesity, circulating FGF21 levels are increased whereas plasma adiponectin concentrations are reduced, perhaps due to FGF21 resistance, suggesting that dysfunctional FGF21-adiponectin axis is an important contributor to the pathogenesis of obesity-related cardio-metabolic syndrome. The FGF21-adiponectin axis protects against a cluster of cardio-metabolic disorders via mediating multi-organ communications, and is a promising target for therapeutic interventions of these chronic diseases.

TATA boxes in gene transcription and poly (A) tails in mRNA stability: New perspective on the effects of berberine.

Berberine (BBR) is a natural compound with variable pharmacological effects and a broad panel of target genes. We investigated berberine's pharmacological activities from the perspective of its nucleotide-binding ability and discovered that BBR directly regulates gene expression by targeting TATA boxes in transcriptional regulatory regions as well as the poly adenine (poly (A)) tail at the mRNA terminus. BBR inhibits gene transcription by binding the TATA boxes in the transcriptional regulatory region, but it promotes higher levels of expression by targeting the poly (A) tails of mRNAs. The present study demonstrates that TATA boxes and poly (A) tails are the first and second primary targets by which BBR regulates gene expression. The final outcome of gene regulation by BBR depends on the structure of the individual gene. This is the first study to reveal that TATA boxes and poly (A) tails are direct targets for BBR in its regulation of gene expression. Our findings provide a novel explanation for the complex activities of a small molecule compound in a biological system and a novel horizon for small molecule-compound pharmacological studies.

Charge-conversional zwitterionic copolymer as pH-sensitive shielding system for effective tumor treatment.

A novel pH-responsive gene delivery system for tumor acidity-targeted pDNA delivery is prepared by introducing a rapid charge-conversional zwitterionic copolymer to the positive surface of PEI/pDNA complexes through electrostatic interaction. The shielding system (OEAL) consists of oligoethylenimine (OEI), poly(l-aspartate) (PBLA), and poly(l-lysine) (PLL). The charge-conversional behavior of the OEAL/PEI/DNA ternary complex is evaluated by zeta potential assay. The surface charges of the complexes can change from negative to positive in the pH range of 7.4-6.8. Under a simulative in vivo environment, OEAL/PEI/DNA exhibits promotion of cellular uptake by tumor cells and enhanced gene transfection efficiency because of its good charge-conversional properties. Antitumor experiments further show that the pH-responsive charge-conversional system can mediate a therapeutic gene that can induce tumor apoptosis (pKH3-rev-casp-3) to achieve effective tumor inhibition. Accordingly, OEAL can be regarded as a promising tumor microenvironment-sensitive gene delivery shielding system for antitumor therapy. STATEMENT OF SIGNIFICANCE: This manuscript focused on the novel pH-responsive gene delivery system for tumor acidity-targeted pDNA delivery. The novel system is prepared by introducing a rapid charge-conversional zwitterionic copolymer, consisting of oligoethylenimine, poly(l-aspartate) and poly(l-lysine), to the positive surface of PEI/pDNA complexes. The surface charges of the complexes can change from negative to positive from pH 7.4 to 6.8. OEAL/PEI/DNA shows promoting cellular uptake by tumor cells and enhanced gene transfection efficiency. The antitumor experiments further show that the pH responsive charge conversional system can mediate pKH3-rev-casp-3 to achieve effective tumor inhibition. Accordingly, OEAL can be regarded as a promising tumor microenvironment sensitive gene delivery shielding system for antitumor therapy.

Adiponectin Enhances Cold-Induced Browning of Subcutaneous Adipose Tissue via Promoting M2 Macrophage Proliferation.

Adiponectin is an abundant adipokine with pleiotropic protective effects against a cluster of obesity-related cardiometabolic disorders. However, its role in adaptive thermogenesis has scarcely been explored. Here we showed that chronic cold exposure led to a markedly elevated production of adiponectin in adipocytes of subcutaneous white adipose tissue (scWAT), which in turn bound to M2 macrophages in the stromal vascular fraction. Chronic cold exposure-induced accumulation of M2 macrophages, activation of beige cells, and thermogenic program were markedly impaired in scWAT of adiponectin knockout (ADN KO) mice, whereas these impairments were reversed by replenishment with adiponectin. Mechanistically, adiponectin was recruited to the cell surface of M2 macrophages via its binding partner T-cadherin and promoted the cell proliferation by activation of Akt, consequently leading to beige cell activation. These findings uncover adiponectin as a key efferent signal for cold-induced adaptive thermogenesis by mediating the crosstalk between adipocytes and M2 macrophages in scWAT.

Transportation of berberine into HepG2, HeLa and SY5Y cells: a correlation to its anti-cancer effect.

The anti-cancer activities of berberine (BBR) have been reported extensively in various cancer cell lines. However, the minimal inhibitory concentrations of BBR varied greatly among different cell lines and very few studies have been devoted to elucidate this aspect. In this study, we employed three cancer cell lines, HepG2, HeLa and SY5Y, to compare the transportation and distribution of BBR. HPLC results demonstrated that BBR was capable of penetrating all the cell lines whereas the cumulative concentrations were significantly different. HepG2 cells accumulated higher level of BBR for longer duration than the other two cell lines. Molecular docking studies revealed the BBR binding site on P-glycoprotein 1 (P-gp). In addition, we elucidated that BBR regulated P-gp at both mRNA and protein levels. BBR induced the transcription and translation of P-gp in HeLa and SY5Y cells, whereas BBR inhibited P-gp expression in HepG2 cells. Further study showed that BBR regulates P-gp expression depending on different mechanisms (or affected by different factors) in different cell lines. To summarize, our study has revealed several mechanistic aspects of BBR regulation on P-gp in different cancer cell lines and might shed some useful insights into the use of BBR in the anti-cancer drug development.

Synergistic co-delivery of doxorubicin and paclitaxel by porous PLGA microspheres for pulmonary inhalation treatment.

PLGA porous microspheres loaded with doxorubicin (DOX) and paclitaxel (PTX) were developed for in situ treatment of metastatic lung cancer. The synergistic effect of the combined drugs was investigated against B16F10 cells to obtain the optimal prescription for in vivo studies. The combination therapy showed great synergism when DOX was the majority in the combination therapy, while they showed moderate antagonism when PTX is in major. The combination of DOX and PTX at a molar ratio of 5/1 showed the best synergistic therapeutic effect in the free form. However, the drugs exhibited more synergism in the PLGA microspheres at a molar ratio of 2/1, due to the difference in drug release rate. The in vivo study verified the synergism of DOX and PTX at the optimal molar ratio. These results suggested that dual encapsulation of DOX and PTX in porous PLGA microspheres would be a promising technology for long effective lung cancer treatment.

Transport and metabolism behavior of brazilein during its entrance into neural cells.

Brazilein, a natural small molecule, shows a variety of pharmacological activities, especially on nervous system and immune system. As a potential multifunctional drug, we studied the distribution and the transport behavior and metabolic behavior of brazilein in vivo and in vitro. Brazilein was found to be able to distribute in the mouse brain and transport into neural cells. A metabolite was found in the brain and in the cells. Positive and negative mode-MS/MS and Q-TOF were used to identify the metabolite. MS/MS fragmentation mechanisms showed the methylation occurred at the 10-hydroxyl of brazilein (10-O-methylbrazilein). Further, catechol-O- methyltransferase (COMT) was confirmed as a crucial enzyme correlated with the methylated metabolite generation by molecular docking and pharmacological experiment.

[Understanding differences between Rheum palmatum and R. franzenbachii from perspective of chemistry, efficacy and toxicity].

Rheum franzenbachii (called Tudahuang in local) has some similarities with R. palmatum (rhubarb) collected by "China Pharmacopoeia" and is often used as a substitute of rhubarb. Can Tudahuang simply replace rhubarb in the application or whether is there difference between Tudahuang and rhubarb, and what is the difference it is important to verify the difference and understand its proper application in the field of clinical practice. In this paper, we discussed the differences of the two herbs from the views of chemistry, efficacy and toxicity based on the author's previous research work as well as literatures, by using the major role of the rhubarb "diarrhea" as the basic point. The analysis result showed that the role of diarrhea Tudahuang was much weaker than that of rhubarb. The reason lies in the difference between the contents of combined anthraquinones component. While acute toxicity in mice of Tudahuang is stronger than that of rhubarb. Thus, Tudahuang should not simply replace rhubarb in practice.