The Role of Autophagy in the Progression and Treatment of Tumors

Autophagy is a conserved homeostatic mechanism enabling cells to cope with various stresses. The pathways leading up to the activation of autophagy are interconnected with those of tumorigenesis. However, the relationship between the two events is not a straightforward one and very often context-dependent. Generally, autophagy appears to act against the tumor during the initiation stage and most often drives cancer progression subsequently. Published clinical trials for the treatment of various tumors, where autophagy was pharmacologically inhibited, were obtained and tabulated. Targeting autophagy for the treatment of tumors can be rewarding in the appropriate context, such as cancer type, grade, and microenvironment.

Metaplasticity in the human swallowing system: clinical implications for dysphagia rehabilitation

Dysphagia is a common and devastating complication following brain damage. Over the last 2 decades, dysphagia treatments have shifted from compensatory to rehabilitative strategies that facilitate neuroplasticity, which is the reorganization of neural networks that is essential for functional recovery. Moreover, there is growing interest in the application of cortical and peripheral neurostimulation to promote such neuroplasticity. Despite some preliminary positive findings, the variability in responsiveness toward these treatments remains substantial. The purpose of this review is to summarize findings on the effects of neurostimulation in promoting neuroplasticity for dysphagia rehabilitation and highlight the need to develop more effective treatment strategies. We then discuss the role of metaplasticity, a homeostatic mechanism of the brain to regulate plasticity changes, in helping to drive neurorehabilitation. Finally, a hypothesis on how metaplasticity could be applied in dysphagia rehabilitation to enhance treatment outcomes is proposed.

Curcumin: A Systematic Review

Many pharmacologically active compounds can be found in medicinal plants. Phytochemicals are currently being studied by scientists to treat a variety of human illnesses. Turmeric (Curcuma longa), a rhizomatous perennial plant in the Zingiberaceae family, is widely used as a food ingredient and in traditional medicine to cure a variety of diseases. Anti-inflammatory, antifungal, anti-angiogenesis, virucidal, anti-mutagenic, and antioxidant activities are all present in it. Angiogenesis, or the formation of new blood vessels, is an important homeostatic mechanism that controls vascular populations in response to physiological and pathological demands, such as chronic inflammation and cancer. Curcumin, a natural polyphenol compound has an activity to inhibit angiogenesis by suppressing tumor neovasculature formation. This study aims to investigate the anti-angiogenesis effect of curcumin.

G4-Selective Ligand Induced Autophagy

G-quadruplex (G4) structures have emerged as singular therapeutic targets for cancer and neurodegeneration. Autophagy is a housekeeping cellular homeostatic mechanism and deregulation of autophagy is common in cancer and in neurodegenerative diseases. In this study, we identified the presence of 46 putative G4 sequences in the MTOR gene by use of QGRS mapper tool. We sought to connect these putative G4 sequences to a functional context by leveraging G4-targeting ligands. A G4-selective dimeric carbocyanine dye Bis-4,3 and the porphyrin TMPyP4 were used to affect the replication, transcription and translation of the MTOR gene. The ligand-induced induction of autophagic pathway via MTOR gene regulation was monitored upon treatment of HeLa and SHSY-5Y cells with G4-targeting ligands. The use of Bis-4,3 was compared with the known G4-stabilizing activity of TMPyP4. Our results show that treatment with G4-selective ligands downregulates mTOR activity and leads to the induction of excessive autophagy. This is first report on effect of G4-selective ligands on MTOR regulation and mTOR expression. mTOR being the key negative regulator of autophagy, the current work suggests potential of G4 stabilizing ligands towards induction of autophagy through the downregulation of mTOR.

Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults, with a poor median survival of approximately 15 months after diagnosis. Despite several decades of intensive research on its cancer biology, treatment for GBM remains a challenge. Autophagy, a fundamental homeostatic mechanism, is responsible for degrading and recycling damaged or defective cellular components. It plays a paradoxical role in GBM by either promoting or suppressing tumor growth depending on the cellular context. A thorough understanding of autophagy’s pleiotropic roles is needed to develop potential therapeutic strategies for GBM. In this paper, we discussed molecular mechanisms and biphasic functions of autophagy in gliomagenesis. We also provided a summary of treatments for GBM, emphasizing the importance of autophagy as a promising molecular target for treating GBM.

Progesterone Might Be an Active Component of the Sleep-Wake Homeostatic Mechanism

Background: Using a randomized, double blind, placebo-controlled, crossover protocol, we have shown previously that progesterone may prevent sleep disturbances but has no action on undisturbed sleep. In that study, 8 healthy postmenopausal women took daily at 2300 h for 3 wk a capsule of either 300 mg of progesterone or placebo. Sleep was polygraphically recorded during the last two nights and, during the second night, blood samples were collected at 15-min intervals using an iv catheter,. During the first night, sleep was normal under placebo and progesterone had no effect. During the second night, blood sampling procedure was associated under placebo with marked sleep disturbances, which were considerably reduced under progesterone: at the group level, mean ± SEM duration of wake after sleep onset (WASO) dropped from 152 ± 37 min to 71 ± 19 min (P = 0.01), and slow-wave sleep (SWS) duration increased from 53 ± 6 min to 79 ± 10 min (P = 0.04). Objective: To submit individual data collected in that study to new analyses designed to further investigate possible mechanism(s) of progesterone actions on sleep architecture. Results: Among individual subjects, no relation could be evidenced between progesterone levels and sleep variables, or between individual progesterone-associated improvements and absolute values of corresponding sleep variables under placebo. By contrast, for WASO and SWS, significant positive correlations (Spearman test) were evidenced between individual responses to progesterone (i.e. the difference, during night 2, between value under progesterone and value under placebo) and corresponding individual alterations caused under placebo by the blood sampling procedure (i.e. the difference, under placebo, between value during night 1 and value during night 2): WASO: rs = 0.74, P = 0.037, n = 8; SWS: rs = 0.86, P = 0.014, n = 7. (Pearson test yielded similar results: WASO: r = 0.85, P = 0.008; SWS: r = 0.76, P = 0.047). Conclusions: Although they obviously need to be confirmed by larger studies performed in a variety of clinical conditions, the present findings suggest that progesterone action on sleep architecture is specifically tailored to restore individual normality rather than group normality. Since SWS is mainly regulated by the sleep-wake homeostatic mechanism relating sleep pressure to the duration of prior wakefulness, it is tempting to speculate that progesterone might be an active component of this mechanism.

Asymmetric crypt fission in colectomy specimens in patients with ulcerative colitis

AimsWe previously found colonic crypts with asymmetric fission bordering regenerating ulcers in ulcerative colitis (UC). The present objective was to assess the frequency of asymmetric crypt-fission in colectomy specimens from patients with long-lasting UC.MethodsH&E-stained sections from seven colectomies from patients with UC without dysplasia or carcinoma were investigated. Symmetric fission was characterised by branched colon crypts showing ≥2 identical crypts, whereas asymmetric fission exhibited branched colon crypt portraying ≥2 dissimilar crypts, differing in diameter, length and/or shape.ResultsThe number of crypts in fission in the 89 sections was 3586; of those, 2930 (81.7%) were asymmetric and the remaining 656 (18.3%), symmetric. Out of 927 vertically-cut crypts (in well-oriented sections), 912 (98.4%) were asymmetric, and the remaining 14 (1.6%), symmetric, and out 2660, cross-cut (transected) crypts in fission, 2018 (75.9%) were asymmetric and the remaining 642 (24.1%), symmetric.ConclusionCrypt fission is rarely found in the normal colon in adults. Symmetric crypt fission found in UC is possibly triggered by a compensatory homeostatic mechanism of crypt production in mucosal areas replaced by chronic inflammation. But asymmetric crypt fission is a pathological aberration that affects crypts in patients with a particular predisposition to develop mucosal dysplasia. It is suggested that this previously unattended histological parameter be included in the pathological descriptions of colectomy specimens from patients with UC.

Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration

The ability to sense proteasome insufficiency and respond by directing the transcriptional synthesis of de novo proteasomes is a trait that is conserved in evolution and is found in organisms ranging from yeast to humans. This homeostatic mechanism in mammalian cells is driven by the transcription factor NRF1. Interestingly, NRF1 is synthesized as an endoplasmic reticulum (ER) membrane protein and when cellular proteasome activity is sufficient, it is retrotranslocated into the cytosol and targeted for destruction by the ER-­associated degradation pathway (ERAD). However, when proteasome capacity is diminished, retrotranslocated NRF1 escapes ERAD and is activated into a mature transcription factor that traverses to the nucleus to induce proteasome genes. In this Perspective, we track the journey of NRF1 from the ER to the nucleus, with a special focus on the various molecular regulators it encounters along its way. Also, using human pathologies such as cancer and neurodegenerative diseases as examples, we explore the notion that modulating the NRF1-proteasome axis could provide the basis for a viable therapeutic strategy in these cases.

A computational model of homeostatic cerebellar compensation of ageing in vestibulo-ocular reflex adaptation

The vestibulo-ocular reflex (VOR) stabilises vision during head motion. Age-related structural changes predict a linear VOR decay, whereas epidemiological data show a non-linear temporal profile. Here, we model cerebellar-dependent VOR adaptation to link structural and functional changes throughout ageing. We posit that three neurosynaptic factors codetermine VOR ageing patterns: electrical coupling between inferior olive neurons, intrinsic plasticity at Purkinje cell synapses, and long-term spike timing dependent plasticity at parallel fibre - Purkinje cell synapses as well as mossy fibre - medial vestibular nuclei synapses. Our cross-sectional simulations show that long-term plasticity acts as a global homeostatic mechanism mediating the non-linear temporal profile of VOR. Our results also suggest that intrinsic plasticity at Purkinje cells acts as a local homeostatic mechanism sustaining VOR at old ages. Importantly, longitudinal simulations show that residual fibres coding for the peak and trough of the VOR cycle constitute a predictive hallmark of VOR ageing trajectories.