Hepatic Expression of NTN4 and Its Receptors in Patients with Hepatocellular Carcinoma.

BACKGROUND: Angiogenesis contributes to hepatocellular carcinoma (HCC) progression by promoting tumor growth and metastasis. Netrin-4 (NTN4) is a secreted glycoprotein that has been reported to control angiogenesis and preserve endothelial homeostasis. Macrovascular invasion of the portal vein, referred to as portal vein invasion (PVI) is associated with poor prognosis in HCC patients. In this work, we sought to understand more about the systemic and hepatic level expression of NTN4 and its receptors in HCC patients with and without portal vein invasion. METHODS: A total of 154 patients with HCC, and 90 healthy volunteers were recruited in this case-control study. Patients with HCC were further subdivided into those with portal vein invasion (PVI) (n=68), and those without portal vein invasion (NPVI) (n=86). Clinical characteristics and liver function parameters were recorded among the study subjects PVI and NPVI. The serum levels of NTN4 (pg/ml) were estimated by ELISA. HCC tissues and normal non-tumorous liver tissues (controls) were collected for gene expression analysis of NTN4 and its receptors. RESULTS: ALT, ALP, and GGT levels were significantly elevated in the serum of HCC patients with PVI compared to NPVI and control subjects. Systemic NTN4 was significantly reduced in both PVI and NPVI patients compared to control subjects. At the tissue level, the hepatic NTN4 followed a similar trend with significantly lower mRNA expression in both patients with PVI and NPVI compared to control subjects. CONCLUSIONS: Systemic and hepatic NTN4 levels were reduced in both PVI and NPVI subjects. The hepatic expression of NTN4 receptors Neogenin and UNC5B were markedly elevated in patients with HCC with PVI compared to NPVI. Future experimental studies might shed the role of NTN4 and its receptors in the development of PVI in HCC.

Precision bound and optimal control in periodically modulated continuous quantum thermal machines.

We use Floquet formalism to study fluctuations in periodically modulated continuous quantum thermal machines. We present a generic theory for such machines, followed by specific examples of sinusoidal, optimal, and circular modulations, respectively. The thermodynamic uncertainty relations (TUR) hold for all modulations considered. Interestingly, in the case of sinusoidal modulation, the TUR ratio assumes a minimum at the heat engine to refrigerator transition point, while the chopped random basis optimization protocol allows us to keep the ratio small for a wide range of modulation frequencies. Furthermore, our numerical analysis suggests that TUR can show signatures of heat engine to refrigerator transition, for more generic modulation schemes. We also study bounds in fluctuations in the efficiencies of such machines; our results indicate that fluctuations in efficiencies are bounded from above for a refrigerator and from below for an engine. Overall, this study emphasizes the crucial role played by different modulation schemes in designing practical quantum thermal machines.

Floquet quantum thermal transistor.

We apply periodic control to realize a quantum thermal transistor, which we term as the Floquet quantum thermal transistor. Periodic modulation allows us to control the heat flows and achieve large amplification factors even for fixed bath temperatures. Importantly, this transistor effect persists in the cutoff region, where traditional quantum thermal transistors operating in the absence of periodic modulation, fail to act as viable heat modulation devices.

Bath Engineering Enhanced Quantum Critical Engines.

Driving a quantum system across quantum critical points leads to non-adiabatic excitations in the system. This in turn may adversely affect the functioning of a quantum machine which uses a quantum critical substance as its working medium. Here we propose a bath-engineered quantum engine (BEQE), in which we use the Kibble-Zurek mechanism and critical scaling laws to formulate a protocol for enhancing the performance of finite-time quantum engines operating close to quantum phase transitions. In the case of free fermionic systems, BEQE enables finite-time engines to outperform engines operating in the presence of shortcuts to adiabaticity, and even infinite-time engines under suitable conditions, thus showing the remarkable advantages offered by this technique. Open questions remain regarding the use of BEQE based on non-integrable models.

Many-body quantum thermal machines.

Thermodynamics of quantum systems and quantum thermal machines are rapidly developing fields, which have already delivered several promising results, as well as raised many intriguing questions. Many-body quantum machines present new opportunities stemming from many-body effects. At the same time, they pose new challenges related to many-body physics. In this short review we discuss some of the recent developments on technologies based on many-body quantum systems. We mainly focus on many-body effects in quantum thermal machines. We also briefly address the role played by many-body systems in the development of quantum batteries and quantum probes.

Phytosteroid 28-homobrassinolide targets cholesterol and glucose homeostasis implicating ABCA1 and SREBP role in regulation.

Oxysterols are natural ligands of certain nuclear receptors known as liver X receptors (LXR). LXRs are regulators of fatty acid, cholesterol, and glucose homeostasis. Dietary phyto-oxysterol 28-homobrassinolide (28-HB) has been demonstrated to transactivate rat LXR α and ß. In this study we assessed the potential of 28-HB to effect such changes in - (1) human HepG2 cancer cell line, (2) isolated perfused goat liver, and (3) high-fat diet-fed C57BL/6J mice. Serum and perfusate marker levels along with hexokinase activity were determined through enzyme assays. Fat deposition was studied by Oil Red O staining, ATP-binding cassette transporter (ABCA1), and sterol regulatory element-binding transcription factor 2 (SREBP2) protein expression by Western blot and their mRNA expression through real-time PCR. In HepG2 cells, 28-HB (5-20 µM) treatment indicated a 2-fold increase in glucose utilization and ABCA1 and SREBP2 protein expression within 12 h. Tissue glucose and cholesterol levels decreased in 28-HB perfused goat liver within 2 h, whereas cholesterol level increased 54% in the perfusate (p < 0.05) and tissue hexokinase activity increased 23% (p < 0.05). Glucokinase, ABCA1, and SREBF1 gene expression increased 2.6, 5.37, and 2.85 fold respectively in the perfused tissue after 4 h. High-fat diet-fed C57BL/6J mice when treated with 28-HB (1-20 µg/day) for 6 weeks exhibited a marked decrease in aortic fat deposit and serum marker levels. Our study suggests that 28-HB modulates cholesterol and glucose homeostasis in animal cells through activation of LXR involving ABCA1 and SREBP-1 and 2 augmentations.

Enhanced drug retention, sustained release, and anti-cancer potential of curcumin and indole-curcumin analog-loaded polysorbate 80-stabilizied PLGA nanoparticles in colon cancer cell line SW480.

The major therapeutic limitation of curcumin and indole-incorporated curcumin analog is its low bioavailability. We hypothesized that nano-encapsulation of indole-incorporated curcumin analog and curcumin as a biodegradable polymeric nanoparticle may enhance its bioavailability with extended drug retention time. Indole-incorporated curcumin analog and curcumin loaded PLGA nanoparticles were synthesized by solvent evaporation technique. Physicochemical characterizations and anti-cancer potential of the nanoparticles were evaluated in human colon cancer cell line SW480. The synthesized NPs had a size range of 50-150 nm diameter. The nano-formulation preserved the drug from degradation in wide ranges of pH environments. The nanoparticles treatment against SW480 cancer cell line triggered nuclear fragmentation, cell cycle blockade, inhibition of apoptosis and metastatic biomarkers. These drug-loaded nanoparticles may be potent nano-formulations against colon cancer because of its ability to tolerate extreme pH environments, thus having potential of oral drug-delivery.

Redox Nano-Architectures: Perspectives and Implications in Diagnosis and Treatment of Human Diseases.

SIGNIFICANCE: Efficient targeted therapy with minimal side-effects is the need of the hour. Locally altered redox state is observed in several human ailments, such as inflammation, sepsis, and cancer. This has been taken advantage of in designing redox-responsive nanodrug carriers. Redox-responsive nanosystems open a door to a multitude of possibilities for the control of diseases over other drug delivery systems. Recent Advances: The first-generation nanotherapy relies on novel properties of nanomaterials to shield the drug and deliver it to the diseased tissue or organ. The second generation is based on targeting the drug or diagnostic material to the diseased cell-specific receptors, or to a particular organ to improve the efficacy of the drug. The third and the latest generation of nanocarriers, the stimuli-responsive nanocarriers exploit the disease condition or environment to specifically deliver the drug or diagnostic probe for the best diagnosis and treatment. Several different kinds of stimuli such as temperature, magnetic field, pH, and altered redox state-responsive nanosystems have educed immense promise in the field of nanomedicine and therapy. CRITICAL ISSUES: We describe the evolution of nanomaterial since its inception with an emphasis on stimuli-responsive nanocarriers, especially redox-sensitive nanocarriers. Importantly, we discuss the future perspectives of redox-responsive nanocarriers and their implications. FUTURE DIRECTIONS: Redox-responsive nanocarriers achieve a near-to-zero premature release of the drug, thus avoiding off-site toxicity associated with the free drug. This bears great potential for the development of more effective drug delivery with better pharmacokinetics and pharmacodynamics.

Quantum engine efficiency bound beyond the second law of thermodynamics.

According to the second law, the efficiency of cyclic heat engines is limited by the Carnot bound that is attained by engines that operate between two thermal baths under the reversibility condition whereby the total entropy does not increase. Quantum engines operating between a thermal and a squeezed-thermal bath have been shown to surpass this bound. Yet, their maximum efficiency cannot be determined by the reversibility condition, which may yield an unachievable efficiency bound above unity. Here we identify the fraction of the exchanged energy between a quantum system and a bath that necessarily causes an entropy change and derive an inequality for this change. This inequality reveals an efficiency bound for quantum engines energised by a non-thermal bath. This bound does not imply reversibility, unless the two baths are thermal. It cannot be solely deduced from the laws of thermodynamics.

In-silico and in-vitro anti-cancer potential of a curcumin analogue (1E, 6E)-1, 7-di (1H-indol-3-yl) hepta-1, 6-diene-3, 5-dione.

PURPOSE: Previously we showed that BDMC, an analogue of curcumin suppresses growth of human breast and laryngeal cancer cell line by causing apoptosis. Here, we demonstrate the enhanced anti-cancer activity of a heterocyclic ring (indole) incorporated curcumin analogue ((1E, 6E)-1, 7-di (1H-indol-3-yl) hepta-1, 6-diene-3, 5-Dione), ICA in short, in comparison to curcumin. METHOD: ICA was synthesized by a one pot condensation reaction. Anti-cancer potential of ICA was assessed in three human cancer cell lines of different origin (Lung adenocarcinoma (A549), leukemia (K562) and colon cancer (SW480)) by MTT assay. Mode of cell death was determined by acridine orange-ethidium bromide (Ao-Eb) staining. Putative cellular targets of ICA were investigated by molecular docking studies. Cell cycle analysis following curcumin or ICA treatment in SW480 cell line was carried out by flow cytometry. Expression levels of Cyclin D1 and apoptotic markers, such as Caspase 3, 8 and 9 were studied by western blot analysis in SW480 cell line treated with or without ICA and curcumin. RESULTS: The yield of ICA synthesis was found to be 69% with a purity of 98%. ICA demonstrated promising anti-cancer activity compared to curcumin alone, as discerned by MTT assay. ICA was non-toxic to the cell line of normal origin. We further observed that ICA is ∼2 fold more potent than curcumin in inhibiting the growth of SW480 cells. Ao-Eb staining revealed that ICA could induce apoptosis in all the cell lines tested. Molecular docking studies suggest that ICA may possibly exhibit its anticancer effect by inhibiting EGFR in A549, Bcr-Abl in K562 and GSK-3ß kinase in SW480 cell line. Moreover, ICA showed strong binding avidity for Bcl-2 protein in silico, which could result in induction of apoptosis. Cell cycle analysis revealed that both curcumin and ICA induced concomitant cell cycle arrest at G0/G1 and G2/M phase. Western blot shows that ICA could effectively down regulate the expression of cell cycle protein cyclin D1, while promoting the activation of Caspase 3, 8 and 9 when compared to curcumin in human colon cancer cell line SW480. CONCLUSION: The result of this study indicates that ICA could hold promise to be a potential anti-cancer agent. Since ICA has shown encouraging results in terms of its anti-cancer activity compared to curcumin, further research is necessary to fully delineate the underlying molecular mechanism of its anticancer potential.

A plant oxysterol, 28-homobrassinolide binds HMGCoA reductase catalytic cleft: stereoselective avidity affects enzyme function.

Understanding the influence of ubiquitously present plant steroids on mammalian cell biology is currently of interest. Feedback inhibition of HMGCoA reductase (HMGCR) catalytic activity in the transformation of HMG-CoA to mevalonate is a significant regulatory step in sterol biosynthetic pathway. To assess the role of dietary steroids in this biochemical transformation, the phytosteroid isoform 28-homobrassinolide (28-HB), 90 % pure, obtained from Godrej Agrovet (India) was used to determine its effect on mammalian HMG-CoA reductase. Photometric assay of pure human and select rat tissue HMGCR post 28-HB oral feed, PCR-HMGCR gene expression, and in silico docking of 28-HB and HMGCoA on HMGCR protein template were carried out. Using an oral feed regimen of pure 28-HB, we noted a decrease of 16 % in liver, 17.1 % in kidney and 9.3 % in testicular HMGCR enzyme activity, 25 % in HMGCR gene expression and 44 % in the activity of pure human HMGCR due to this plant oxysterol. In silico docking studies yielded binding metrics for 28-HB-HMGCR lower than for HMGCoA-HMGCR, indicating stronger binding of HMGCR by this ligand. 28-HB exerts differential effects on rat tissue HMGCR, down regulates liver HMGCR gene expression and significantly inhibits HMGCR activity.