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Gamma-oryzanol as a potential modulator of oxidative stress and inflammation via PPAR-y in adipose tissue: a hypothetical therapeutic for cytokine storm in COVID-19?
Abstract
The literature has reported a higher prevalence of negative clinical outcomes due to Coronavirus disease 19 (COVID-19) in obese individuals. This can be explained by the cytokine storm, result from the cytokine production from both obesity and viral infection. Gamma-oryzanol (γOz) is a compound with anti-inflammatory and antioxidant activities. However, little is known about the γOz action as a possible agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ). The aim of this study was to test the hypothesis that γOz attenuates the cytokine storm by stimulating PPAR-γ in the adipose tissue.
Methods:
Male Wistar rats were randomly divided into three experimental groups and fed ad libitum for 30 weeks with control diet (C, n = 6), high sugar-fat diet (HSF, n = 6) or high sugar-fat diet + γOz (HSF + γOz, n = 6). HSF groups also received water + sucrose (25%). The γOz dose was 0.5% in the chow. Evaluation in animals included caloric intake, body weight, adiposity index, plasma triglycerides, and HOMA-IR. In adipose tissue was evaluated: PPAR-γ gene and protein expression, inflammatory and oxidative stress parameters, and histological analysis.
Results:
Adipose tissue dysfunction was observed in HSF group, which presented remarkable PPAR-γ underexpression and increased levels of cytokines, other inflammatory markers and oxidative stress. The γOz treatment prevented adipose tissue dysfunction and promoted PPAR-γ overexpression.
Conclusion:
Natural compounds as γOz can be considered a coadjutant therapy to prevent the cytokine storm in COVID-19 patients with obesity conditions.
... This finding may partly reflect the increased usage of refined wheat flour in the U.S. [54]. Adipose tissue dysfunction was observed in a U.S. high-sucrose, high-fat diet group, which showed marked PPAR-γ underexpression and increased levels of cytokines and other inflammatory markers and oxidative stress [55]. In addition, γ-oryzanol prevented adipose tissue dysfunction and the cytokine storm in COVID-19 obese patients and promoted peroxisome proliferator-activated receptor γ overexpression [55]. ...
... Adipose tissue dysfunction was observed in a U.S. high-sucrose, high-fat diet group, which showed marked PPAR-γ underexpression and increased levels of cytokines and other inflammatory markers and oxidative stress [55]. In addition, γ-oryzanol prevented adipose tissue dysfunction and the cytokine storm in COVID-19 obese patients and promoted peroxisome proliferator-activated receptor γ overexpression [55]. ...
... These conditions were each associated with an increased in-hospital case fatality rate ranging from 1% to 56% [75]. In addition, the Japanese diet contains many more functional substances that prevent COVID-19 infection, including fish fatty acids (EPA/DHA) [42,43], soybean isoflavones [45][46][47], seaweed components (fucoidan, porphyrin, fucoxanthin, fucosterol) [48,49], green tea (epigallocatechin-3-gallate) [50][51][52][53], and rice oryzanol and GABA [54,55]. Thus, the nearly 10-times greater prevalence of obesity in the U.S. than in Japan (Figure 3) is induced by the U.S. diet (Figures 8 and 9), and the low incidence and mortality due to COVID-19 in Japan can be partly attributed to the protective effects of the many functional substances in Japanese foods. ...
The U.S. and Japan are both democratic industrialized societies, but the numbers of COVID-19 cases and deaths per million people in the U.S. (including Japanese Americans) are 12.1-times and 17.4-times higher, respectively, than those in Japan. The aim of this study was to investigate the effects of diet on preventing COVID-19 infection. An analysis of dietary intake and the prevalence of obesity in the populations of both countries was performed, and their effects on COVID-19 infection were examined. Approximately 1.5-times more saturated fat and less eicosapentaenoic acid/docosahexaenoic acid are consumed in the U.S. than in Japan. Compared with food intakes in Japan (100%), those in the U.S. were as follows: beef 396%, sugar and sweeteners 235%, fish 44.3%, rice 11.5%, soybeans 0.5%, and tea 54.7%. The last four of these foods contain functional substances that prevent COVID-19. The prevalence of obesity is 7.4- and 10-times greater in the U.S. than in Japan for males and females, respectively. Mendelian randomization established a causal relationship between obesity and COVID-19 infection. Large differences in nutrient intakes and the prevalence of obesity, but not racial differences, may be partly responsible for differences in the incidence and mortality of COVID-19 between the U.S. and Japan.
... There is a confusion in the people's mind that it only effect lungs however it's not correct but the literature reports that it can also harm other organs of the infected person. The entry of virus in human body is mediated through the spikes present on the structure of new virus means they have S-protein and acts on the binding site of the receptor (Bojkova et al., 2020;Chadchan et al., 2021;Francisqueti-Ferron et al., 2021;Saraswat et al., 2021;Yavuz & € Unal, 2020). Afterwards, with the use of protease and endoribonuclease virus starts holding the host cell mechanism. ...
... Furthermore, gamma oryzanol can easily converted to androgens results in anabolic enhancement. It is a natural antioxidant and widely used to improve the lucidity of food, cosmetics and vegetable oils (Bumrungpert et al., 2019;Chakuton et al., 2012;Eslami et al., 2014;Francisqueti-Ferron et al., 2021;Francisqueti et al., 2017). However, the fast degradation of GO limited its usefulness or the exploration. ...
... The kinetics of degradation of oryzanol has been studied at different temperature and found to be followed first-order kinetics model; the rate constant is directly propositional to the heating temperature. For increasing the stability and effectiveness of oryzanol, the approach has been made to incorporate solid lipid nanoparticle (SLN) and with the help of kinetic model, it has been identified that the complex formed by the inclusion of SLN protects GO from photodegradation without harming its antioxidant efficacy (Francisqueti-Ferron et al., 2021;Juliano et al., 2005;Lee et al., 2021;M€ akynen et al., 2012;Patel & Naik, 2004). The most important point about the GO is its low toxicity as their absorption level in the human body is very less. ...
COVID-19 has affected more or less every nation across the world and affected the economy very
badly. Infection of this virus in human took the life of millions. We have already faced the first and the
second waves of COVID-19 and recently, the nations or humanity is afraid of new strain, that is,
OMICRON. Considered to highly infectious than the previous strains. Therefore, the researchers are
working to find a promising molecule with no or permissible toxicity. In the present work, authors
have chosen 10 molecules including the molecules used in curing the infection from nCoV. All the
molecules were docked against Mpro of nCoV using iGemdock, a reliable computational tool. Based
on the binding energy obtained, it can be seen that only latermovir; remdesivir; zanamivir showed
better binding affinity than the gamma oryzanol, the molecule of interest in this work. These three
molecules are already in use to cure the patients siffering from the infection of nCoV. But, we need a
cost effective and easily available molecule to fight against this viral infection. The binding energy
obtained for the formation of complex of gamma oryzanol with Mpro of nCoV through molecular
docking is �118.787 kcal/mol. It forms conventional hydrogen bonds with the CYS145 (3.63 Å), LEU141
(6.46 Å) and SER144 (3.18 and 2.87 Å); forms C-H bonds with PHE140 (5.08 Å), pi-alkyl interactions with
CYS145 (6.72 Å); forms alkyl interaction with PRO168 (4.08 and 6.88 Å), ALA191 (5.04 Å), LEU141 (5.96
and 6.14 Å). One interesting information is obtained that the value of log Kp of gamma oryzanol is
least means more permeable to skin in comparison of other molecules used in the work. Gamma oryzanol in known for to its biological potency like it can modulate the oxidative stress as well as inflammation. DFT calculations of gamma oryzanol (GO) was made at different temperature and no change
in the delocalization of electron density as well no change in free energy is observed. Molecular
dynamics (MD) simulations of gamma oryzanol with the Mpro of nCoV at different temperatures was
performed. The formation of the complex between GO and Mpro of CoV at 290 K, 300 K, 310 K and
320 K for 100 ns was investigated. It has been observed that the effective binding is observed at 290 K,
therefore, it can be said that the inhibition of the Mpro of nCoV with GO is maximum at 290 K
... In contrast, the HSF plus γOz group was protected against obesity development. Although the compound action mechanism is not fully clarified, a recent study published by our group [20], around the same time that the study was published by Jung et al. [21], showed that γOz was able to increase proliferator-activated gamma receptor (PPAR-γ) gene expression in adipose tissue, which may explain obesity attenuation, because this nuclear receptor is involved in the expression of several genes associated with lipogenesis and adipocyte differentiation. ...
... On the other hand, the HSF plus γOz group that received the compound along with the HSF diet presented, at the end of the experiment, insulin resistance attenuation, lower plasma insulin and triglycerides levels, and lower hepatic values of IL-6 and TNF-α. These results confirm the positive effect of gamma oryzanol on obesity-related disorders and the reduction in inflammation [11,20,29]. ...
Nonalcoholic fatty liver disease (NAFLD) is the main cause of liver disease. The physiopathological processes involved in the disease are metabolic syndrome (MetS) components (central obesity, dyslipidemia, insulin resistance/type 2 diabetes, hypertension), genetic, and dietary factors, including unsaturated fats and sweetened beverages, which are able to lead to inflammation and oxidative stress, conditions associated with progression and severity of NAFLD. Gamma-oryzanol (γOz) is a nutraceutical obtained from rice brain oil with many benefits to health, from immunological to metabolic. The aim of this study is to test the preventive effect of γOz on the physiopathological process related to nonalcoholic fatty liver disease in animals submitted to high sugar/fat diet. Male Wistar rats (±187 g) were randomly divided into four experimental groups to receive: control diet (C, n = 6), control diet plus γOz (C + γOz, n = 6), high sugar/fat diet (HSF, n = 6), or high sugar/fat diet plus γOz (HSF + γOz, n = 6) during 30 weeks. HSF groups also received water plus sucrose (25%). γOz was added to diets to reach 0.5% of final concentration. The HSF group presented MetS, liver inflammation and oxidative stress, and micro and macrovesicular steatosis. HSF plus γOz was protected against these changes. It is possible to conclude that gamma-oryzanol was effective in modulating the physiopathological process related to nonalcoholic fatty liver disease in animals submitted to a high sugar/fat diet.
... A recent study demonstrated that cannabidiol attenuated inflammation and epithelial damage in colonic epithelial cells exposed to the SARS-CoV-2 spike protein through a PPARγ-dependent mechanism [85]. The natural compound γ-oryzanol may also serve as an adjunctive therapy to reduce the cytokine storm associated with COVID-19; the material stimulated PPARγ to modulate oxidative stress and the inflammatory response in adipose tissues [86]. The Middle East respiratory syndrome coronavirus (MERS-CoV)-derived S glycoprotein activates PPARγ to suppress the pathologic inflammatory responses of macrophages [87]. ...
Peroxisome proliferator-activated receptors (PPARs) α, β, and γ are nuclear receptors that orchestrate the transcriptional regulation of genes involved in a variety of biological responses, such as energy metabolism and homeostasis, regulation of inflammation, cellular development, and differentiation. The many roles played by the PPAR signaling pathways indicate that PPARs may be useful targets for various human diseases, including metabolic and inflammatory conditions and tumors. Accumulating evidence suggests that each PPAR plays prominent but different roles in viral, bacterial, and parasitic infectious disease development. In this review, we discuss recent PPAR research works that are focused on how PPARs control various infections and immune responses. In addition, we describe the current and potential therapeutic uses of PPAR agonists/antagonists in the context of infectious diseases. A more comprehensive understanding of the roles played by PPARs in terms of host-pathogen interactions will yield potential adjunctive personalized therapies employing PPAR-modulating agents.
... Oxidative stress then provokes neutrophils and macrophages to release pro-inflammatory cytokines and the development of ALI (110). Similarly, oxidative stress injury in SARS-CoV-2 infection escalates the release of pro-inflammatory cytokines in an oxidative-dependent manner in the development of CS (111). Notably, myeoloperoxidase (MPO) is regarded as a linking marker between oxidative stress and inflammation. ...
... 62 Lower leptin levels were observed in an animal model supplemented with an antiinflammatory and antioxidant substance, revealing that this molecule may be downregulated by anti-inflammatory agents. 48 Due to its immunometabolic roles, leptin plays a major inflammatory role, triggering inflammatory responses. 152 In fact, one of the studies summarized in the present scoping review revealed that key inflammatory genes in the leptin pathway, SOCS3, STAT1, NFKB1, and IL1B, are upregulated in infected human epithelial cells. ...
In the 2 years since the COVID‐19 pandemic was officially declared, science has made considerable strides in understanding the disease's pathophysiology, pharmacological treatments, immune response, and vaccination, but there is still much room for further advances, especially in comprehending its relationship with obesity. Science has not yet described the mechanisms that explain how obesity is directly associated with a poor prognosis. This paper gathers all published studies over the past 2 years that have described immune response, obesity, and COVID‐19, a historical and chronological record for researchers and the general public alike. In summary, these studies describe how the cytokine/adipokine levels and inflammatory markers, such as the C‐reactive protein, are associated with a higher body mass index in COVID‐19‐positive patients, suggesting that the inflammatory background and immune dysregulation in individuals with obesity may be expressed in the results and that adiposity may influence the immune response. The timeline presented here is a compilation of the results of 2 years of scientific inquiry, describing how the science has progressed, the principal findings, and the challenges ahead regarding SARS‐CoV‐2, COVID‐19, and emerging variants, especially in patients with obesity.
... Natural compounds have also been investigated as possible coadjuvant therapy to prevent the cytokine storm in COVID-19 patients with obesity conditions. Gamma-oryzanol, the main bioactive constituent from rice bran and germ, has been found to positively modulate PPARγ expression in adipose tissue, reducing the levels of TNF-α, interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) [73]. ...
The manipulation of host metabolisms by viral infections has been demonstrated by several studies, with a marked influence on the synthesis and utilization of glucose, nucleotides, fatty acids, and amino acids. The ability of virus to perturb the metabolic status of the infected organism is directly linked to the outcome of the viral infection. A great deal of research in recent years has been focusing on these metabolic aspects, pointing at modifications induced by virus, and suggesting novel strategies to counteract the perturbed host metabolism. In this review, our attention is turned on PPARs, nuclear receptors controlling multiple metabolic actions, and on the effects played by PPAR ligands during viral infections. The role of PPAR agonists and antagonists during SARS-CoV-2, HCV, and HCMV infections will be analyzed.
... Wyniki badań przeprowadzonych na szczurach wykazały, że gamma-oryzanol wpływał na ekspresję PPAR-gamma w tkance tłuszczowej redukując poziom cytokin i tym samym hamując stan zapalny. W związku z tymi obiecującymi doniesieniami upatruje się w gamma-oryzanolu potencjalnego kandydata do blokowania zjawiska "burzy cytokin" wywołanych podczas choroby COVID-19, w szczególności u osób z nadwagą [51]. ...
Rośliny są naturalnymi laboratoriami, których wtórny metabolizm produkuje całe bogactwo związków chemicznych o ogromnym potencjale terapeutycznym. Olej ekstrahowany z otrębów ryżowych, stanowiących frakcję uboczną w procesie obróbki brązowego ryżu, obfituje w substancje biologicznie cenne. Jednym z głównych składników oleju ryżowego jest gamma-oryzanol stanowiący mieszaninę będących pochodnymi fitosteroli lub triterpenów oraz kwasu ferulowego. Substraty te charakteryzują się szeroką aktywnością biologiczną ściśle skorelowaną z ich właściwościami chemicznymi. Kluczowe w kontekście poprawy fizjologii i funkcjonowania organizmu są hipocholesterolemiczne oraz antyoksydacyjne właściwości tych związków. Z tego względu coraz więcej badań skupia się na wykorzystywaniu gamma-oryzanolu w terapiach wielu chorób przewlekłych, a nawet jako obiecującego, niefarmakologicznego środka leczniczego wspomagającego leczenie COVID-19 u osób cierpiących na nadwagę. W pracy scharakteryzowano strukturę chemiczną i działanie gamma-oryzanolu w oparciu o aktywność biologiczną estrów fitosteroli i kwasu ferulowego będących składnikami tej złożonej mieszaniny. Ponadto, opisano przykłady oddziaływania gamma oryzanolu na niektóre procesy fizjologiczne w organizmie człowieka i zwierząt.
... Oxidative stress then provokes neutrophils and macrophages to release pro-inflammatory cytokines and the development of ALI (110). Similarly, oxidative stress injury in SARS-CoV-2 infection escalates the release of pro-inflammatory cytokines in an oxidative-dependent manner in the development of CS (111). Notably, myeoloperoxidase (MPO) is regarded as a linking marker between oxidative stress and inflammation. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. β2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. β-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, β-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of β-blockers in the management of Covid-19.
... Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a nuclear receptor that has a role in inflammation through regulating related gene expression and is vastly expressed in the adipose tissue. Gammaoryzanol has shown a reduction in adipose tissue inflammatory status in male Wistar rats treated with this agent in a previous study (71). ...
Coronavirus disease 2019 or COVID-19, caused by the novel human coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first emerged in late 2019, in the city of Wuhan, Hubei province, China. Unfortunately, despite many efforts to find cures for SARS-CoV-2 disease, still the management of severe cases remains challenging. In severe forms of COVID-19, proinflammatory cytokines are notably elevated (3) and reminiscent of the secondary hemophagocytic lymphohistiocytosis (HLH). According to many studies, immune imbalance and an uncontrolled massive release of inflammatory cytokines have a significant role in COVID-19 severity and ARDS pathophysiology. Accordingly, targeting the over-activated immune system to prevent tissue damage is now one of the most noticed possible strategies to manage severe COVID-19 cases. In the present study, we reviewed studies and clinical trials conducted in this regard.
... Gamma oryzanol is a substance extracted from rice bran oil and wheat [285]. Recently, based on its anti-inflammatory, antioxidant, and neuroprotective functions, gamma oryzanol has also been used by Traditional Chinese Medicine as a therapeutic for controlling the cytokine storm in COVID-19 [285][286][287][288]. Studies have also shown that gamma oryzanol improves the clinical course in the treatment of some comorbidities related to obesity and reduces cholesterol levels by limiting its absorption from food and, for this reason, it is mainly proposed to treat cases in which cholesterol is high by intervening in the attenuation of the proinflammatory cytokine cascade [287]. ...
Background:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the coronavirus disease of 2019 (COVID-19) that emerged in December 2019 in Wuhan, China, and rapidly spread worldwide, with a daily increase in confirmed cases and infection-related deaths. The World Health Organization declared a pandemic on the 11th of March 2020. COVID-19 presents flu-like symptoms that become severe in high-risk medically compromised subjects. The aim of this study was to perform an updated overview of the treatments and adjuvant protocols for COVID-19.
Methods:
A systematic literature search of databases was performed (MEDLINE PubMed, Google Scholar, UpToDate, Embase, and Web of Science) using the keywords: "COVID-19", "2019-nCoV", "coronavirus" and "SARS-CoV-2" (date range: 1 January 2019 to 31st October 2020), focused on clinical features and treatments.
Results:
The main treatments retrieved were antivirals, antimalarials, convalescent plasma, immunomodulators, corticosteroids, anticoagulants, and mesenchymal stem cells. Most of the described treatments may provide benefits to COVID-19 subjects, but no one protocol has definitively proven its efficacy.
Conclusions:
While many efforts are being spent worldwide in research aimed at identifying early diagnostic methods and evidence-based effective treatments, mass vaccination is thought to be the best option against this disease in the near future.
... Pioglitazone is another available thiazolidinedione that may inhibit the activation of NF-kB and MAPK pathways by reducing the expression of CARD9 in COVID-19 patients (15,86). Several reports have indicated that PPARg agonists could be candidates for modulating the cytokine storm in the COVID-19 disease (87,149,150). A possible therapeutic role for pioglitazone has been identified with respect to the SARS-CoV-2 infection (16). ...
The Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has quickly reached pandemic proportions. Cytokine profiles observed in COVID-19 patients have revealed increased levels of IL-1β, IL-2, IL-6, and TNF-α and increased NF-κB pathway activity. Recent evidence has shown that the upregulation of the WNT/β-catenin pathway is associated with inflammation, resulting in a cytokine storm in ARDS (acute respire distress syndrome) and especially in COVID-19 patients. Several studies have shown that the WNT/β-catenin pathway interacts with PPARγ in an opposing interplay in numerous diseases. Furthermore, recent studies have highlighted the interesting role of PPARγ agonists as modulators of inflammatory and immunomodulatory drugs through the targeting of the cytokine storm in COVID-19 patients. SARS-CoV2 infection presents a decrease in the angiotensin-converting enzyme 2 (ACE2) associated with the upregulation of the WNT/β-catenin pathway. SARS-Cov2 may invade human organs besides the lungs through the expression of ACE2. Evidence has highlighted the fact that PPARγ agonists can increase ACE2 expression, suggesting a possible role for PPARγ agonists in the treatment of COVID-19. This review therefore focuses on the opposing interplay between the canonical WNT/β-catenin pathway and PPARγ in SARS-CoV2 infection and the potential beneficial role of PPARγ agonists in this context.
... In light of safety and efficacy evaluations, the LHQW administration could be considered useful for the treatment of COVID-19 to improve the clinical symptoms [235]. Recently, the gamma-oryzanol has also been hypothesized by traditional Chinese medicine as therapeutic for cytokine storms in COVID-19 according to its anti-inflammatory, antioxidant activities and neuroprotective functions [237,238]. ...
The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a high-risk viral agent involved in the recent pandemic stated worldwide by the World Health Organization. The infection is correlated to a severe systemic and respiratory disease in many cases, which is clinically treated with a multi-drug pharmacological approach. The purpose of this investigation was to evaluate through a literature overview the effect of adjuvant therapies and supplements for the SARS-CoV-2 infection. The research has analyzed the advantage of the EK1C4, by also assessing the studies on the resveratrol, vitamin D, and melatonin as adjuvant supplements for long hauler patients' prognosis. The evaluated substances reported important benefits for the improvement of the immune system and as a potential inhibitor molecules against SARS-CoV-2, highlighting the use of sartans as therapy. The adjuvant supplements seem to create an advantage for the healing of the long hauler patients affected by chronic symptoms of constant chest and heart pain, intestinal disorders, headache, difficulty concentrating, memory loss, and tachycardia.
Low-grade chronic inflammation in obesity is associated with leptin resistance. In order to alleviate this pathological condition, bioactive compounds capable of attenuating oxidative stress and inflammation have been researched, and bergamot (Citrus bergamia) presents these properties. The aim was to evaluate the effect of bergamot leaves extract on leptin resistance in obese rats. Animals were divided into 2 groups: control diet (C, n = 10) and high sugar-fat diet (HSF, n = 20) for 20 weeks. After detecting hyperleptinemia, animals were divided to begin the treatment with bergamot leaves extract (BLE) for 10 weeks: C + placebo (n = 7), HSF + placebo (n = 7), and HSF + BLE (n = 7) by gavage (50mg/Kg). Evaluations included nutritional, hormonal and metabolic parameters; adipose tissue dysfunction; inflammatory, oxidative markers and hypothalamic leptin pathway. HSF group presented obesity, metabolic syndrome, adipose tissue dysfunction, hyperleptinemia and leptin resistance compared to control group. However, the treated group showed a decrease in caloric consumption and attenuation of insulin resistance. Moreover, dyslipidemia, adipose tissue function, and leptin levels showed an improvement. At the level of the hypothalamus, the treated group showed a reduction of oxidative stress, inflammation and modulation of leptin signaling. In conclusion, BLE properties were able to improve leptin resistance through recovery of the hypothalamic pathway.
Coronavirus disease 2019 (COVID-19) is a severe respiratory disease caused by
infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
that affects the lower and upper respiratory tract in humans. SARS-CoV-2
infection is associated with the induction of a cascade of uncontrolled
inflammatory responses in the host, ultimately leading to hyperinflammation or
cytokine storm. Indeed, cytokine storm is a hallmark of SARS-CoV-2
immunopathogenesis, directly related to the severity of the disease and
mortality in COVID-19 patients. Considering the lack of any definitive
treatment for COVID-19, targeting key inflammatory factors to regulate the
inflammatory response in COVID-19 patients could be a fundamental step to
developing effective therapeutic strategies against SARS-CoV-2 infection.
Currently, in addition to well-defined metabolic actions, especially lipid
metabolism and glucose utilization, there is growing evidence of a central role
of the ligand-dependent nuclear receptors and peroxisome proliferator activated
receptors (PPARs) including PPARa, PPARb/d, and PPARg in the
control of inflammatory signals in various human inflammatory diseases. This
makes them attractive targets for developing therapeutic approaches to control/
suppress the hyperinflammatory response in patients with severe COVID-19. Inthis review, we (1) investigate the anti-inflammatory mechanisms mediated by
PPARs and their ligands during SARS-CoV-2 infection, and (2) on the basis of the
recent literature, highlight the importance of PPAR subtypes for the development
of promising therapeutic approaches against the cytokine storm in severe
COVID-19 patients.
The current work presents the development of a nanostructured lipid carrier (NLC) as a colloidal encapsulation and controlled release system for bioactive γ-oryzanol (GO) from rice bran oil. GO-loaded NLC (GO-NLC) were prepared using rice bran oil GO via a hot homogenisation method with sunflower oil (liquid lipid) and stearic acid (solid lipid) as the encapsulating lipid matrix, and rice bran phospholipids and Tween 80 as stabilisers. Fabricated GO-NLC had a 95% encapsulation efficiency with a spherical ‘yolk–shell’ morphology and a 143 nm mean particle diameter. A 60-day storage stability study showed that GO-NLC had high GO retention (>90%) at ambient temperature in light and dark conditions. In vitro release studies demonstrated that GO can be released from GO-NLC via different modes: slow controlled release into simulated intestinal fluid, following the Korsmeyer-Peppas model, and rapidly into a surfactant solution (Tween 80), following first-order release kinetics. Lastly, in vitro studies showed encapsulation of GO in NLCs afforded an 18-fold increase in free radical-scavenging activity, a two-fold increase in hyaluronidase-inhibitory, and a 200-fold improvement in anti-inflammatory activity. These suggest that GO-NLC is a suitable GO delivery system, which can either perform as an oral extended-release formulation or a rapid-release, surfactant triggered system, with improved health-promoting bioactivities.
The clinical presentation that emerges from the extensive coronavirus disease 2019 (COVID-19) mental health literature suggests high correlations among many conventional psychiatric diagnoses. Arguments against the use of multiple comorbidities for a single patient have been published long before the pandemic. Concurrently, diagnostic recommendations for use of transdiagnostic considerations for improved treatment have been also published in recent years. In this review, we pose the question of whether a transdiagnostic mental health disease, including psychiatric and neuropsychiatric symptomology, has emerged since the onset of the pandemic. There are many attempts to identify a syndrome related to the pandemic, but none of the validated scales is able to capture the entire psychiatric and neuropsychiatric clinical presentation in infected and non-infected individuals. These scales also only marginally touch the issue of etiology and prevalence. We suggest a working hypothesis termed Complex Stress Reaction Syndrome (CSRS) representing a global psychiatric reaction to the pandemic situation in the general population (Type A) and a neuropsychiatric reaction in infected individuals (Type B) which relates to neurocognitive and psychiatric features which are part (excluding systemic and metabolic dysfunctions) of the syndrome termed in the literature as long COVID. We base our propositions on multidisciplinary scientific data regarding mental health during the global pandemic situation and the effects of viral infection reviewed from Google Scholar and PubMed between February 1, 2022 and March 10, 2022. Search in-clusion criteria were "mental health", "COVID-19" and "Long COVID", English language and human studies only. We suggest that this more comprehensive way of understanding COVID-19 complex mental health reactions may promote better prevention and treatment and serve to guide implementation of recommended administrative regulations that were recently published by the World Psychiatric Association. This review may serve as a call for an international investigation of our working hypothesis.
Cannabidiol (CBD) can prevent the inflammatory response of SARS-CoV-2 spike protein in Caco-2-cells. This action is coupled with the inhibition of IL-1beta, IL-6, IL-18, and TNF-alpha, responsible for the inflammatory process during SARS-CoV-2 infection. CBD can act on the different proteins encoded by SARS-CoV-2 and as an antiviral agent to prevent the viral infection. Furthermore, recent studies have shown the possible action of CBD as an antagonist of cytokine release syndromes. In the SARS-CoV-2 pathophysiology, the angiotensin-converting enzyme 2 (ACE2) seems to be the key cell receptor for SARS-CoV-2 infection. The WNT/β-catenin pathway and PPARγ interact in an opposite manner in many diseases, including SARS-CoV-2 infection. CBD exerts its activity through the interaction with PPARγ in SARS-CoV-2 infection. Thus, we can hypothesize that CBD may counteract the inflammatory process of SARS-CoV-2 by its interactions with both ACE2 and the interplay between the WNT/β-catenin pathway and PPARγ. Vaccines are the only way to prevent COVID-19, but it appears important to find therapeutic complements to treat patients already affected by SARS-CoV-2 infection. The possible role of CBD should be investigated by clinical trials to show its effectiveness.
Gamma‐oryzanol (Orz), a mixture of the ferulic acid ester of triterpene alcohols and phytosterols, was found abundantly in rice bran and rice bran oil which could be available and served as an antioxidant. The present study was to explore the potential protective effects of Orz on oxidative stress and cell apoptosis in human hepatic cells (L02 cells) induced by hydrogen peroxide (H2O2). Flow cytometry detection and Hoechst 33258 staining showed that Orz significantly restored cell cycle and ameliorated apoptosis in H2O2‐challenged L02 cells. Orz pretreatment inhibited H2O2‐induced cell apoptosis by increasing the scavenging of hydroxyl radicals (OH·), and efficiently decreasing the production of nitric oxide (NO). Moreover, a loss of total antioxidant capacity (T‐AOC) and adenosine triphosphatase (ATPase) were enhanced in H2O2‐mediated L02 cells pretreated with Orz. Furthermore, preincubation with Orz reduced H2O2‐mediated the proapoptotic protein of Bak expression and the phosphorylation of ASK1, p38, JNK, and ERK, and increased the anti‐apoptotic protein of Bcl‐xl expression and anti‐oxidative stress proteins of Nrf2 and HO‐1 expression. The findings suggested that Orz exerts the cytoprotective effects in H2O2‐induced L02 cells apoptosis by ameliorating oxidative stress via inhibiting MAPK signaling pathway and activating Nrf2 signaling pathway.
Practical applications
Gamma‐oryzanol (Orz), a mixture of the ferulic acid ester of triterpene alcohols and phytosterols, was found abundantly in rice bran and rice bran oil which could be availably served as an antioxidant. In this study, it was found that Orz exerts the cytoprotective effects in H2O2‐induced L02 cell apoptosis by ameliorating oxidative stress via the inhibition of MAPK signaling pathway and the activation of Nrf2 signaling pathway, which provides a theoretical basis for dietary adding natural products to prevent or treat oxidative stress‐related diseases.
Background and aims
Many patients with coronavirus disease 2019 (COVID-19) have comorbidities related to metabolic syndrome (MS) during the disease course. Its presence in different ethnicities and continents places MS as an important risk factor for COVID-19. Adequate understanding of the interplay between MS, COVID-19 and proposed therapies is required for optimum management of these patients.
Methods
We systematically searched the PubMed and Google Scholar databases until June 1st, 2020 and accessed the full text on COVID-19 and MS to prepare a narrative review on this topic.
Results
Patients with metabolic disorders like obesity, diabetes, cardiovascular and liver disease may face a higher risk of infection of COVID-19, greatly affecting the development and prognosis of the disease, being associated with significantly worse outcome in these patients. The proposed drugs that are in clinical trial for COVID-19 treatment must be carefully considered for clinical use, especially in patients with MS.
Conclusion
MS is a risk factor influencing the progression and prognosis of COVID-2019. The drugs currently evaluated for the infection treatment are promising but need further studies to prove their efficacy and safety, due to the adverse effects may be exacerbated by combination therapy or due to viral infection. The development of a vaccine for immunization is still the best long-term solution.
COVID-19 infection has a heterogenous disease course; it may be asymptomatic or causes only mild symptoms in the majority of the cases, while immunologic complications such as macrophage activation syndrome also known as secondary hemophagocytic lymphohistiocytosis, resulting in cytokine storm syndrome and acute respiratory distress syndrome, may also occur in some patients. According to current literature, impairment of SARS-CoV-2 clearance due to genetic and viral features, lower levels of interferons, increased neutrophil extracellular traps, and increased pyroptosis and probable other unknown mechanisms create a background for severe disease course complicated by macrophage activation syndrome and cytokine storm. Various genetic mutations may also constitute a risk factor for severe disease course and occurrence of cytokine storm in COVID-19. Once, immunologic complications like cytokine storm occur, anti-viral treatment alone is not enough and should be combined with appropriate anti-inflammatory treatment. Anti-rheumatic drugs, which are tried for managing immunologic complications of COVID-19 infection, will also be discussed including chloroquine, hydroxychloroquine, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, intravenous immunoglobulin (IVIG), and colchicine. Early recognition and appropriate treatment of immunologic complications will decrease the morbidity and mortality in COVID-19 infection, which requires the collaboration of infectious disease, lung, and intensive care unit specialists with other experts such as immunologists, rheumatologists, and hematologists.
The novel coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has engulfed the world, affecting more than 180 countries. As a result, there has been considerable economic distress globally and a significant loss of life. Sadly, the vulnerable and immunocompromised in our societies seem to be more susceptible to severe COVID-19 complications. Global public health bodies and governments have ignited strategies and issued advisories on various handwashing and hygiene guidelines, social distancing strategies, and, in the most extreme cases, some countries have adopted "stay in place" or lockdown protocols to prevent COVID-19 spread. Notably, there are several significant risk factors for severe COVID-19 infection. These include the presence of poor nutritional status and pre-existing noncommunicable diseases (NCDs) such as diabetes mellitus, chronic lung diseases, cardiovascular diseases (CVD), obesity, and various other diseases that render the patient immunocompromised. These diseases are characterized by systemic inflammation, which may be a common feature of these NCDs, affecting patient outcomes against COVID-19. In this review, we discuss some of the anti-inflammatory therapies that are currently under investigation intended to dampen the cytokine storm of severe COVID-19 infections. Furthermore, nutritional status and the role of diet and lifestyle is considered, as it is known to affect patient outcomes in other severe infections and may play a role in COVID-19 infection. This review speculates the importance of nutrition as a mitigation strategy to support immune function amid the COVID-19 pandemic, identifying food groups and key nutrients of importance that may affect the outcomes of respiratory infections.
Coronavirus disease 2019 (COVID-19) and the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a particular risk to people living with preexisting conditions that impair immune response or amplify pro-inflammatory response. Low-grade chronic systemic inflammation, common in people with obesity, is associated with the development of atherosclerosis, type 2 diabetes, and hypertension, well known comorbidities that adversely affect the outcomes of patients with COVID-19. Risk stratification based on the Edmonton Obesity Staging System (EOSS), which classifies obesity based on the presence of medical, mental, and/or functional complications rather than on body mass index (BMI), has been shown to be a better predictor of all-cause mortality and it may well be that EOSS stages may better describe the risk of hyperinflammation in patients with COVID-19 infection. Analyzing a group of metabolic ill patients with obesity (EOSS 2 and 3), we found an increased interleukin-6 and linear regression analysis showed a positive correlation with C-reactive protein (CRP) (p = 0.014) and waist-to-hip-ratio (WHR) (p = 0.031). Physicians should be aware of these findings in patients with COVID-19 infection. Early identification of possible hyperinflammation could be fundamental and should guide decision making regarding hospitalization, early respiratory support, and therapy with immunosuppression to improve mortality.
Background and aims
The outbreak of the new coronavirus, SARS-CoV-2, causes a respiratory disease and individuals with pre-existing cardiometabolic disorders display worse prognosis through the infection course. The aim of this minireview is to present epidemiological data related to metabolic comorbidities in association with the SARS-CoV-2.
Methods
This is a narrative mini-review with Pubmed search until April 23, 2020 using the keywords COVID-19, SARS-CoV-2, treatment of coronavirus and following terms: diabetes mellitus, obesity, arterial hypertension, ACE-inhibitors, cytokine storm, immune response and vitamin D.
Results
Studies indicate that obese individuals are more likely to develop infections, and that adipose tissue serves as a pathogen reservoir. In diabetic individuals higher rate of inflammatory processes is seen due to constant glucose recognition by C type lectin receptors. Hypertensive individuals, usually grouped with other conditions, are treated with drugs to reduce blood pressure mostly through ACEi and ARB, that leads to increased ACE2 expression, used by SARS-CoV-2 for human's cell entry. Until now, the studies have shown that individuals with those conditions and affected by COVID-19 present an uncontrolled release of pro-inflammatory cytokines and an unbalanced immune response, leading to the cytokine storm phenomenon. Vitamin D is highlighted as a potential therapeutic target, because in addition to acting on the immune system, it plays an important role in the control of cardiometabolic diseases.
Conclusion
Currently, since there is no proven and effective antiviral therapy for SARS-CoV-2, the efforts should focus on controlling inflammatory response and reduce the risks of associated complications.
The cytokine storm is an abnormal production of inflammatory cytokines, due to the over-activation of the innate immune response. This mechanism has been recognized as a critical mediator of influenza-induced lung disease, and it could be pivotal for COVID-19 infections. Thus, an immunomodulatory approach targeting the over-production of cytokines could be proposed for viral aggressive pulmonary disease treatment. In this regard, the peroxisome proliferator-activated receptor (PPAR)-γ, a member of the PPAR transcription factor family, could represent a potential target. Beside the well-known regulatory role on lipid and glucose metabolism, PPAR-γ also represses the inflammatory process. Similarly, the PPAR-γ agonist thiazolidinediones (TZDs), like pioglitazone, are anti-inflammatory drugs with ameliorating effects on severe viral pneumonia. In addition to the pharmacological agonists, also nutritional ligands of PPAR-γ, like curcuma, lemongrass, and pomegranate, possess anti-inflammatory properties through PPAR-γ activation. Here, we review the main synthetic and nutritional PPAR-γ ligands, proposing a dual approach based on the strengthening of the immune system using pharmacological and dietary strategies as an attempt to prevent/treat cytokine storm in the case of coronavirus infection.
Preliminary data suggest that people with obesity are at increased risk of severe COVID-19. However, as data on metabolic parameters (such as BMI and levels of glucose and insulin) in patients with COVID-19 are scarce, increased reporting is needed to improve our understanding of COVID-19 and the care of affected patients.
In the veterinary sector, many papers deal with the relationships between inflammation and oxidative stress. However, few studies investigate the mechanisms of action of oxidised molecules in the regulation of immune cells. Thus, authors often assume that these events, sometime leading to oxidative stress, are conserved among species. The aim of this review is to draw the state-of-the-art of the current knowledge about the role of oxidised molecules and dietary antioxidant compounds in the regulation of the immune cell functions and suggest some perspectives for future investigations in animals of veterinary interest.
The kidney is an important organ in the maintenance of body homeostasis. Dietary compounds, reactive metabolites, obesity, and metabolic syndrome (MetS) can affect renal filtration and whole body homeostasis, increasing the risk of chronic kidney disease (CKD) development. Gamma oryzanol ( γ Oz) is a compound with antioxidant and anti-inflammatory activity that has shown a positive action in the treatment of obesity and metabolic diseases. Aim . To evaluate the effect of γ Oz to recover renal function in obese animals by high sugar-fat diet by modulation of adiponectin receptor 2/PPAR- α axis Methods . Male Wistar rats were initially randomly divided into 2 experimental groups: control and high sugar-fat diet (HSF) for 20 weeks. When proteinuria was detected, HSF animals were allocated to receive γ Oz or maintain HSF for more than 10 weeks. The following were analyzed: nutritional and biochemical parameters, systolic blood pressure, and renal function. In the kidney, the following were evaluated: inflammation, oxidative stress, and protein expression by Western blot. Results . After 10 weeks of γ Oz treatment, γ Oz was effective to improve inflammation, increase antioxidant enzyme activities, increase the protein expression of adiponectin receptor 2 and PPAR- α , and recover renal function. Conclusion . These results permit us to confirm that γ Oz is able to modulate PPAR- α expression, inflammation, and oxidative stress pathways improving obesity-induced renal disease.
Peroxisome proliferator-activated receptors (PPARs) are members of a family of nuclear hormone receptors that exert their transcriptional control on genes harboring PPAR-responsive regulatory elements (PPRE) in partnership with retinoid X receptors (RXR). The activation of PPARs coordinated by specific coactivators/repressors regulate networks of genes controlling diverse homeostatic processes involving inflammation, adipogenesis, lipid metabolism, glucose homeostasis, and insulin resistance. Defects in PPARs have been linked to lipodystrophy, obesity, and insulin resistance as a result of the impairment of adipose tissue expandability and functionality. PPARs can act as lipid sensors, and when optimally activated, can rewire many of the metabolic pathways typically disrupted in obesity leading to an improvement of metabolic homeostasis. PPARs also contribute to the homeostasis of adipose tissue under challenging physiological circumstances, such as pregnancy and aging. Given their potential pathogenic role and their therapeutic potential, the benefits of PPARs activation should not only be considered relevant in the context of energy balance-associated pathologies and insulin resistance but also as potential relevant targets in the context of diabetic pregnancy and changes in body composition and metabolic stress associated with aging. Here, we review the rationale for the optimization of PPAR activation under these conditions.
Background:
The high consumption of fat and sugar contributes to the development of obesity and co-morbidities, such as diabetes, and cardiovascular and kidney diseases. Different strategies have been used to prevent these diseases associated with obesity, such as changes in eating habits and/or the addition of dietary components with anti-inflammatory and anti-oxidant properties, such as gamma-oryzanol (γOz) present mainly in bran layers and rice germ.
Methods:
Animals were randomly divided into four experimental groups and fed ad libitum for 20 weeks with control diet (C, n = 8), control diet + γOz (C + γOz, n = 8), high-sugar and high-fat diet (HSF, n = 8), and high-sugar and high-fat diet + γOz (HSF + γOz, n = 8). HSF groups also received water + sucrose (25%). The dose of γOz was added to diets to reach 0.5% of final concentration (w/w). Evaluation in animals included food and caloric intake, body weight, plasma glucose, insulin, triglycerides, uric acid, HOMA-IR, glomerular filtration rate, protein/creatinine ratio, systolic blood pressure, and Doppler echocardiographic.
Results:
Animals that consumed the HSF diet had weight gain compared to group C, increased insulin, HOMA, glucose and triglycerides, there were also atrial and ventricular structural alterations, deterioration of systolic and diastolic function, decreased glomerular filtration rate, and proteinuria. Gamma-oryzanol is significantly protective against effects on body weight, hypertriglyceridemia, renal damage, and against structural and functional alteration of the heart.
Conclusion:
Gamma-oryzanol shows potential as a therapeutic to prevent Cardiorenal Metabolic Syndrome.
Obesity is associated with low-grade inflammation, triggered in adipose tissue, which may occur due to an excess of SFA from the diet that can be recognised by Toll-like receptor-4. This condition is involved in the development of components of the metabolic syndrome associated with obesity, especially insulin resistance. The aim of the study was to evaluate the manifestation of the metabolic syndrome and adipose tissue inflammation as a function of the period of time in which rats were submitted to a high-sugar/fat diet (HSF). Male Wistar rats were divided into six groups to receive the control diet (C) or the HSF for 6, 12 or 24 weeks. HSF increased the adiposity index in all HSF groups compared with the C group. HSF was associated with higher plasma TAG, glucose, insulin and leptin levels. Homeostasis model assessment increased in HSF compared with C rats at 24 weeks. Both TNF-α and IL-6 were elevated in the epididymal adipose tissue of HSF rats at 24 weeks compared with HSF at 6 weeks and C at 24 weeks. Only the HSF group at 24 weeks showed increased expression of both Toll-like receptor-4 and NF-κB. More inflammatory cells were found in the HSF group at 24 weeks. We can conclude that the metabolic syndrome occurs independently of the inflammatory response in adipose tissue and that inflammation is associated with hypertrophy of adipocytes, which varies according to duration of exposure to the HSF.
Ƴ-oryzanol (Orz), a steryl ferulate extracted from rice bran layer, exerts a wide spectrum of biological activities. In addition to its antioxidant activity, Orz is often associated with cholesterol-lowering, anti-inflammatory, anti-cancer and anti-diabetic effects. In recent years, the usefulness of Orz has been studied for the treatment of metabolic diseases, as it acts to ameliorate insulin activity, cholesterol metabolism, and associated chronic inflammation. Previous studies have shown the direct action of Orz when downregulating the expression of genes that encode proteins related to adiposity (CCAAT/enhancer binding proteins (C/EBPs)), inflammatory responses (nuclear factor kappa-B (NF-κB)), and metabolic syndrome (peroxisome proliferator-activated receptors (PPARs)). It is likely that this wide range of beneficial activities results from a complex network of interactions and signals triggered, and/or inhibited by its antioxidant properties. This review focuses on the significance of Orz in metabolic disorders, which feature remarkable oxidative imbalance, such as impaired glucose metabolism, obesity, and inflammation.
Restraint stress may be associated with elevated free radicals, and thus, chronic exposure to oxidative stress may cause tissue damage. Several studies have reported that carvacrol (CAR) has a protective effect against oxidative stress. The present study was designed to investigate the protective effects of CAR on restraint stress induced oxidative stress damage in the brain, liver, and kidney. For chronic restraint stress, rats were kept in the restrainers for 6 h every day, for 21 consecutive days. The animals received systemic administrations of CAR daily for 21 days. To evaluate the changes of the oxidative stress parameters following restraint stress, the levels of malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT) activities were measured in the brain, liver, and kidney. In the stressed animals that received vehicle, the MDA level was significantly higher (
P
<
0.001
) and the levels of GSH and antioxidant enzymes were significantly lower than the nonstressed animals (
P
<
0.001
). CAR ameliorated the changes in the stressed animals as compared with the control group (
P
<
0.001
). This study indicates that CAR can prevent restraint stress induced oxidative damage.
The prevalence of obesity has increased in the past two decades. This growth has been attributed to changes in dietary habits, especially increased consumption of fats and sugars. It is clear that obesity is a risk factor for cardiovascular disease and insulin resistance, and the inflammatory process favors this context. Aim: To address the inflammatory aspects of obesity and associated metabolic complications. Data Sources: Original data from articles found through search of scientific databases. Summary of findings: Micro hypoxia, reticulum stress, and activation of toll-like receptor 4 are responsible for triggering inflammation in adipose tissue, which is the place where the process begins. Thus, there is an increased production of various adipokines, such as IL-6 and TNF-α, which impair insulin signaling pathway, leading to resistance to hormone, one of the first complications of obesity. From this, with the intensity of stimulation, the condition may worsen triggering type 2 diabetes and other comorbidities. Conclusion: Thus, the elucidation of the roles and mechanisms of the main adipokines lead to a better understanding of the pathogenesis of obesity-related disorders.
Many in vitro studies have been performed to investigate whether oxygen tension is involved in the regulation of metabolic and inflammatory processes in adipose tissue, as extensively reviewed elsewhere (6, 20). Earlier studies examined the effects of acute, short-term (1–24 h) exposure to extremely low PO2 (usually 1% O2) as compared to a ~20-fold higher O2 concentration (ambient air, 21% O2) on the expression and/or secretion of key adipokines involved in inflammation and metabolism. Most of these studies have demonstrated that extremely low PO2 induces a pro-inflammatory response in 3T3-L1 adipocytes (18, 27–31), human adipocytes (32), stromal–vascular cells (33, 34), and macrophages (18, 35), although conflicting results have also been reported (36, 37). On the other hand, 95% O2 also increased pro-inflammatory gene expression and reactive oxygen species (ROS) content, and reduced glucose uptake in 3T3-L1 adipocytes (38). These in vitro studies should be interpreted with some caution, because these cells were acutely exposed to extremely low (or high) PO2. In addition, two independent laboratories, including ours, have recently provided evidence that human abdominal subcutaneous AT PO2 ranges between ~3 and 11% O2 (~23–84 mmHg) (9, 10). Therefore, cell culture experiments investigating the effects of chronic exposure to more physiological PO2 are urgently warranted.
Studies that have examined the relationship between in vivo AT PO2 and the inflammatory phenotype of adipose tissue in humans have yielded conflicting results, showing both positive (9) and inverse (10) correlations. Interestingly, human primary adipocytes have recently been exposed to physiological PO2 levels (5 versus 10 versus 21% O2) during differentiation (14 days) (39). Of note, 5 and 10% O2 reflect the mean AT PO2 values that we have previously found in lean insulin sensitive and obese insulin resistant individuals, respectively (9). The authors were able to demonstrate that exposure to 10% O2 increased adipocyte triacylglycerol (TAG) content and boosted the secretion rates of IL-6 and DPP-4 (39). Interestingly, DPP-4 is involved in cross talk between adipose tissue and skeletal muscle, and has been shown to inhibit skeletal muscle insulin signaling (40).
The high morbidity of metabolic dysfunction diseases has heightened interest in seeking natural and safe compounds to maintain optimal health. γ-Oryzanol (OZ), the ferulic acid (FA) ester with phytosterols, mainly present in rice bran has been shown to improve markers of metabolic syndrome. This study investigates the effects of FA and OZ on alleviating high-fat and high-fructose diet (HFFD)-induced metabolic syndrome parameters.
Male SD rats were fed with a regular rodent diet, HFFD, or HFFD supplemented with 0.05% FA or 0.16% OZ (equimolar concentrations) for 13 weeks. Food intake, organ indices, serum lipid profiles, glucose metabolism, insulin resistance (IR) index and cytokine levels were analyzed. The mechanisms were further investigated in oleic acid-stimulated HepG2 cells by analyzing triglyceride (TG) content and lipogenesis-related gene expressions.
In the in vivo study, FA and OZ exhibited similar effects in alleviating HFFD-induced obesity, hyperlipidemia, hyperglycemia, and IR. However, only OZ treatment significantly decreased liver index and hepatic TG content, lowered serum levels of C-reactive protein and IL-6, and increased serum concentration of adiponectin. In the in vitro assay, only OZ administration significantly inhibited intracellular TG accumulation and down-regulated expression of stearoyl coenzyme-A desaturase-1, which might facilitate OZ to enhance its hepatoprotective effect.
OZ is more effective than FA in inhibiting hepatic fat accumulation and inflammation. Thus, FA and OZ could be used as dietary supplements to alleviate the deleterious effects of HFFD.
Background/Aims
The aim of this study was to evaluate whether supplementation of high doses of cholecalciferol for two months in normotensive rats results in increased systolic arterial pressure and which are the mechanisms involved. Specifically, this study assesses the potential effect on cardiac output as well as the changes in aortic structure and functional properties.
Methods
Male Wistar rats were divided into three groups: 1) Control group (C, n = 20), with no supplementation of vitamin D, 2) VD3 (n = 19), supplemented with 3,000 IU vitamin D/kg of chow; 3) VD10 (n = 21), supplemented with 10,000 IU vitamin D/kg of chow. After two months, echocardiographic analyses, measurements of systolic arterial pressure (SAP), vascular reactivity, reactive oxygen species (ROS) generation, mechanical properties, histological analysis and metalloproteinase-2 and -9 activity were performed.
Results
SAP was higher in VD3 and VD10 than in C rats (p = 0.001). Echocardiographic variables were not different among groups. Responses to phenylephrine in endothelium-denuded aortas was higher in VD3 compared to the C group (p = 0.041). Vascular relaxation induced by acetylcholine (p = 0.023) and sodium nitroprusside (p = 0.005) was impaired in both supplemented groups compared to the C group and apocynin treatment reversed impaired vasodilation. Collagen volume fraction (<0.001) and MMP-2 activity (p = 0.025) was higher in VD10 group compared to the VD3 group. Elastin volume fraction was lower in VD10 than in C and yield point was lower in VD3 than in C.
Conclusion
Our findings support the view that vitamin D supplementation increases arterial pressure in normotensive rats and this is associated with structural and functional vascular changes, modulated by NADPH oxidase, nitric oxide, and extracellular matrix components.
Increased adipocyte size and number are associated with many of the adverse effects observed in metabolic disease states. While methods to quantify such changes in the adipocyte are of scientific and clinical interest, manual methods to determine adipocyte size are both laborious and intractable to large scale investigations. Moreover, existing computational methods are not fully automated. We, therefore, developed a novel automatic method to provide accurate measurements of the cross-sectional area of adipocytes in histological sections, allowing rapid high-throughput quantification of fat cell size and number. Photomicrographs of H&E-stained paraffin sections of murine gonadal adipose were transformed using standard image processing/analysis algorithms to reduce background and enhance edge-detection. This allowed the isolation of individual adipocytes from which their area could be calculated. Performance was compared with manual measurements made from the same images, in which adipocyte area was calculated from estimates of the major and minor axes of individual adipocytes. Both methods identified an increase in mean adipocyte size in a murine model of obesity, with good concordance, although the calculation used to identify cell area from manual measurements was found to consistently over-estimate cell size. Here we report an accurate method to determine adipocyte area in histological sections that provides a considerable time saving over manual methods.
Lipid storage is an evolutionary conserved process that exists in all organisms from simple prokaryotes to humans. In Metazoa, long-term lipid accumulation is restricted to specialized cell types, while a dedicated tissue for lipid storage (adipose tissue) exists only in vertebrates. Excessive lipid accumulation is associated with serious health complications including insulin resistance, type 2 diabetes, cardiovascular diseases and cancer. Thus, significant advances have been made over the last decades to dissect out the molecular and cellular mechanisms involved in adipose tissue formation and maintenance. Our current understanding of adipose tissue development comes from in vitro cell culture and mouse models, as well as recent approaches to study lipid storage in genetically tractable lower organisms. This Commentary gives a comparative insight into lipid storage in uni- and multi-cellular organisms with a particular emphasis on vertebrate adipose tissue. We also highlight the molecular mechanisms and nutritional signals that regulate the formation of mammalian adipose tissue.
Several missense mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor (PPAR)gamma have been described in subjects with dominantly inherited severe insulin resistance associated with partial lipodystrophy, hypertension, and dyslipidemia. These mutant receptors behave as dominant-negative inhibitors of PPARgamma signaling when studied in transfected cells. The extent to which such dominant-negative effects extend to signaling through other coexpressed PPAR isoforms has not been evaluated. To examine these issues further, we have created a PPARalpha mutant harboring twin substitutions, Leu459Ala and Glu462Ala, within the ligand binding domain (PPARalpha(mut)), examined its signaling properties, and compared the effects of dominant-negative PPARalpha and PPARgamma mutants on basal and ligand-induced gene transcription in adipocytes and hepatocytes. PPARalpha(mut) was transcriptionally inactive, repressed basal activity from a PPAR response element-containing promoter, inhibited the coactivator function of cotransfected PPAR-gamma coactivator 1alpha, and strongly inhibited the transcriptional response to cotransfected wild-type receptor. In contrast to PPARgamma, wild-type PPARalpha failed to recruit the transcriptional corepressors NCoR and SMRT. However, PPARalpha(mut) avidly recruited these corepressors in a ligand-dissociable manner. In hepatocytes and adipocytes, both PPARalpha(mut) and the corresponding PPARgamma mutant were capable of inhibiting the expression of genes primarily regulated by PPARalpha, -gamma, or -delta ligands, albeit with some differences in potency. Thus, dominant-negative forms of PPARalpha and PPARgamma are capable of interfering with PPAR signaling in a manner that is not wholly restricted to their cognate target genes. These findings may have implications for the pathogenesis of human syndromes resulting from mutations in this family of transcription factors.
For infectious-disease outbreaks, clinical solutions typically focus on efficient pathogen destruction. However, the COVID-19 pandemic provides a reminder that infectious diseases are complex, multisystem conditions, and a holistic understanding will be necessary to maximize survival. For COVID-19 and all other infectious diseases, metabolic processes are intimately connected to the mechanisms of disease pathogenesis and the resulting pathology and pathophysiology, as well as the host defence response to the infection. Here, I examine the relationship between metabolism and COVID-19. I discuss why preexisting metabolic abnormalities, such as type 2 diabetes and hypertension, may be important risk factors for severe and critical cases of infection, highlighting parallels between the pathophysiology of these metabolic abnormalities and the disease course of COVID-19. I also discuss how metabolism at the cellular, tissue and organ levels might be harnessed to promote defence against the infection, with a focus on disease-tolerance mechanisms, and speculate on the long-term metabolic consequences for survivors of COVID-19. The importance of metabolism in the course of SARS-Cov-2 infection is highlighted by the metabolic comorbidities of COVID-19. In this Perspective, Ayres provides insight into how current knowledge of immunometabolism and metabolic diseases can inform the understanding of COVID-19 pathology, and proposes potential metabolism-based clinical solutions.
•The rate of obesity was increased during this era of the COVID-19 epidemic.
•Obesity is dangerous in COVID-19 patients.
. Obesity is associated with other co-morbidities could affect the prognosis of COVID-19 patients.
Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes.
Obesity is gaining acceptance as a serious primary health burden that impairs the quality of life because of its associated complications, including diabetes, cardiovascular diseases, cancer, asthma, sleep disorders, hepatic dysfunction, renal dysfunction, and infertility. It is a complex metabolic disorder with a multifactorial origin. Growing evidence suggests that oxidative stress plays a role as the critical factor linking obesity with its associated complications. Obesity per se can induce systemic oxidative stress through various biochemical mechanisms, such as superoxide generation from NADPH oxidases, oxidative phosphorylation, glyceraldehyde auto-oxidation, protein kinase C activation, and polyol and hexosamine pathways. Other factors that also contribute to oxidative stress in obesity include hyperleptinemia, low antioxidant defense, chronic inflammation, and postprandial reactive oxygen species generation. In addition, recent studies suggest that adipose tissue plays a critical role in regulating the pathophysiological mechanisms of obesity and its related co-morbidities. To establish an adequate platform for the prevention of obesity and its associated health risks, understanding the factors that contribute to the cause of obesity is necessary. The most current list of obesity determinants includes genetic factors, dietary intake, physical activity, environmental and socioeconomic factors, eating disorders, and societal influences. On the basis of the currently identified predominant determinants of obesity, a broad range of strategies have been recommended to reduce the prevalence of obesity, such as regular physical activity, ad libitum food intake limiting to certain micronutrients, increased dietary intake of fruits and vegetables, and meal replacements. This review aims to highlight recent findings regarding the role of oxidative stress in the pathogenesis of obesity and its associated risk factors, the role of dysfunctional adipose tissue in development of these risk factors, and potential strategies to regulate body weight loss/gain for better health benefits.
Severe influenza remains unusual in its virulence for humans. Complications or ultimately death arising from these infections are often associated with hyperinduction of proinflammatory cytokine production, which is also known as 'cytokine storm'. For this disease, it has been proposed that immunomodulatory therapy may improve the outcome, with or without the combination of antiviral agents. Here, we review the current literature on how various effectors of the immune system initiate the cytokine storm and exacerbate pathological damage in hosts. We also review some of the current immunomodulatory strategies for the treatment of cytokine storms in severe influenza, including corticosteroids, peroxisome proliferator-activated receptor agonists, sphingosine-1-phosphate receptor 1 agonists, cyclooxygenase-2 inhibitors, antioxidants, anti-tumour-necrosis factor therapy, intravenous immunoglobulin therapy, statins, arbidol, herbs, and other potential therapeutic strategies.Cellular & Molecular Immunology advance online publication, 20 July 2015; doi:10.1038/cmi.2015.74.
Metabolic syndrome (MS) includes the presence of arterial hypertension, insulin resistance, dyslipidemia, cardiovascular disease (CVD) and abdominal obesity, which is associated with a chronic inflammatory response, characterized by abnormal adipokine production, and the activation of certain pro-inflammatory signaling pathways. Furthermore, the changes presented by the adipose tissue in MS favors the secretion of several molecular mediators capable of activating or suppressing a number of transcription factors, such as the peroxisome proliferator-activated receptors (PPARs), whose main functions include storage regulation and fatty acid catabolization. When they are activated by their ligands (synthetic or endogenous), they control several genes involved in intermediate metabolism, which make them, together with the PPAR gamma coactivator-1-α (PGC-1) and the silent information regulator T1 (SIRT1), good targets for treating metabolic diseases and their cardiovascular complications.
The process of adipogenesis is known to involve the interplay of several transcription factors. Activation of one of these factors, the nuclear hormone receptor PPARγ, is known to promote fat cell differentiation in vitro. Whether PPARγ is required for this process in vivo has remained an open question because a viable loss-of-function model for PPARγ has been lacking. We demonstrate here that mice chimeric for wild-type and PPARγ null cells show little or no contribution of null cells to adipose tissue, whereas most other organs examined do not require PPARγ for proper development. In vitro, the differentiation of ES cells into fat is shown to be dependent on PPARγ gene dosage. These data provide direct evidence that PPARγ is essential for the formation of fat.
The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-DeltaDeltaCr) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-DeltaDeltaCr) method. In addition, we present the derivation and applications of two variations of the 2(-DeltaDeltaCr) method that may be useful in the analysis of real-time, quantitative PCR data. (C) 2001 Elsevier science.
During the 2009 H1N1 influenza pandemic, obesity was convincingly identified as a novel, independent risk factor for multiple markers of disease severity. Associations between numerous nosocomial and community-acquired clinical infections have previously been established; yet, little is known about the mechanisms underpinning the increased susceptibility to severe outcomes following pandemic H1N1/09 infection in obesity. Here, we present a brief synthesis of the recent advances in our understanding of the immunomodulatory effects of obesity on outcomes following respiratory viral infection, with a particular focus on pandemic influenza.
The effects of oryzanol and ferulic acid on the glucose metabolism of high-fat-fed mice were investigated. Male C57BL/6N mice were randomly divided into 4 groups: NC group fed with normal control diet; HF group fed with high-fat (17%) diet; HF-O group fed with high-fat diet supplemented with 0.5% oryzanol; and HF-FA group fed with high-fat diet supplemented with 0.5% ferulic acid. All animals were allowed free access to the experimental diets and water for 7 wk. At the end of the experimental period, the HF-O and HF-FA groups exhibited significantly lower blood glucose level and glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities, and higher glycogen and insulin concentrations and glucokinase (GK) activity compared with NC and HF groups. The results of this study illustrate that both oryzanol and ferulic acid could reduce the risk of high-fat diet-induced hyperglycemia via regulation of insulin secretion and hepatic glucose-regulating enzyme activities.
Newly emerged influenza viruses have attracted extensive attention due to their high infectivity, proinflammatory actions, and potential to induce worldwide pandemics. Frequent mutations and gene reassortments between viruses complicate the development of protective vaccines and antiviral therapeutics. In contrast, targeting the host response for the development of novel cost-effective, broad-based prophylactic or therapeutic agents holds greater promise. Since inflammation often parallels the development of productive immune responses, virus-induced pulmonary inflammation and injury represents an additional challenge to the development of broad-based immunotherapeutics. Excessive inflammatory responses to respiratory viruses, also known as "cytokine storm," are largely due to immune dysregulation that manifests as proinflammatory cytokine secretion. In addition to modulating lipid and glucose metabolism, peroxisome proliferator-activated receptors (PPAR) play important roles in antagonizing core inflammatory pathways such as NF-kappaB, AP1, and STAT. Their role in regulating inflammatory responses caused by pulmonary pathogens is receiving increasing attention, setting the stage for the discovery of novel applications for anti-diabetic and lipid-lowering drugs. This review focuses on the potential use of PPAR-gamma agonists to downregulate the inflammatory responses to respiratory virus-related pulmonary inflammation.
A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data.
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