Hypothesis: ubiquitous circadian disruption can cause cancer

Abstract

Circadian disruption (CD) was implicated in chains of cancer causation when the International Agency for Research on Cancer classified shift-work involving circadian disruption as probably carcinogenic in 2007. In the following decade, epidemiological studies into causal concepts associated with circadian disruption were inconclusive. Unappreciated complexity with an exclusive focus on shift-work, light-at-night, sleep, and melatonin in regard to circadian disruption may be accountable. With compelling non-epidemiological evidence, we posit that ubiquitous circadian disruption causes cancer and, moreover, that this is unexplored epidemiologically. This hypothesis offers a novel explanation why numerous studies in shift-workers evince inconsistent results: If circadian disruption is a ubiquitous causal phenomenon, confining assessments to the workplace, ignoring circadian disruption at play, and potential misclassification of 'who' is 'when' and 'how much' exposed to circadian disruption may disallow detecting the existence and magnitude of cancer risks. The rationale herein provides plausible explanations for previous observations and makes falsifiable predictions.

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The Apgar paradox

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Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model

Abstract

Immune checkpoint inhibitors are currently tested in different combinations in patients with advanced hepatocellular carcinoma (HCC). Nivolumab, an anti-PD-1 agent, has gained approval in the second-line setting in the USA. Epigenetic drugs have immune-mediated antitumor effects that may improve the activity of immunotherapy agents. Our aim was to study the therapeutic efficacy of checkpoint inhibitors (anti-CTLA-4 and anti-PD-1 antibodies) in combination with the histone deacetylase inhibitor (HDACi) Belinostat. In a subcutaneous Hepa129 murine HCC model, we demonstrated that Belinostat improves the antitumor activity of anti-CTLA-4 but not of anti-PD-1 therapy. This effect correlated with enhanced IFN-γ production by antitumor T-cells and a decrease in regulatory T-cells. Moreover, the combination induced early upregulation of PD-L1 on tumor antigen-presenting cells and late expression of PD-1 on tumor-infiltrating effector T-cells, suggesting the suitability of PD-1 blockade. Indeed, Belinostat combined with the simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection. These results provide a rationale for testing Belinostat in combination with checkpoint inhibitors to enhance their therapeutic activity in patients with HCC.

https://ift.tt/2LfeXf1

Magnetic Regulation of Thermo‐Chemotherapy from a Cucurbit[7]uril‐Crosslinked Hybrid Hydrogel

This work presents a noncovalent‐bonded hydrogel network, which is assembled by utilizing cucurbit[7]uril as a supramolecular linker to "stick" superparamagnetic γ‐Fe₂O₃ nanoparticles onto catechol‐functionalized chitosan. Cucurbit[7]uril not only facilitates host‐guest recognition with the catechol derivatives, but also forms robust electrostatic interactions with the γ‐Fe₂O₃ nanoparticles, endowing the formed hybrid hydrogel with both thermo‐ and chemotherapy modalities under an alternating magnetic field.

Abstract

The fabrication, characterization, and therapy efficiency of a noncovalent‐bonded hydrogel network, which is assembled by utilizing cucurbit[7]uril as a supramolecular linker to "stick" superparamagnetic γ‐Fe₂O₃ nanoparticles onto the polymer backbone of catechol‐functionalized chitosan are described. The unique barrel‐shaped structure of cucurbit[7]uril not only facilitates host–guest recognition with the catechol derivatives, but also forms robust electrostatic interactions between its carbonyl portals and the γ‐Fe₂O₃ nanoparticles in a supramolecular manner, which leaves the physical and chemical properties of the nanoparticles intact. The γ‐Fe₂O₃ nanoparticles display vibrational movement and heat generation under an alternating magnetic field, endowing the formed hybrid supramolecular hydrogel with both thermo‐ and chemotherapy modalities, which are demonstrated both in vitro and in vivo. Here, a facile strategy is introduced to construct noncovalent interactions between a polymer matrix and the incorporated nanoparticles, which is amendable to a wide range of biomedical and industrial applications.

https://ift.tt/2QvhOGe

Strategies of Combination Drug Delivery for Immune Checkpoint Blockades

To address low objective response rate of immune checkpoint blockade (ICB) therapy, combination strategies are vastly explored and recommended. This review introduces recent advances in combination of ICB therapy with therapeutic agents based on stimulation of the five steps in the context of the cancer immunity circle (antigen release, tumor antigen presentation, T‐cell activation, recognition of tumor by T‐cells, and tumor‐killing activity).

Abstract

The past few years have witnessed vast clinical accomplishments of immune checkpoint blockades (ICB), which block the regulatory receptor expressed on immune cells or tumor cells to prevent the suppression of antitumor cytotoxic T‐cell responses. Despite this, limitations still exist, such as low objective response rate (ORR) and the risk of immune‐related side effects. To address these issues, combination treatment strategies are vastly explored and recommended. This review summarizes recent advances in combination of ICB with therapies that participate in different stages of cancer immune cycle, including tumor antigen release, tumor antigen presentation, T‐cell activation, recognition of cancer cells by T‐cells, and tumor‐killing activity. Challenges and potential opportunities of combination approaches in this field are also discussed.

https://ift.tt/2RWMwF8

ShenShuai II Recipe Attenuates Apoptosis and Renal Fibrosis in Chronic Kidney Disease by Increasing Renal Blood Flow and Improving Oxygen Consumption

Background. Hypoxia plays a significant role in the progression of chronic kidney disease (CKD) and renal fibrosis. In China, Chinese herbal medicine has been widely used to treat CKD. ShenShuai II Recipe (SSR) is a commonly used prescription which has shown good results against CKD. However, the exact mechanisms of SSR are still unknown. In this study, chronic renal failure (CRF) was induced in rats by the 5/6 renal ablation/infarction (A/I) surgery; we investigated the efficacy and mechanisms of SSR on CKD in the current study. Male Sprague-Dawley (SD) rats were divided into the four groups: (1) sham operation group, (2) 5/6 (A/I) model group, (3) 5/6 (A/I) +SSR group, and (4) 5/6 (A/I) +Losartan group (5/6 (A/I) +Los). After 8 weeks of treatment, we evaluated renal blood flow (RBF) and oxygen consumption along with renal function, apoptosis, and renal fibrosis. Our results showed that SSR significantly improved RBF and reduced intrarenal oxygen consumption and apoptosis. Moreover, SSR markedly attenuated interstitial fibrosis, accompanied by decreased levels of serum creatinine (Scr), serum uric acid (UA), increased hemoglobin (HB), and evaluated glomerular filtration rates (eGFRs). These results suggest that SSR could mediate renal protection by improving intrarenal hypoxia and, furthermore, participate in the antiapoptotic effects by downregulating apoptosis markers (cleaved caspase-3 and the ratio of Bax/Bcl2) in 5/6 (A/I) model with CRF rats.

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Mulberry Fruit Extract Ameliorates Nonalcoholic Fatty Liver Disease (NAFLD) through Inhibition of Mitochondrial Oxidative Stress in Rats

Mulberry is known to have pharmacological effects against cholesterol, obesity, and dyslipidemia. Many studies have revealed that mulberry leaf possesses hepatoprotective properties against nonalcoholic fatty liver disease (NAFLD); however, mulberry fruit is less studied in this context. Therefore, this study aimed to investigate the preventive effects of mulberry fruit against high fat diet- (HFD-) induced NAFLD. To evaluate the effects of mulberry fruit on NAFLD, two doses of mulberry fruit ethanol extracts [MB, 100, and 200 mg/kg BW (body weight)] were given to HFD-fed rats for 10 weeks. MB dramatically prevented liver damage as shown by biochemical analysis of the liver injury markers, alanine transaminase, and aspartate transaminase. MB treatment significantly inhibited the increased levels of total cholesterol, triacylglycerol, and low-density lipoprotein-cholesterol but restored the level of high-density lipoprotein-cholesterol in HFD-fed rats. Notably, histological analysis of liver tissues demonstrated that MB substantially ameliorated lipid accumulation. Expression of cholesterol-regulating genes was also suppressed by MB treatment. For its underlying mechanisms, MB suppressed hepatic reactive oxygen species (ROS) overproduction and mitochondrial oxidative stress in HFD-fed rats. MB potentially protects liver tissue against NAFLD by inhibition of mitochondrial oxidative stress, suggesting its possible use as a therapeutic agent for treatment of NAFLD.

https://ift.tt/2RWYdeK