Lithium chloride (LiCl) can induce autophagy by inhibiting inositol monophosphatase (IMPase), which reduces inositol and inositol-1,4,5-triphosphate (IP3) levels. Since lithium has already been approved by the FDA for patients with bipolar disorder, it can easily be adapted for other diseases. Long-term oral lithium administration enhanced autophagy in a tauopathy mouse model by inhibiting glycogen synthase kinase-3. L-690,330, a bisphosphonate inhibitor of IMPase, exhibits a similar function to lithium by clearing mutant synucleins and EGFP-HDQ74. Valproic acid is an angio-suppressive compound which suppresses the Akt/mTOR signaling pathway by acting as a histone deacetylase inhibitor and promotes autophagy, as evidenced by the increased concentrations of LC3-II and Beclin 1 after its administration in prostate cancer cell lines. Carbamazepine and valproic acid can both reduce intracellular inositol-1,4,5 trisphosphate levels. Therefore, other IMPase inhibitors could also be incorporated into therapeutic strategies.

Anacardic acid, curcumin, garcinol, and spermidine increase autophagy by reducing the level of acetylation in cultured human cells, as evidenced by depleted sequestosome-1 levels and mTORC1 inhibition. Spermidine also inhibits EP300 and the major autophagy proteins, Atg5, Atg7, Atg12, and LC3 to repress autophagy. Supplementing the diet of mice with coffee beans rich in polyphenols concomitantly increased autophagy and decreased acetylation levels, whilst natural polyamines can inhibit acetyltransferases, and their dietary intake can improve the life span of short-living mouse strains and the health of long-living ones.

The goal of this study was to find new and more powerful dual agonists for PPARα and PPARγ. The new technique of “core hopping” adopted in this study allows for the rapid screening of novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties. A set of 10 novel compounds were found in this regard. Compared with the existing dual agonist, the new agonists not only had the similar function in activating PPARα and PPARγ, but also assumed the conformation more favorable in binding to PPARα and PPARγ. It is anticipated that the new agonists may become potential drug candidates. Or at the very least, they may stimulate new strategy for developing novel dual agonists against type-2 diabetes.

A complex network of metabolic alterations sustained by hypercatabolism, energy deficit, and systemic inflammation is the milieu underlying cancer cachexia. While becoming overtly detectable in advanced cancer patients, such perturbations likely take place very early in the course of the disease, at least at the molecular level.

Protein and energy dysmetabolism in cachexia are quite well recognized; however, the available therapeutic strategies, although frequently promising from the preclinical point of view, have not yet reached validation to be used in the clinical practice. Several drugs identified by experimental studies are currently tested in clinical trials for their ability to improve muscle metabolism in cancer patients. Other emerging strategies are those aimed at interfering with the intestinal microbiota, previously reported to improve cachexia in a preclinical model.

The available results of both experimental and clinical studies, however, have clearly indicated that single-targeted therapies will hardly be successful in the treatment of cachexia. In this regard, the view of a multidirectional approach, selectively tailored and, whenever possible, personalized, is gaining a growing consensus. Such an approach should not just rely on nutritional counseling and pharmacologic treatment with anti-inflammatory and anticatabolic drugs but also include exercise training and/or exercise-mimicking agents. In this regard, exercise mimetics could not only merely replace exercise training in depleted patients but also improve exercise tolerance and effectiveness in precachectic individuals, thus amplifying the beneficial action of exercise itself. Last but not least, treatments aimed at preventing/correcting the metabolic alterations underlying cancer-induced muscle wasting might also impinge on tumor-targeted therapies improving their effectiveness and/or enhancing patient tolerance to chemotherapy. In addition, metabolic modulators could also directly affect tumor growth. This is the case, for example, of exercise, that was shown to prevent or at least delay tumor growth.

No additional information is available for this paper.

Despite the evidence that PPARγ agonists could obviously bring benefits to renal functions as stated above, these beneficial effects were shadowed by the risk for fluid retention, peripheral edema, or blood volume expansion, which could increase various degrees of burdens on kidney. For example, some studies proved that TZDs contributed the fluid retention by altered sodium and water reabsorption in the distal collecting ducts of the kidney [23, 110]. Clinical research figured out that uncomplicated diabetic patients' combined use of RAAS inhibitors and PPARγ agonists promotes anemia. Besides, people with long-term TZDs drug treatment are also peculiarly prone to the osteoporosis and heart failure. Safety warnings and even drug withdrawal in Europe have come out because of the increasing risk in bladder cancer by pioglitazone [113–115]. A combined therapy including PPARγ agonists and other renoprotective measures appears to be more reasonable than one single intervention. Ongoing efforts have been made to identify more selective modulators of PPARγ that reduce or eliminate the adverse effects of PPARγ agonists.

The QikProp, is a program for predicting the ADME (absorption, distribution, metabolism, and excretion) properties of the compounds. With the QikProp software, a total of 44 properties of compounds can be predicted, including the principal descriptors and physiochemical properties.

All the compounds investigated need not the treatment for neutralization before using QikProp because it will be automatically done in QikProp. The normal mode was applied in the program. The property analyses for the partition coefficient (QP logP o/w), van der Waals surface area of polar nitrogen and oxygen atoms (PSA), predicted aqueous solubility (QP logSb ), and apparent MDCK permeability (QPP MDCKc), were considered in the QikPro to evaluate the acceptability of the compounds.

In conclusion, ON is a challenging orthopaedic condition which resulted from unwanted adverse effects of corticosteroids administration. Normally, no single factor is involved in the pathophysiology of SAON initiation and its development. Evaluation of approaches developed for prevention and treatment of ON in both animal and human studies indicated that a certain pathophysiology resulted in ON, including abnormality of BMSCs pool, bone matrix and cartilage degeneration cell apoptosis, abnormality of lipid metabolism and clotting disorders, decreased angiogenesis and elevated vasoconstriction, and oxidation injury. Orthopaedic surgery is important for the treatment of SAON, yet its prognosis is rather poor. This implies the importance of prevention in two aspects, including: (1) to prevent the happening of SAON after the administration of steroid; and (2) to prevent the development of SAON from early stage to late stage.

Based on the possible pathophysiology and the effective prevention or therapy performed in animals and humans with steroid administration, much more bench to clinic translational work shall be done in the future to promote efficiency of early prevention, diagnosis, and treatment of SAON. Good prevention requires good predictive diagnosis. Gene analysis or hypercoagulability of plasma might be earlier methods to predict ON development, although dynamic perfusion MRI is another advanced and promising bioimaging approach. Chinese herb and statins treatment produced significantly lower incidences of SAON both in humans and animal models, implying that they might be promising alternatives for prevention and eventually treatment of SAON. The apoptosis of osteoblasts, osteoclasts, and osteocytes suggested a new mechanism for the effect of steroids, giving a new insight into mechanisms responsible for bone loss in patients with SAON. Core decompression combined with bone grafting, bone marrow or cells transplantation, and growth factors is the best documented therapy for early SAON stage(s). The newly tested osteopromotive porous composite scaffolds were also promising for enhancing repair of ON lesions after core decompression,. Gene therapy was proven to be effective in animal models, but its safety and ethical issues are still controversial. Despite all treatments, joint replacement is still advocated for patients at the late ON stage(s). How to improve postoperative prognosis after joint replacement therapy remains a challenging topic for not only orthopaedic surgeons, but also biomedical engineers and biomaterial scientists. We hope that with all collective efforts, more scientifically confirmed approaches will be available for clinical applications and will benefit patients suffering from ON, especially SAON.

Tangminling pill is effective and safe for glycemic control and β-cell function in T2DM patients, and it could be used to treat T2DM as a promising complementary approach. However, more rigorously designed trials are warranted to investigate the impacts of Tangminling pill on diabetes and diabetic complications.

Nonsurgical treatments of ON are limited and are commonly indicated for patients at the early stage of ON with localised necrotic lesions. The objects of such intervention usually focus on pain relief, prevention of ON progression, and improvement of the joint function. According to the different pathophysiologies of SAON, numerous medical and biophysical treatments have been tested and have demonstrated treatment efficacy, especially for patients in early ON stages, including biological and pharmacological treatments such as statins,, bisphosphonates, low molecular weight heparin, stanozolol, iloprost, hyperbaric oxygen, herbal (puerarin and Epimedium), or nonpharmacological treatments including extracorporeal shock wave therapy, and electromagnetic therapy,.

PPARγ agonists have shown great clinical effects in treating metabolic disorders. Many agonists have been developed, including 15-deoxy-Δ12, 14-prostaglandin J2 (15dPGJ2), and TZDs. PPARγ agonists appear to be useful in reversing this early stage of the renal fibrosis (epithelial-mesenchymal transition, EMT) in the condition of the high glucose and to restore the function of SGLT-proteins mediated glucose uptake [56, 60]. TZDs, which used in the treatment of T2D, were proved to indirectly slow down the progression of renal disease by improving glucose intolerance and reducing the urinary albumin [21, 94]. A meta-analysis involving 2860 diabetic patients demonstrated that TZDs produced significant decreases in the levels of urinary albumin, which was in addition to that of RAS blockade because practically all patients in the latter studies were treated with ACEI or ARBs.

Accumulating evidence suggested that PPARγ agonists could also provide a protection in wider spectrum of kidney diseases, such as the acute nephrotic syndrome, nondiabetic glomerulosclerosis, and the polycystic kidney [96, 97]. Pioglitazone was reported to improve the renal functions in animal models of renal ischemia reperfusion-induced AKI via regulating Tnf and Nrf2 expression. Furthermore, recent studies have highlighted beneficial roles of PPARγ agonists for patients with chronic renal failure, hemodialysis, as well as peritoneal dialysis (PD) could also benefit from [99, 100]. Liu et al. pointed out that rosiglitazone could protect against high phosphate-induced vascular calcification in CKD mice. Zhang et al. provided the evidence that rosiglitazone had the protective effects on rat peritoneal mesothelial cells against PD solution-induced damage probably by inhibiting inflammation and regulating AQP 1 and ZO 1 gene expressions.

Interestingly, as a member of the RAAS inhibitors is widely used in the treatment of renal disease, telmisartan (characterized as selective PPARγ modulators in 2005) had advantages in reducing albuminuria, serum creatinine, and glomerulosclerosis in a nondiabetic model by its partial agonistic activity on PPARγ. Besides, treatment with telmisartan confirmed the protective effects against daunorubicin- (DNR-) induced nephrotoxicity by reducing the level of Ang II and ET-1 expression, which was associated with reduced inflammation and oxidative stress in part through the activation of PPARγ [103–105].

Previous studies have shown that PPARγ agonists may have some protective effects on CVD end of CKD. In a PROactive study, CKD patients treated with pioglitazone were less likely to reach a composite end point of all-cause death, MI, and stroke. These effects may be related to anti-inflammation effect and protection of endothelial cells. Short-term rosiglitazone therapy reduced insulin resistance, markers of inflammation, and abnormal endothelial function in patients with CKD. In nondiabetic ESRD patients, pioglitazone significantly changes the visceral-subcutaneous fat distribution and improves the adipokine profile with a decrease in hepatic insulin resistance. In nondiabetic renal allograft recipients, pioglitazone treatment reduces the progression of carotid IMT and improves insulin resistance. However, the protective effect of PPARγ agonists on the progress of renal function needs further exploration.

Cobalt protoporphyrin (CoPP) is an exogenous inducer of HO-1 that theoretically acts through the FoxO1 protein. Current literature hypothesizes that FoxO1 negatively regulates adipogenesis by preventing transcription of PPARγ; decreased adipogenesis leads to a decrease in systemic oxidative stress and inflammatory cytokines. Previous studies have shown that HO-1 induction by CoPP reduces visceral adiposity and attenuates metabolic imbalance, increases levels of phosphorylated AKT, AMPK, mTOR in adipocytes, improved oxidative stress, decreased release of inflammatory cytokines, decreased lipid accumulation and increased adiponectin levels. Pharmacological inductions of HO-1 are not only limited to CoPP; hemin and epoxyeicosatrienoic acid (EET) have been implicated as pharmacological inducers of HO-1.

Lentiviral vectors have been utilized as a gene targeting therapy in various models of disease, and HO-1 induction has been proven as successful. Utilization of an adipocyte-specific (under the control of the aP2 promoter) lentiviral vector expressing HO-1 decreased adiposity and vascular dysfunction, improved metabolic parameters and attenuated serum levels of inflammatory cytokines in an in vivo model of diet-induced obesity. Induction of HO-1 was accompanied by an increase in Wnt10b (pre-adipocyte marker) and a decrease in MEST (protein that correlates with adiposity and adipocyte size). Increased HO-1 expression also resulted in decreased levels of the genes involved in adipogenesis (PPARγ, C/EBPα and aP-2), which explains the decrease in adiposity. In addition, adiponectin, manufactured only in adipocytes, was increased after adipocyte-specific targeting of the HO-1 gene with a resultant improvement in adipocyte function.

Dietary antioxidants have been shown to increase HO-1 expression in vitro, and the potential use of this natural substances to regulate immune response should be carefully addressed. A study performed by Scapagnini et. al. showed that low concentrations of caffeic acid phenethyl ester, or CAPE, and curcumin significantly increase HO-1 expression in astrocytes, and curcumin exerts a cytoprotective effect in endothelial cells, mediated by an increase in HO-1 gene expression and thus a decrease in oxidative stress. It is believed that certain active components in medicinal plants induce the HO-1 gene; CAPE and curcumin are both known to inhibit NF-kB and cyclooxygenase activity. They have also been shown to inhibit lipid peroxidation and cellular growth. Increased physical activity has been shown to increase HO-1 induction and protect against oxidative stress in various models as well.

Life-span extension can be achieved by calorie restriction (glucose, protein, amino acids deprivation), or by pharmacological interventions, such as rapamycin and other small molecules (e.g., metformin and resveratrol). Side effects from acute or long-term treatments could be diminished by intermittent and/or very low doses of rapamycin treatment, fasting-mimicking diets, intermittent fasting, among other regimes. The exact extent of stress (quality, quantity and intensity) and how it affects different cell types, developmental stages and disorders, needs to be evaluated in order to poise the cell and the organism into a protective mode. Although we have focused on a TOR centred view in yeast, other signalling routes, interconnected with TOR itself, like Growth Hormone (GH), Insulin/IGF-1-like, and PI3K-AKT are however important players in more complex higher eukaryotes. Other age-related processes such as mitochondrial dysfunction, also influenced by sirtuins and TORC1, should be taken into account as well. Inhibiting TOR signalling could mediate longevity through both sirtuin and ribosome production (amid others) and its effect on (but not only) rDNA and nucleolar structure and stability. Thus, the nucleolus could be serving as both a genome buffering system and a stress sensor for the cell. In fact, a whole rDNA theory of aging in budding yeast has been proposed by Kobayashi. In addition, a role for the rDNA as an evolutionary conserved clock of aging has been postulated as well. Could a central hub or integrator in the cell, such as TOR, be communicating (through its inhibition) the stress signals into a sensor or buffering system like the rDNA/nucleolus, linking growth and stress and, in that way, enhancing stress responses and protecting the rest of the genome from further damage? This is an interesting hypothesis that remains to be further elucidated. In relation to cancer biology, the use of the nucleolus as a marker in a wide range of tumours continues as a valuable prognostic tool for the pathologist. Meanwhile, the specialized nucleolar nature opens new avenues for potential treatments with less genotoxicity. Finally, one clear conclusion is drawn, the nucleolus is dramatically reduced upon TOR inhibition or caloric restriction, and this is related to longevity. By contrast, an enlarged nucleolus is indicative of aging. This should be used as a predictive hallmark (among others) in aging and longevity research with potential translation into the clinic.

We have shown that SIRT1 activators attenuate RGC loss during EAE optic neuritis however, neuronal damage in the MHV model of MS occurs by different mechanisms than in EAE, including direct viral infection of neurons and macrophage-mediated myelin stripping of axons. The ability of SRTAW04 to attenuate neuronal loss in MHV-A59 infected mice was therefore examined. RGCs of 4 week old C57BL/6 mice were labeled with fluorogold and mice were inoculated with MHV-A59 one week later. The treatment group was administered SRTAW04 (100 mg/kg/day) by oral gavage starting from day 1 for 30 days. The decrease in RGC numbers in untreated MHV-A59 mice, compared to controls, was significantly attenuated by SRTAW04 treatment (Figure 3a). To further confirm the neuroprotective effect of SRTAW04, 4 week old C57BL/6 mice were inoculated with recombinant strain of MHV, RSA59 and the treatment group was administered the same dose of SRTAW04 for 30 days with and without SIRT1 inhibitor EX527 (10 mg/kg/day i.p.). After 30 days RGCs were labeled by Brn3a staining and counted. Consistent with MHV-A59 results (Figure 3a) RSA59 induced a significant decrease in RGCs and treatment with SRTAW04 attenuated RGC loss. The SRTAW04 treatment group receiving EX527 showed a significant decrease in RGC numbers compared to the group that only received SRTAW04 (Figure 3b, c) demonstrating that the RGC protective effect of SRTAW04 is dependent on SIRT1. Treatment with SIRT1 inhibitor alone does not further reduce RGC survival (data not shown), similar to prior studies.

Oxidative stress has been reported to be an underlying factor that mediates neuronal dysfunction in the brain (de Morais et al., 2018, Comoglio et al., 2008). Ang II is considered as the main instigator that leads to the release of ROS and inflammatory mediators in neurodegenerative diseases (Chen et al., 2016). Ang II induced inflammatory cascades result in cognitive dysfunction and neurodegeneration in the brain (Sun et al., 2018, Martire et al., 2015). On the other hand, decreased amount of ACE2 and Ang (1–7) damages cells in cerebral arteries and enhances the level of oxidative stress (Peña Silva et al., 2012). Activation of ACE 2/Ang (1–7)/MASR axis is considered as a novel approach for neuroprotection, since it suppresses NF-kB signaling pathway and reduces oxidative stress. In cerebral ischemia, ang(1–7) showed anti-inflammatory effects to protect brain ischemia (Jiang et al., 2012). In addition, ang IV is reported to be the natural inhibitor of the insulin-regulated aminopeptidase receptor and used as a neuroprotective agent (Naveri et al., 1994). The ARBs could represent another class of drugs that safeguards the neurophysiological milieu from various cognitive defects (Villapol and Saavedra, 2015). ARBs have been shown to reduce brain disorders via several mechanisms, including reducing neuroinflammation and hypoxia (Saavedra et al., 2011). The two well-known ARBs, irbesartan and telmisartan have been reported to significantly reduce the production of ROS in the retina and retinal explants (Ola et al., 2013, White et al., 2015). Moreover, few studies reported neuroprotection by inhibition of NOX due to antioxidant effect of ARBs. It is also established that ARBs protected the cerebral vasculature and reversed other cerebrovascular pathologies (Farag et al., 2017). Thus, ARBs’ treatment of several neurodegenerative brain disorders in humans might be the new therapeutic intervention to protect physiological and pharmacological insults.

Western analysis of ventricular tissue was performed on lysates created from ~25 mg tissue placed in 1× Cell Signaling Lysis Buffer (for 10 ml: 1 ml 10× Cell Signaling Lysis Buffer, Cat. #9803S; 0.108 g β-glycerol phosphate, Sigma, Cat. #G6251; 1 tablet protease inhibitor, Roche Cat. #11 836 153 001; 100 μl 100X phosphatase inhibitor cocktail, Roche Cat. #04 906 837 001) and was homogenized on ice (Fisher Scientific, Power Gen 125, setting 5) for ~15–20 s. The homogenate was incubated on ice for 30 min, centrifuged at 4°C, ×16,000×g for 15 min and the supernatant stored at −80°C. Protein concentration was determined using the Bio-Rad DC Protein Assay Reagent Package (Bio-Rad Laboratories, Inc., Hercules, CA, Cat. #500-0116). Proteins (30–50 μg/lane) were resolved on NuPAGE Bis–Tris or Tris–Acetate 10 well gels. Mouse anti-NFκB p65, rabbit anti-phospho-NFκB p65 (Ser536), rabbit anti-phospho-NFκB p65 (Ser468) were used to measure NFκB signaling (Cell Signaling Technologies, Cat. #6956, #3033, and #3039, 1:500). IRS-1 signaling was detected using rabbit anti-phospho-IRS-1 (Ser1101) and rabbit anti-IRS-1 (Cell Signaling Technologies, Inc. Cat. #2385 and #2383, 1:500). cJun signaling was detected by rabbit anti-p-cJun (Ser73), Rb anti-p-cJun (Thr91) or Rb anti-cJun 60A8 (Cell Signaling Technologies, Cat. #9164, #2303, #9165, 1:500). Rabbit anti-PPARα (Abcam Inc. Cat. #24509,1:1000), rabbit anti-PPARβ/δ (Abcam Inc. Cat. #8937, 1:500), and rabbit anti-PPARγ (Cell Signaling Technologies, Inc. Cat. #2443, 1:500) were used to measure protein expression of the PPAR isoforms. MuRF2 protein expression was detected by goat anti-MuRF2 (Abcam Inc. Cat. #4387, 1:1000). Primary antibodies were diluted in 5% milk or bovine serum albumin and incubated at 4°C overnight. HRP-labeled secondary antibodies against mouse (Sigma #A9917, 1:10,000), goat (Sigma #A4174, 1:10,000), and rabbit (Sigma #A9169, 1:5,000) were used to detect the primary antibodies diluted in 1× TBS-T and incubated 1 h at room temperature. Mouse anti-β-actin (Sigma, Inc., Cat. #A2228, 1:4,000) and mouse anti-GAPDH (Sigma, Inc., Cat. #G8795, 1:4,000) were used as a loading controls throughout. Secondary antibody HRP was detected using ECL Select (GE Healthcare, Cat. #RPN2235) and imaged using the MultiDoc-it Imaging System (UVP, LLC Ultra-violet Products, Ltd., Upland, CA, USA).

To analyze experiments performed in HeLa cells (Figure 6), statistical analysis was performed using Prism (GraphPad, La Jolla, CA). Statistical significance was determined by one-way analysis of variance (ANOVA) and Tukey's post hoc test in G and two-way ANOVA and Bonferroni post tests in H.

The Animal Experimental Ethics Committee of the principal investigator's institution reviewed and approved the experimental protocols (Ref. No. 15-150-MIS). Both the Guide for the Care and Use of Laboratory Animal (1996) and the ARRIVE (Animals in Research: Reporting In Vivo Experiments) guidelines were followed.

As the prevalence of obesity increases, it is paramount to note that the incidence of comorbidities, such as metabolic syndrome, NASH and cardiovascular disease, are going to increase as well. Obesity is associated with systemic oxidative stress, and it is suggested that impaired mitochondrial function and severe inflammation in the adipocyte underlie the pathogenesis of obesity. Hypertriglyceridemia and hyperglycemia, both associated with increased adiposity, have been shown to increase plasma FFA, which can lead to increased ROS generation and oxidative stress; this imbalance and oxidative stress has been implicated in both NASH and cardiovascular diseases. Understanding the role of ROS and oxidative stress in these disease states is a crucial step towards better therapeutic strategies. To this end, recent advancements in the understanding of both the Na/K-ATPase oxidant amplification loop and HO-1, provide a unique opportunity to better elucidate the redox mechanisms that modify inflammation and manipulate localized redox signaling pathways. It is highly possible that the mechanisms operant in both the Na/K-ATPase oxidant amplification loop and HO-1 may also involve other mediators (as yet unidentified) that directly modulate cellular oxidative and inflammatory responses. Although, the pharmacological and non-pharmacological interventions targeting these mechanisms have been demonstrated to be effective, it is possible that implementation of other strategies or targeting other pathways might prove to have better clinical outcomes. However, the success of these strategies will open up new avenues and approaches toward the antagonism of obesity and subsequent NASH, once we bridge the gap from mice to humans.

The above mentioned strategies to inhibit ZIKV infection provide the experimental proof-of-concept of the feasibility of strategies targeting lipids to combat viral infections. However, it is important to note that most of these studies are still in their initial stages and are mainly based on infections performed in cell culture. Remarkably, limited in vivo experiments also support the viability of this kind of approach for therapeutic intervention, as is the case of 25-HC or the peptide that disrupts the viral envelope. Although it could seem risky to think in antiviral strategies based on lipid metabolism, because it constitutes one of the key cellular metabolic pathways, it is important to remember that lipid metabolism is actually a first order pharmaceutical target for the treatment of human disorders. Both SREBP and AMPK, antiviral targets already validated for ZIKV, currently constitute important pharmacological targets for human diseases (obesity, metabolic syndrome, type II diabetes and cancers). Some of these drugs have undergone diverse phases of clinical trials and others are even licensed for human use. For instance, metformin, an indirect AMPK activator, is a drug licensed for humans and constitutes one of the most commonly prescribed drugs for the treatment of diabetes, supporting the safety of this kind of approach for the treatment of human illnesses. Sphingomyelin metabolism modulators, and specifically the inhibitors of sphingomyelin to ceramide conversion, also constitute therapeutic targets currently under evaluation. Likewise, drugs targeting cholesterol biosynthesis (i.e., statins) are commonly prescribed for the treatment of cardiovascular diseases and provide a further example of the safety and therapeutic success of drugs that interfere with lipid metabolism. In this sense, imipramine, which inhibits ZIKV infection by altering cholesterol traffic, is an antidepressant also approved for human use, providing an additional example of a lipid modulator with an ability to cross the BBB that could be useful for the treatment of ZIKV. Considering that most of the data supporting the antiviral potential of lipid-based antiviral strategies comes from cell cultures or small animal models, it could be interesting to test the reliability of these strategies in the real world. This could be initially addressed by taking advantage of lipid-lowering drugs already licensed (i.e., statins, metformin or imipramine). To this end, epidemiological surveys in patient cohorts from ZIKV-endemic regions could be performed. Both virological (viremia, viral load in urine, the severity of the infection) and biological parameters related to lipid metabolism such as the serum lipid profile, which is a biomarker for the severity of the infection of the related DENV, should be potentially included in these analyses.

Another important point that has to be taken into consideration is that most of the drugs targeting lipid metabolism here reviewed are effective against more than one flavivirus, confirming their broad-spectrum potential. Because most flaviviruses constitute neglected human pathogens, which complicates the development of specific antiviral strategies, repositioning drugs that target lipid metabolism as antiviral candidates could lead to more affordable broad-spectrum compounds. Although the utilization of antivirals to combat ZIKV infection, especially in pregnant women, raises multiple safety concerns, it should be noted that they could be useful for the treatment of other infected patients for the prevention of ZIKV-associated illnesses. Even more, effective antiviral treatments lowering the viral load should be useful to prevent ZIKV transmission by diminishing the risk of mosquito infection during blood-feeding, and by reducing the viral burden in the reproductive system of infected patients that could therefore also block any sexual transmission of the virus. It is important to remark that the antiviral effect exerted by some of the compounds targeting lipid metabolism in the infection models used is not very strong (showing a reduction of only about 1 log of virus production), so we still have to be cautious about the relevance of these drugs for more advanced studies. Nevertheless, lipid-targeting drugs could ideally be utilized, not only alone, but also in combinatorial therapies, together with other antivirals (i.e., DAAs), providing another weapon in the arsenal to combat the ZIKV.

In any case, and although a long way has yet to be completed before the implementation of these antiviral strategies in clinical practice, the current scenario and their potential benefits support future research efforts aimed to repositioning of lipid metabolism modulators as antiviral compounds.

The following primary antibodies were used for studies in yeast: HRP-conjugated rat monoclonal anti-HA high-affinity (3F10; Roche), anti-HA mouse monoclonal (Roche), G6PD rabbit polyclonal antibody (Sigma-Aldrich), a ubiquitin (P4D1) mouse monoclonal antibody from Santa Cruz (Dallas, TX; sc-8017), and a polyclonal rabbit anti-Kar2 (Brodsky and Schekman, 1993). A polyclonal rabbit anti-Pma1 was a gift from Amy Chang (University of Michigan, Ann Arbor, MI). The following secondary antibodies were used in yeast: HRP-conjugated goat anti-mouse and goat anti-rabbit antibodies (Jackson ImmunoResearch, West Grove, PA) and Alexa Fluor 568 goat anti-rabbit and Alexa Fluor 488 goat anti-mouse (Invitrogen, Carlsbad, CA). The following antibodies were used for studies in HeLa cells: HA mouse monoclonal antibody (Covance, Princeton, NJ), HA rabbit monoclonal antibody (Cell Signaling, Danvers, MA), CD63 mouse monoclonal antibody (Invitrogen), TSG101 mouse monoclonal antibody (GeneTex, Irvine, CA), HRS (HGS) mouse monoclonal antibody (Abcam), and VPS35 goat polyclonal antibody (Abcam). The following secondary antibodies were used for immunofluorescence studies in HeLa cells: anti-mouse and anti-rabbit Alexa Fluor–conjugated secondary antibodies (Molecular Probes).

We describe the first mechanism by which an ubiquitin ligase inhibits multiple cardiac PPAR isoforms, to protect against high fat diet-induced diabetic cardiomyopathy. We identified that MuRF2 protein levels increase ~20% during the development of diabetic cardiomyopathy induced by high fat diet. Compared to littermate wildtype hearts, MuRF2−/− hearts exhibit an exaggerated diabetic cardiomyopathy, characterized by an early onset systolic dysfunction, larger left ventricular mass, and higher heart weight. MuRF2−/− hearts had significantly increased PPARα- and PPARγ1-regulated gene expression by RT-qPCR, consistent with MuRF2’s regulation of these transcription factors in vivo. Recent studies have described MuRF2 mutations to contribute to the severity of familial hypertrophic cardiomyopathy. The present study suggests that the lack of MuRF2 activity, as found in these patients, can result in an exaggerated diabetic cardiomyopathy. These present studies also identify MuRF2 as the first ubiquitin ligase to regulate cardiac PPARα and PPARγ1 activities in vivo via post-translational modification without degradation and may represent a novel potential therapeutic target against heart failure in diabetes.

The G-quadruplex structure is an important secondary structures of nucleic acids. The widespread existence in vital regulatory genome regions and a series of reported biological functions make this structure a promising drug target in anti-tumor drug discovery. In this review, we discuss the structures, existence, and functions of G-quadruplexes. Basing on this, we summarize some typical G-quadruplex ligands with promising anti-tumor activities. Since G-quadruplexes exert their regulatory functions mainly through the binding proteins of multiple nucleic acids, especially the helicases, we further introduce some G-quadruplex-related proteins, especially the helicase. The fact that designing molecules to block the interactions between nucleic acids and proteins is feasible makes this novel anti-tumor strategy more and more attractive.

RSK helped design these studies, performed all experiments, analyzed the data, and prepared the manuscript. KD assisted with induction of MHV disease, prepared tissue sections, and performed histological studies. JDS helped with experimental design, data analysis and preparation of the manuscript. KSS oversaw all aspects of these studies and was involved in experimental design, data analysis and manuscript preparation. All authors read and approved the final manuscript.

Diarrhoea is defined as a situation in which an adult daily stool exceeds 200 g and contains 60–95% water and it constitutes one of the leading causes of morbidity and mortality in developing countries, where people still rely on healing practices and medicinal plants. As a result, despite the advances of Modern Medicine, the World Health Organization encouraged studies for the treatment and prevention of diarrheal diseases depending on traditional medical practices.

In vivo studies showed that the methanol extract Rosa canina had a significant antidiarrhoeal activity mediated by an antisecretory mechanism that induce a fluid accumulation comparable to that obtained with the standard drug, diphenoxylate. Furthermore, Rosa canina extract significantly reduced intestinal transit, thereby increasing the absorption of water and electrolytes.

The molecular mechanism underlying the antidiarrheal activity of Rosa canina extract could be based on the inhibition of acetylcholine and histamine through some secondary metabolites present in the leaf extract, such as flavonoids, and saponins.

Although further studies are needed to identify the active principle responsible for the anti-diarrhoeal activity of Rosa canina, its use could constitute a potential therapy for this intestinal alteration.