Search

Atherosclerosis is a major instigator of cardiovascular disease (CVD) and a main cause of global morbidity and mortality. The high prevalence of CVD calls for urgent attention to possible preventive measures in order to curb its incidence. Traditional risk factors of atherosclerosis, like age, smoking, diabetes mellitus, dyslipidemia, hypertension and chronic inflammation, are under extensive investigation. However, these only account for around 50% of the etiology of atherosclerosis, mandating a search for different or overlooked risk factors. In this regard, chronic infections, by Helicobacter pylori for instance, are a primary candidate. H. pylori colonizes the gut and contributes to several gastrointestinal diseases, but, recently, the potential involvement of this bacterium in extra-gastric diseases including CVD has been under the spotlight. Indeed, H. pylori infection appears to stimulate foam cell formation as well as chronic immune responses that could upregulate key inflammatory mediators including cytokines, C-reactive protein, and lipoproteins. These factors are involved in the thickening of intima-media of carotid arteries (CIMT), a hallmark of atherosclerosis. Interestingly, H. pylori infection was found to increase (CIMT), which along with other evidence, could implicate H. pylori in the pathogenesis of atherosclerosis. Nevertheless, the involvement of H. pylori in CVD and atherosclerosis remains controversial as several studies report no connection between H. pylori and atherosclerosis. This review examines and critically discusses the evidence that argues for a potential role of this bacterium in atherogenesis. However, additional basic and clinical research studies are warranted to convincingly establish the association between H. pylori and atherosclerosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Aramouni, Assaf, Azar, Jabbour, Shaito, Sahebkar, Eid, Rizzo and Eid.)

Pulmonary fibrosis (PF) is a feared component in over 200 interstitial pulmonary diseases, which are characterized by increased alveolar wall thickness, excessive scarring, and aberrant extracellular matrix restructuring that, ultimately, affect lung compliance and capacity. As a result of its broad range of biological activities, including antioxidant, anti-inflammatory, antiapoptotic, and many others, resveratrol has been shown to be an effective treatment for respiratory system diseases, including interstitial lung disease, infectious diseases, and lung cancer. This work reviews the known molecular therapeutic targets of resveratrol and its potential mechanisms of action in attenuating PF in respiratory diseases, including cancer, COVID-19, interstitial lung diseases (ILDs) of known etiologies, idiopathic interstitial pneumonia, and ILDs associated with systemic disorders, such as rheumatoid arthritis, systemic sclerosis, Schrödinger's syndrome, systemic lupus erythematosus, and pulmonary hypertension. The current issues and controversies related to the possible use of resveratrol as a pharmaceutical drug or supplement are also discussed., Competing Interests: The authors declare no conflict of interest. Given his role as Editor, Gianfranco Pintus had no involvement in the peer-review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Md Soriful Islam., (© 2023 The Author(s). Published by IMR Press.)

Cellular oxidation-reduction (redox) systems, which encompass pro- and antioxidant molecules, are integral components of a plethora of essential cellular processes. Any dysregulation of these systems can cause molecular imbalances between the pro- and antioxidant moieties, leading to a state of oxidative stress. Long-lasting oxidative stress can manifest clinically as a variety of chronic illnesses including cancers, neurodegenerative disorders, cardiovascular disease, and metabolic diseases like diabetes. As such, this review investigates the impact of oxidative stress on the human body with emphasis on the underlying oxidants, mechanisms, and pathways. It also discusses the available antioxidant defense mechanisms. The cellular monitoring and regulatory systems that ensure a balanced oxidative cellular environment are detailed. We critically discuss the notion of oxidants as a double-edged sword, being signaling messengers at low physiological concentrations but causative agents of oxidative stress when overproduced. In this regard, the review also presents strategies employed by oxidants including redox signaling and activation of transcriptional programs such as those mediated by the Nrf2/Keap1 and NFk signaling. Likewise, redox molecular switches of peroxiredoxin and DJ-1 and the proteins they regulate are presented. The review concludes that a thorough comprehension of cellular redox systems is essential to develop the evolving field of redox medicine., (© 2023 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)

The tremendous success of immunotherapy in clinical trials has led to its establishment as a new pillar of cancer therapy. However, little clinical efficacy has been achieved in microsatellite stable colorectal cancer (MSS-CRC), which constitutes most CRC tumors. Here, we discuss the molecular and genetic heterogeneity of CRC. We review the immune escape mechanisms, and focus on the latest advances in immunotherapy as a treatment modality for CRC. By providing a better understanding of the tumor microenvironment (TME) and the molecular mechanisms underlying immunoevasion, this review offers an insight into developing therapeutic strategies that are effective for patients with various subsets of CRC., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cadmium is an environmental toxicant that instigates cognitive deficits with excessive glutamate excitatory neuroactivity in the brain. Topiramate, a glutamate receptor antagonist, has displayed favorable neuroprotection against epilepsy, cerebral ischemia, and Huntington's disease; however, its effect on cadmium neurotoxicity remains to be investigated. In this study, topiramate was tested for its potential to combat the cognitive deficits induced by cadmium in rats with an emphasis on hippocampal oxidative insult, apoptosis, and autophagy. After topiramate intake (50 mg/kg/day; p.o.) for 8 weeks, behavioral disturbances and molecular changes in the hippocampal area were explored. Herein, Morris water maze, Y-maze, and novel object recognition test revealed that topiramate rescued cadmium-induced memory/learning deficits. Moreover, topiramate significantly lowered hippocampal histopathological damage scores. Mechanistically, topiramate significantly replenished hippocampal GLP-1 and dampened Aβ42 and p-tau neurotoxic cues. Notably, it significantly diminished hippocampal glutamate content and enhanced acetylcholine and GABA neurotransmitters. The behavioral recovery was prompted by hippocampal suppression of the pro-oxidant events with notable activation of SIRT1/Nrf2/HO-1 axis. Moreover, topiramate inactivated GSK-3β and dampened the hippocampal apoptotic changes. In tandem, stimulation of hippocampal pro-autophagy events, including Beclin 1 upregulation, was triggered by topiramate that also activated AMPK/mTOR pathway. Together, the pro-autophagic, antioxidant, and anti-apoptotic features of topiramate contributed to its neuroprotective properties in rats intoxicated with cadmium. Therefore, it may be useful to mitigate cadmium-induced cognitive deficits.

Cadmium is an environmental contaminant associated with marked neurotoxicity and cognitive impairment. Linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated promising neuroprotection against cerebral ischemia and diabetic dementia. However, there has been no study of its effect on cadmium-induced cognitive deficits. In the present work, linagliptin's prospective neuroprotective effects against cadmium-evoked cognitive decline were examined in vivo in rats. The molecular pathways related to oxidative stress, apoptosis, and autophagy were investigated. Histology, immunohistochemistry, ELISA, and biochemical assays were performed on brain hippocampi after receiving linagliptin (5 mg/kg/day). The current findings revealed that cadmium-induced learning and memory impairment were improved by linagliptin as seen in the Morris water maze, Y-maze, and novel object recognition test. Moreover, linagliptin lowered hippocampal neurodegeneration as seen in histopathology. At the molecular level, linagliptin curtailed hippocampal DPP-4 and augmented GLP-1 levels, triggering dampening of the hippocampal neurotoxic signals Aβ42 and p-tau in rats. Meanwhile, it enhanced hippocampal acetylcholine and GABA and diminished the glutamate spike. The behavioral recovery was associated with dampening of the hippocampal pro-oxidant response alongside SIRT1/Nrf2/HO-1 axis stimulation. Meanwhile, linagliptin counteracted hippocampal apoptosis markers and inhibited the pro-apoptotic kinase GSK-3β. In tandem, linagliptin activated hippocampal autophagy by lowering SQSTM-1/p62 accumulation, upregulating Beclin 1, and stimulating AMPK/mTOR pathway. In conclusion, linagliptin's antioxidant, antiapoptotic, and pro-autophagic properties advocated its promising neuroprotective impact. Thus, linagliptin may serve as a management approach against cadmium-induced cognitive deficits.

Cadmium (Cd) is a widespread environmental pollutant that triggers testicular dysfunction. Dapagliflozin is a selective sodium-glucose co-transporter-2 inhibitor with notable antioxidant and anti-apoptotic features. It has shown marked cardio-, reno-, hepato-, and neuroprotective effects. Yet, its effect on Cd-evoked testicular impairment has not been examined. Hence, the goal of the current study was to investigate the potential positive effect of dapagliflozin against Cd-induced testicular dysfunction in rats, with an emphasis on autophagy, apoptosis, and oxidative insult. Dapagliflozin (1 mg/kg/day) was given by oral gavage, and testicular dysfunction, impaired spermatogenesis, and biomolecular events were studied via immunohistochemistry, histopathology, and ELISA. The current findings demonstrated that dapagliflozin improved relative testicular weight, serum testosterone, and sperm count/motility and reduced sperm abnormalities, signifying mitigation of testicular impairment and spermatogenesis disruption. Moreover, dapagliflozin attenuated Cd-induced histological abnormalities and preserved testicular structure. The testicular function recovery was prompted by stimulating the cytoprotective SIRT1/Nrf2/HO-1 axis, lowering the testicular oxidative changes, and augmenting cellular antioxidants. As regards apoptosis, dapagliflozin counteracted the apoptotic machinery by downregulating the pro-apoptotic signals together with Bcl-2 upregulation. Meanwhile, dapagliflozin reactivated the impaired autophagy, as seen by a lowered accumulation of SQSTM-1/p62 and Beclin 1 upregulation. In the same context, the testicular AMPK/mTOR pathway was stimulated as evidenced by the increased p-AMPK (Ser487)/total AMPK ratio alongside the lowered p-mTOR (Ser2448)/total mTOR ratio. Together, the favorable mitigation of Cd-induced testicular impairment/disrupted spermatogenesis was driven by the antioxidant, anti-apoptotic, and pro-autophagic actions of dapagliflozin. Thus, it could serve as a tool for the management of Cd-evoked testicular dysfunction.

Anthocyanins are colored polyphenolic compounds that belong to the flavonoids family and are largely present in many vegetables and fruits. They have been used in traditional medicine in many cultures for a long time. The most common and abundant anthocyanins are those presenting an O-glycosylation at C-3 (C ring) of the flavonoid skeleton to form -O-β-glucoside derivatives. The present comprehensive review summarized recent data on the anticancer properties of cyanidings along with natural sources, phytochemical data, traditional medical applications, molecular mechanisms and recent nanostrategies to increase the bioavailability and anticancer effects of cyanidins. For this analysis, in vitro, in vivo and clinical studies published up to the year 2022 were sourced from scientific databases and search engines such as PubMed/Medline, Google scholar, Web of Science, Scopus, Wiley and TRIP database. Cyanidins' antitumor properties are exerted during different stages of carcinogenesis and are based on a wide variety of biological activities. The data gathered and discussed in this review allows for affirming that cyanidins have relevant anticancer activity in vitro, in vivo and clinical studies. Future research should focus on studies that bring new data on improving the bioavailability of anthocyanins and on conducting detailed translational pharmacological studies to accurately establish the effective anticancer dose in humans as well as the correct route of administration., Competing Interests: Conflict of interest statement The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Hypertension remains a major contributor to cardiovascular disease (CVD), a leading cause of global death. One of the major insults that drive increased blood pressure is inflammation. While it is the body's defensive response against some homeostatic imbalances, inflammation, when dysregulated, can be very deleterious. In this review, we highlight and discuss the causative relationship between inflammation and hypertension. We critically discuss how the interplay between inflammation and reactive oxygen species evokes endothelial damage and dysfunction, ultimately leading to narrowing and stiffness of blood vessels. This, along with phenotypic switching of the vascular smooth muscle cells and the abnormal increase in extracellular matrix deposition further exacerbates arterial stiffness and noncompliance. We also discuss how hyperhomocysteinemia and microRNA act as links between inflammation and hypertension. The premises we discuss suggest that the blue-sky scenarios for targeting the underlying mechanisms of hypertension necessitate further research., (© 2023 Wiley Periodicals LLC.)

Breast cancer continues to be the leading cause of cancer-related deaths among women worldwide. The most aggressive type of breast cancer is triple-negative breast cancer (TNBC). Indeed, not only does TNBC not respond well to several chemotherapeutic agents, but it also frequently develops resistance to various anti-cancer drugs, including taxane mitotic inhibitors. This necessitates the search for newer, more efficacious drugs. In this study, we synthesized two novel chromene derivatives ( C1 and C2 ) and tested their efficacy against a battery of luminal type A and TNBC cell lines. Our results show that C1 and C2 significantly and specifically inhibited TNBC cell viability but had no effect on the luminal A cell type. In addition, these novel compounds induced mitotic arrest, cell multinucleation leading to senescence, and apoptotic cell death through the activation of the extrinsic pathway. We also showed that the underlying mechanisms for these actions of C1 and C2 involved inhibition of microtubule polymerization and disruption of the F-actin cytoskeleton. Furthermore, both compounds significantly attenuated migration of TNBC cells and inhibited angiogenesis in vitro. Finally, we performed an in silico analysis, which revealed that these novel variants bind to the colchicine binding site in β-tubulin. Taken together, our data highlight the potential chemotherapeutic properties of two novel chromene compounds against TNBC.

In 1957, cyclic adenosine monophosphate (cAMP) was identified as the first secondary messenger, and the first signaling cascade discovered was the cAMP-protein kinase A (PKA) pathway. Since then, cAMP has received increasing attention given its multitude of actions. Not long ago, a new cAMP effector named exchange protein directly activated by cAMP (Epac) emerged as a critical mediator of cAMP's actions. Epac mediates a plethora of pathophysiologic processes and contributes to the pathogenesis of several diseases such as cancer, cardiovascular disease, diabetes, lung fibrosis, neurological disorders, and others. These findings strongly underscore the potential of Epac as a tractable therapeutic target. In this context, Epac modulators seem to possess unique characteristics and advantages and hold the promise of providing more efficacious treatments for a wide array of diseases. This paper provides an in-depth dissection and analysis of Epac structure, distribution, subcellular compartmentalization, and signaling mechanisms. We elaborate on how these characteristics can be utilized to design specific, efficient, and safe Epac agonists and antagonists that can be incorporated into future pharmacotherapeutics. In addition, we provide a detailed portfolio for specific Epac modulators highlighting their discovery, advantages, potential concerns, and utilization in the context of clinical disease entities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

This systematic review and meta-analysis evaluated the effect of nuts in decreasing circulating levels of oxidized low-density lipoproteins (ox-LDL). A literature search was performed of major electronic databases (MEDLINE/PubMed, Scopus, and ISI Web of Science) from inception up to November 15th, 2021 to find randomized controlled trials (RCTs) evaluating the effect of different nuts on circulating levels of ox-LDL. The effect size was determined using standardized mean difference (SMD) and corresponding 95% confidence intervals (CI). Evaluation of funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used to assess the presence of publication bias in the meta-analysis. This systematic review and meta-analysis included 15 RCTs involving 997 subjects. Meta-analysis showed that nuts significantly decreased serum levels of ox-LDL. Besides, meta-regression results of the association between confounders such as duration of nuts consumption or delta LDL-cholesterol and levels of ox-LDL, were not significant. The correlation between nuts type and ox-LDL levels was significant in subgroup analyses suggesting the most significant effect of pistachios consumption on reducing the circulating concentrations of ox-LDL. To conclude, nuts consumption decreases the circulating concentrations of ox-LDL which might be beneficial for the prevention and/or progression of ASCVD., (© 2023 John Wiley & Sons Ltd.)

The coronavirus disease-19 (COVID-19) pandemic is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the molecular and cellular levels, the SARS-CoV-2 uses its envelope glycoprotein, the spike S protein, to infect the target cells in the lungs via binding with their transmembrane receptor, the angiotensin-converting enzyme 2 (ACE2). Here, we wanted to investigate if other molecular targets and pathways may be used by SARS-CoV-2. We investigated the possibility of the spike 1 S protein and its receptor-binding domain (RBD) to target the epidermal growth factor receptor (EGFR) and its downstream signaling pathway in vitro using the lung cancer cell line (A549 cells). Protein expression and phosphorylation were examined upon cell treatment with the recombinant full spike 1 S protein or RBD. We demonstrate for the first time the activation of EGFR by the Spike 1 protein associated with the phosphorylation of the canonical Extracellular signal-regulated kinase1/2 (ERK1/2) and AKT kinases and an increase in survivin expression controlling the survival pathway. Our study suggests the putative implication of EGFR and its related signaling pathways in SARS-CoV-2 infectivity and COVID-19 pathology. This may open new perspectives in the treatment of COVID-19 patients by targeting EGFR.

Cancer is the second most life-threatening disease and has become a global health and economic problem worldwide. Due to the multifactorial nature of cancer, its pathophysiology is not completely understood so far, which makes it hard to treat. The current therapeutic strategies for cancer lack the efficacy due to the emergence of drug resistance and the toxic side effects associated with the treatment. Therefore, the search for more efficient and less toxic cancer treatment strategies is still at the forefront of current research. Propolis is a mixture of resinous compounds containing beeswax and partially digested exudates from plants leaves and buds. Its chemical composition varies widely depending on the bee species, geographic location, plant species, and weather conditions. Since ancient times, propolis has been used in many conditions and aliments for its healing properties. Propolis has well-known therapeutic actions including antioxidative, antimicrobial, anti-inflammatory, and anticancer properties. In recent years, extensive in vitro and in vivo studies have suggested that propolis possesses properties against several types of cancers. The present review highlights the recent progress made on the molecular targets and signaling pathways involved in the anticancer activities of propolis. Propolis exerts anticancer effects primarily by inhibiting cancer cell proliferation, inducing apoptosis through regulating various signaling pathways and arresting the tumor cell cycle, inducing autophagy, epigenetic modulations, and further inhibiting the invasion and metastasis of tumors. Propolis targets numerous signaling pathways associated with cancer therapy, including pathways mediated by p53, β-catenin, ERK1/2, MAPK, and NF-κB. Possible synergistic actions of a combination therapy of propolis with existing chemotherapies are also discussed in this review. Overall, propolis, by acting on diverse mechanisms simultaneously, can be considered to be a promising, multi-targeting, multi-pathways anticancer agent for the treatment of various types of cancers.

In addition to their lipid-lowering functions, statins elicit additional pleiotropic effects on apoptosis, angiogenesis, inflammation, senescence, and oxidative stress. Many of these effects have been reported in cancerous and noncancerous cells like endothelial cells (ECs), endothelial progenitor cells (EPCs) and human umbilical vein cells (HUVCs). Not surprisingly, statins' effects appear to vary largely depending on the cell context, especially as pertains to modulation of cell cycle, senescence, and apoptotic processes. Perhaps the most critical reason for this discordance is the bias in selecting the applied doses in various cells. While lower (nanomolar) concentrations of statins impose anti-senescence, and antiapoptotic effects, higher concentrations (micromolar) appear to precipitate opposite effects. Indeed, most studies performed in cancer cells utilized high concentrations, where statin-induced cytotoxic and cytostatic effects were noted. Some studies report that even at low concentrations, statins induce senescence or cytostatic impacts but not cytotoxic effects. However, the literature appears to be relatively consistent that in cancer cells, statins, in both low or higher concentrations, induce apoptosis or cell cycle arrest, anti-proliferative effects, and cause senescence. However, statins' effects on ECs depend on the concentrations; at micromolar concentrations statins cause cell senescence and apoptosis, while at nonomolar concentrations statins act reversely., (© 2023. The Author(s).)

Purpose: This study aimed to ascertain the diagnostic accuracy of non-invasive liver function tests in liver fibrosis and assess their changes after metabolic surgery., Materials and Methods: 1005 individuals with severe obesity who were referred for metabolic surgery were analysed. All participants had blood samples taken for liver enzymes and lipid profile. In addition, hepatic indexes, including AAR, APRI, NFS and Fibrosis-4 (FIB4), were checked. Furthermore, all participants underwent two-dimensional shear wave elastography (2D-SWE). All investigations were repeated 6-8 months after metabolic surgery. The receiver operating characteristic (ROC) curve and the area under the ROC curve was utilised to determine the optimal cut-off values for baseline study parameters. Logistic regression was applied to predict the relationship between study parameters-as predictors-and change in 2D-SWE., Results: AST/ALT (AAR) was the most sensitive (79%) pre-operative non-invasive serological marker for detecting liver fibrosis, whereas NAFLD Fibrosis Score (NFS) was the most specific (84%). AST/upper limit of the normal AST range × 100/platelets (× 10 9 /L) (APRI) showed a positive correlation with 2D-SWE post-metabolic surgery (p-value = 0.021). Regression analysis from both adjusted and unadjusted models showed that baseline AAR was a predictor of postoperative liver status in terms of hepatic fibrosis., Conclusion: AAR has a high sensitivity, whereas NFS exhibits a high specificity in diagnosing liver fibrosis. The authors recommend using both investigations in conjunction with 2D-SWE to increase the likelihood of detecting liver fibrosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Traumatic brain injury (TBI) constitutes a serious public health concern. Although TBI targets the brain, it can exert several systemic effects which can worsen the complications observed in TBI subjects. Currently, there is no FDA-approved therapy available for its treatment. Thus, there has been an increasing need to understand other factors that could modulate TBI outcomes. Among the factors involved are diet and lifestyle. High-fat diets (HFD), rich in saturated fat, have been associated with adverse effects on brain health., Main Methods: To study this phenomenon, an experimental mouse model of open head injury, induced by the controlled cortical impact was used along with high-fat feeding to evaluate the impact of HFD on brain injury outcomes. Mice were fed HFD for a period of two months where several neurological, behavioral, and molecular outcomes were assessed to investigate the impact on chronic consequences of the injury 30 days post-TBI., Key Findings: Two months of HFD feeding, together with TBI, led to a notable metabolic, neurological, and behavioral impairment. HFD was associated with increased blood glucose and fat-to-lean ratio. Spatial learning and memory, as well as motor coordination, were all significantly impaired. Notably, HFD aggravated neuroinflammation, oxidative stress, and neurodegeneration. Also, cell proliferation post-TBI was repressed by HFD, which was accompanied by an increased lesion volume., Significance: Our research indicated that chronic HFD feeding can worsen functional outcomes, predispose to neurodegeneration, and decrease brain recovery post-TBI. This sheds light on the clinical impact of HFD on TBI pathophysiology and rehabilitation as well., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Adverse pregnancy outcomes are considered significant health risks for pregnant women and their offspring during pregnancy and throughout their lifespan. These outcomes lead to a perturbated in-utero environment that impacts critical phases of the fetus's life and correlates to an increased risk of chronic pathological conditions, such as diabetes, obesity, and cardiovascular diseases, in both the mother's and adult offspring's life. The dietary intake of naturally occurring antioxidants promotes health benefits and disease prevention. In this regard, maternal dietary intake of polyphenolic antioxidants is linked to a reduced risk of maternal obesity and cardio-metabolic disorders, positively affecting both the fetus and offspring. In this work, we will gather and critically appraise the current literature highlighting the effect/s of the naturally occurring polyphenol antioxidant resveratrol on oxidative stress, inflammation, and other molecular and physiological phenomena associated with pregnancy and pregnancy conditions, such as gestational diabetes, preeclampsia, and preterm labor. The resveratrol impact on prenatal complications and pregnancy-associated structures, such as the fetus and placenta, will also be discussed. Finally, we will draw conclusions from the current knowledge and provide future perspectives on potentially exploiting resveratrol as a therapeutic tool in pregnancy-associated conditions.

Background: Cancer continues to be the second leading cause of death worldwide, with colorectal cancer (CRC) being the third most common type. Despite significant advances in cancer therapies, the current treatment of CRC remains suboptimal. In addition, the effectiveness of available chemotherapeutic drugs such as 5-Fluorouracil (5-FU) is limited by CRC-acquired resistance., Methods: In this study, we provide innovative approaches employed in synthesizing four novel nucleobase analogs. Equally, we describe the effects of these compounds on proliferation, migration, aggregation, and adhesion of 5-FU-sensitive (HCT116) and -resistant (5-FU-R-HCT116) human CRC cells. In either cell type, our synthesized novel analogs significantly inhibited cell viability in a concentration- and time-dependent manner. This highlights the higher potency of these novel analogs. In addition, these compounds attenuated migration and adhesion of both cell types while they promoted homotypic cell-cell interaction., Results: These changes were reflected by the downregulation of matrix metalloproteases (MMP-2 and MMP-9). Furthermore, our analogs exhibited potent anti-angiogenic activity in vivo., Conclusion: These novel nucleobase analogs reduced the level of secreted vascular endothelial growth factor (VEGF) and nitric oxide (NO) production in both 5-FU-sensitive and -resistant CRC cells. Taken together, our data highlight the potential chemotherapeutic properties of our novel analogs against CRC, including the 5-FU-resistant form., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Given the ambiguity surrounding traumatic brain injury (TBI) pathophysiology and the lack of any Food and Drug Administration (FDA)-approved neurotherapeutic drugs, there is an increasing need to better understand the mechanisms of TBI. Recently, the roles of inflammasomes have been highlighted as both potential therapeutic targets and diagnostic markers in different neurodegenerative disorders. Indeed, inflammasome activation plays a pivotal function in the central nervous system (CNS) response to many neurological conditions, as well as to several neurodegenerative disorders, specifically, TBI. This comprehensive review summarizes and critically discusses the mechanisms that govern the activation and assembly of inflammasome complexes and the major methods used to study inflammasome activation in TBI and its implication for other neurodegenerative disorders. Also, we will review how inflammasome activation is critical in CNS homeostasis and pathogenesis, and how it can impact chronic TBI sequalae and increase the risk of developing neurodegenerative diseases. Additionally, we discuss the recent updates on inflammasome-related biomarkers and the potential to utilize inflammasomes as putative therapeutic targets that hold the potential to better diagnose and treat subjects with TBI., Competing Interests: Declarations of interest JPdRV is a co-founder and managing member of InflamaCORE, LLC, and has licensed patents on inflammasome proteins as biomarkers of injury and disease as well as on targeting inflammasome proteins for therapeutic purposes. JPdRV is a Scientific Advisory Board Member of ZyVersa Therapeutics Inc., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Neurodegenerative disorders include different neurological conditions that affect nerve cells, causing the progressive loss of their functions and ultimately leading to loss of mobility, coordination, and mental functioning. The molecular mechanisms underpinning neurodegenerative disease pathogenesis are still unclear. Nonetheless, there is experimental evidence to demonstrate that the perturbation of mitochondrial function and dynamics play an essential role. In this context, mitochondrial biogenesis, the growth, and division of preexisting mitochondria, by controlling mitochondria number, plays a vital role in maintaining proper mitochondrial mass and function, thus ensuring efficient synaptic activity and brain function. Mitochondrial biogenesis is tightly associated with the control of cell division and variations in energy demand in response to extracellular stimuli; therefore, it may represent a promising therapeutic target for developing new curative approaches to prevent or counteract neurodegenerative disorders. Accordingly, several inducers of mitochondrial biogenesis have been proposed as pharmacological targets for treating diverse central nervous system conditions. The naturally occurring polyphenol resveratrol has been shown to promote mitochondrial biogenesis in various tissues, including the nervous tissue, and an ever-growing number of studies highlight its neurotherapeutic potential. Besides preventing cognitive impairment and neurodegeneration through its antioxidant and anti-inflammatory properties, resveratrol has been shown to be able to enhance mitochondria biogenesis by acting on its main effectors, including PGC-1α, SIRT1, AMPK, ERRs, TERT, TFAM, NRF-1 and NRF-2. This review aims to present and discuss the current findings concerning the impact of resveratrol on the machinery and main effectors modulating mitochondrial biogenesis in the context of neurodegenerative diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

SARS-CoV-2 infects cells through angiotensin-converting enzyme 2 (ACE2), a ubiquitous receptor that interacts with the virus' surface S glycoprotein. Recent reports show that the virus affects the central nervous system (CNS) with symptoms and complications that include dizziness, altered consciousness, encephalitis, and even stroke. These can immerge as indirect immune effects due to increased cytokine production or via direct viral entry into brain tissue. The latter is possible through neuronal access via the olfactory bulb, hematogenous access through immune cells or directly across the blood-brain barrier (BBB), and through the brain's circumventricular organs characterized by their extensive and highly permeable capillaries. Last, the COVID-19 pandemic increases stress, depression, and anxiety within infected individuals, those in isolation, and high-risk populations like children, the elderly, and health workers. This review surveys the recent updates of CNS manifestations post SARS-CoV-2 infection along with possible mechanisms that lead to them.

Cardiometabolic diseases present an escalating global health and economic burden. Such a surge is driven by epidemic prevalence rates of metabolic disorders, such as obesity and type 2 diabetes, and their associated cardiovascular complications, majorly contributing to morbidity and mortality. A fundamental challenge impeding the effective management and therapy of these complications is a lack of clear understanding of the molecular mechanisms underpinning disease initiation and progression. Over the past decade, a role for metabolic disease-associated adipose tissue dysfunction and inflammation in evoking cardiovascular and renal deterioration emerged, together with a growing recognition of the positive impact of pharmacological tools modulating adipose tissue function. Adipose tissue is a plastic endocrine organ whose homeostasis is essentially dependent on the intercellular communication of its comprising cellular components. Yet, despite being a principal regulator of adipose tissue metabolic activity, changes in aspects of adipose tissue mitochondrial biogenesis, dynamics, and bioenergetics in the context of cardiometabolic disorders have not garnered the necessary attention. Here, we gather the available evidence on the contribution of mitochondrial dysfunction to that of the adipose tissue in metabolic diseases, and to the ensuing cardiovascular deterioration. The involved molecular pathways are highlighted together with potential targets for intervention. The effects of several drug classes with known beneficial impact on adipose tissue remodeling and mitochondrial dysfunction in such a context are discussed. Finally, future research aspects in this domain are explored., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Topiramate, a promising drug classically used for the management of neurological disorders including epilepsy and migraine, has demonstrated marked anti-inflammatory and anti-apoptotic actions in murine models of cardiac post-infarction inflammation, wound healing, and gastric/intestinal injury. However, its potential impact on cadmium-induced testicular injury remains to be elucidated. Herein, the present study aimed to explore the effect of topiramate against cadmium-invoked testicular impairment with emphasis on the molecular mechanisms linked to inflammation, apoptosis, and autophagy. Herein, administration of topiramate (50 mg/kg/day, by gavage) continued for 60 days and the testes were examined by histology, immunohistochemistry, and biochemical assays. The present data demonstrated that serum testosterone, sperm count/abnormalities, relative testicular weight, and histopathological aberrations were improved by topiramate administration to cadmium-intoxicated rats. The rescue of testicular dysfunction was driven by multi-pronged mechanisms including suppression of NLRP3/caspase-1/IL-1β cascade, which was evidenced by dampened caspase-1 activity, lowered IL-1β/IL-18 production, and decreased nuclear levels of activated NF-κBp65. Moreover, curbing testicular apoptosis was seen by lowered Bax expression, decreased caspase-3 activity, and upregulation of Bcl-2. In tandem, testicular autophagy was activated as seen by diminished p62 SQSTM1 accumulation alongside Beclin-1 upregulation. Autophagy activation was associated with AMPK/mTOR pathway stimulation demonstrated by decreased mTOR (Ser2448) phosphorylation and increased AMPK (Ser487) phosphorylation. In conclusion, combating inflammation/apoptosis and enhancing autophagic events by topiramate were engaged in ameliorating cadmium-induced testicular impairment.

Exaggerated cold-induced vasoconstriction can precipitate a pathogenesis called Raynaud's phenomenon (RP). Interestingly, RP is significantly more prevalent in females than age-matched men, highlighting the potential implication of 17β-estradiol (E 2 ) in the etio-pathogenesis of this disease. Indeed, we have previously reported that E 2 stimulates the expression of vascular alpha 2C-adrenoceptors (α 2C -AR), the sole mediator of cold-induced constriction of cutaneous arterioles. This induced expression occurs through the cyclic adenosine monophosphate → exchange protein activated by cAMP→ Ras-related protein 1→ c-Jun N-terminal kinase→ activator protein-1 (cAMP/Epac/Rap/JNK/AP-1 pathway). On the basis that estrogen-induced rapid cAMP accumulation and JNK activation occurs so rapidly we hypothesized that a non-classic, plasma membrane estrogen receptor was the mediator. We then showed that an impermeable form of E 2 , namely E 2 :BSA, mimics E 2 effects suggesting a role for the membranous G-protein coupled estrogen receptor (GPER) in E 2 -induced α 2C -AR expression. Our current working hypothesis and unpublished observations further cement this finding, as G1, a GPER agonist, mimics while G15, a GPER antagonist, abrogates estrogen's effect on the expression of vascular α 2C -AR. These, and other observations, highlight the potential of GPER as a tractable target in the management of RP, particularly in pre-menopausal women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fardoun, Mondello, Kobeissy and Eid.)

Colorectal Cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Despite the notable advances achieved over the last few decades, CRC remains a hard-to-treat deadly disease in many patients. This is attributed mainly to chemo- and immuno-resistance, which frequently emerge soon after treatment with conventional therapeutics. Systemic treatments are also constrained by their many undesired and serious side effects. More recently, nanomedicine has emerged as an attractive modality that can overcome issues of therapeutic resistance, improper delivery, or suboptimal targeting of tumor cells. Many nanomaterials, having already been examined in pre-clinical and clinical studies, are now considered biocompatible and relatively safe. Indeed, around 50 nano-formulations have so far been approved as diagnostic and therapeutic agents in humans. Here, in this review, we describe a set of imperative nanoparticles (NPs) involved in diagnosing and treating CRC. In particular, we discuss the theragnostic roles of quantum dots, iron oxide NPs, Polylactide-co-glycolic acid (PLGA) NPs, dendrimer NPs, carbon nanotubes, liposomes, and gold NPs. We dissect the molecular and clinical evidence supporting the use of these NPs in CRC. We also highlight their implications in targeted drug delivery as well as their anti-tumorigenic properties and effects on the cardinal hallmarks of CRC. We conclude by highlighting the notion that nanomedicine is emerging as an attractive approach to address the unmet needs in managing several diseases, including CRC., Competing Interests: Conflict of interest The authors declare there is no conflict of interest to be reported., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Pronounced anti-inflammatory and anti-apoptotic features have been characterized for the angiotensin receptor blocker irbesartan. Yet, its effect on ethanol-induced gastropathy has not been studied. The present work explored the potential modulation of inflammatory, apoptotic, and autophagic events by irbesartan for the attenuation of ethanol-evoked gastric mucosal injury., Methodology: Wistar rats were divided into control, control + irbesartan, ethanol, ethanol + irbesartan, and ethanol + omeprazole groups. Macroscopic examination, histopathology, immunohistochemistry, and biochemical assays were applied to examine the gastric tissues., Key Findings: Irbesartan administration (50 mg/kg; by gavage) in ethanol-evoked gastropathy improved the gastric pathological manifestations (area of gastric lesion and ulcer index scores), histopathological changes, and microscopic damage scores. These beneficial effects were interceded by suppression of the HMGB1-associated inflammatory events and the linked downregulation of the nuclear NF-κBp65 protein expression. In the meantime, curtailing of the NLRP3 inflammasome by irbesartan was observed with consequent decline of the pro-inflammatory cytokine IL-1β. In tandem, upregulation of the antioxidant Nrf2 and the cytoprotective PPAR-γ were seen. Together, suppression of the pro-inflammatory cues and pro-oxidant signals attenuated the pro-apoptotic events as evidenced by Bcl-2 upregulation, Bax downregulation, and caspase 3 dampened activity. Regarding gastric autophagy signals, irbesartan diminished SQSTM-1/p62 accumulation and upregulated Beclin 1. This was associated with gastric AMPK/mTOR pathway activation evidenced by increased AMPK (Ser487) phosphorylation and lowered mTOR (Ser2448) phosphorylation., Conclusion: Suppression of the inflammatory and apoptotic signals and upregulation of the pro-autophagy events may advocate the promising gastroprotective actions of irbesartan against ethanol-induced gastric injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Tumor growth and progression are strictly dependent on the adequate blood supply of oxygen and nutrients. The formation of new blood vessels and vascular networks is essential to ensure this demand. Blood vessels also facilitate the invasion of cancer cells into nearby tissues and their subsequent metastasis. Tumor cells represent the main driver of the neovascularization process through the direct or indirect, by neighboring non-cancer cells, release of pro-angiogenic molecules. The mediators (e.g., growth factors and extracellular matrix components), signaling pathways, cellular components, and processes (e.g., endothelial cell proliferation and migration) activated in tumor angiogenesis are similar to those involved in normal vascular development, except they lack efficient control mechanisms. Consequently, newly formed tumor vessels are typically fragile and hyperpermeable with a reduced and erratic blood flow. Targeting the tumor vasculature has been the focus of intense research over the last 20 years. However, despite the initial interest and expectations, the systemic use of anti-angiogenic drugs has not always led to therapeutic breakthroughs and, in some cases, has been associated with the development of tumor adaptive resistance resulting in a more aggressive phenotype. Therefore, new therapeutic approaches have focused on combining anti-angiogenic agents with chemotherapy or immunotherapy and/or optimizing (normalizing) the structure and function of tumor blood vessels to ensure a more efficient drug delivery. In this context, nanomedicine offers the significant advantage of targeting and releasing anti-angiogenic drugs at specific sites, minimizing toxicity in healthy tissues. Several nanoparticles possess intrinsic modulatory effects on angiogenesis, while others have been developed to facilitate drug delivery in association with chemotherapy, thermotherapy, radiotherapy or in response to specific stimuli within the tumor environment (e.g., enzymes, ions, redox potential) or exogenous stimuli (e.g., temperature, electricity, magnetic fields, and ultrasound). Other nanoparticles can modify, under specific conditions, their physical properties (e.g., dimensions, structure, and interactions) to increase penetration in tumor cells. This review provides a comprehensive appraisal of the critical modulators of tumor vascular biology, the most promising nano-strategies that specifically target such modulators, and the directions for future research and clinical applications., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Objectives: The heterogeneity of the coronavirus disease of 2019 (COVID-19) lies within its diverse symptoms and severity, ranging from mild to lethal. Acute respiratory distress syndrome (ARDS) is a leading cause of mortality in COVID-19 patients, characterized by a hyper cytokine storm. Autoimmunity is proposed to occur as a result of COVID-19, given the high similarity of the immune responses observed in COVID-19 and autoimmune diseases. Here, we investigate the level of autoimmune antibodies in COVID-19 patients with different severities., Results: Initial screening for antinuclear antibodies (ANA) IgG using ELISA revealed that 1.58% (2/126) and 4% (5/126) of intensive care unit (ICU) COVID-19 cases expressed strong and moderate ANA levels, respectively. An additional sample was positive with immunofluorescence assays (IFA) screening. However, all the non-ICU cases (n=273) were ANA negative using both assays. Samples positive for ANA were further confirmed with large-scale autoantibody screening by phage immunoprecipitation-sequencing (PhIP-Seq). The majority of the ANA-positive samples showed "speckled" ANA pattern by microscopy and revealed autoantibody specificities that targeted proteins involved in intracellular signal transduction, metabolism, apoptotic processes, and cell death by PhIP-Seq; further denoting reactivity to nuclear and cytoplasmic antigens., Conclusion: Our results further support the notion of routine screening for autoimmune responses in COVID-19 patients, which might help improve disease prognosis and patient management. Further, results provide compelling evidence that ANA-positive individuals should be excluded from being donors for convalescent plasma therapy in the context of COVID-19., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Abdominal aortic aneurysm (AAA) is a prevalent condition which causes progressive growth and rupture of aortic wall with a high death rate. Several studies have found that treatment with statins may decrease the progress of AAA and the risk of rupture by suppressing the inflammatory mediators, decreasing oxidative stress, and inhibiting mechanisms involved in extracellular matrix (ECM) degradation. Moreover, some studies have reported that prehospital therapy with statins can decrease mortality after surgery. The novelty of this paper is that different studies including those performed in humans and animals were reviewed and the potential mechanisms by which statins can have an effect on AAA were summarized. Overall, the evidence suggested an association between treatment with statins and improvement of AAA., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Obesity, and in particular extreme obesity, as a global health problem is an important risk factor for many diseases, including atherosclerotic cardiovascular disease (ACVD). Bariatric surgery might stop or slow atherogenesis by decreasing excessive weight in the early stages of atherogenesis, by suppressing low-grade systemic inflammation as well as by inhibiting oxidative stress and endothelial dysfunction. The aim of this meta-analysis was to provide an answer to whether bariatric surgery has a significant effect on intima-media thickness (IMT) which is a surrogate marker of early atherosclerosis and has a good correlation with atherosclerotic coronary heart disease., Methods: A systematic literature search in PubMed, Scopus, Embase, and Web of Science as well as grey literature was performed from inception to 1 July 2022. The meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V3 software. Overall, the estimate of effect size was measured by a random effects meta-analysis. To account for the heterogeneity of studies regarding study design, characteristics of the populations, and treatment duration, a random-effects model (using the DerSimonian-Laird method) and the generic inverse variance weighting approach were used. To assess the existence of publication bias in the meta-analysis, the funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used., Results: The meta-analysis of 30 trials, including 1488 subjects, demonstrated a significant decrease in IMT after bariatric surgery. The reduction in IMT was also robust in the leave-one-out sensitivity analysis. It must be stressed that the results of the random-effects meta-regression did not suggest any relationship between the changes in IMT and delta body mass index (BMI) or duration of follow-up after the bariatric surgery. However, the subgroup analyses showed a better IMT reduction after laparoscopic sleeve gastrectomy (LSG) when compared to Roux-en-Y gastric bypass (RYGB). Within a year, the IMT follow-up values showed a further improvement., Conclusions: Bariatric surgery significantly reduced IMT. Significant associations were found between the surgery type and IMT changes, as well as a significant effect of follow-up duration on the changes of IMT after bariatric surgery.

Cardiovascular disease (CVD) continues to be the primary cause of global mortality. Vascular smooth muscle cells (VSMCs) are integral components of vascular structure and function, evident by their vital roles in modulating blood flow and pressure. Such roles exist due to the differentiated contractile phenotype of VSMCs. However, VSMCs may switch to a dedifferentiated, proliferative synthetic phenotype in a phenomenon known as phenotypic switching. This switch involves dramatic changes in VSMC migration, proliferation, gene expression programs, differentiation, cellular stiffness and extracellular matrix (ECM) deposition. In this review, we explore the role of the small GTPase Rho and its effector, Rho-associated kinase (ROCK), in phenotypic switching as well as apoptotic pathways in VSMCs. We critically dissect how RhoA promotes cell migration and proliferation as well as its role in modulating the expression of a battery of VSMC marker proteins. We also discuss how RhoA modulates apoptosis, induces dedifferentiation, increases vascular stiffness, or modifies ECM accumulation. These alterations in VSMC phenotypes contribute to multiple vascular dysfunctions, including hypertension and atherosclerosis. Understanding the molecular underpinnings and the signaling pathways involved in these altered phenotypes may provide novel avenues of drug design and other therapeutic interventions for the management of CVDs., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Inhibition of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by statins is affected by inhibiting the active site of the enzyme in a competitive manner. Statins reduce plasma cholesterol by inhibiting its de novo synthesis. In addition, statins impart 'pleiotropic' activities that do not directly relate to their ability to decrease cholesterol. The proangiogenic and antiangiogenic characteristics of statins are among these pleiotropic effects. These angiogenic-modifying properties could offer new therapeutic applications. Statins stimulate or suppress angiogenesis in a biphasic manner. Whereas low doses of statin stimulate angiogenesis, high doses reduce protein prenylation and limit cell development and angiogenesis. In this review, we discuss how statins impact angiogenesis, with a particular focus on angiogenesis in stroke and cardiovascular disease (CVD)., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Statins are the most widely used drugs for decreasing elevated serum LDL-cholesterol (LDL-C) and thus for the prevention of atherosclerotic cardiovascular disease (ASCVD), but they have also some pleiotropic effects, including anti-inflammatory properties. Atherosclerosis is a low-grade inflammatory disease, and elevated ferritin is considered to be one of the markers of inflammation. Since the results of studies on the effects of statins on serum ferritin levels are conflicting, this meta-analysis was performed., Methods: A literature search was performed using major electronic databases (MEDLINE/PubMed, Scopus, Embase, and ISI Web of Science) from inception up to 5 March 2022 to find studies evaluating the effect of different statins on serum ferritin levels. The effect size was determined using weighted mean differences (WMDs) and the corresponding 95% confidence intervals (CIs)., Results: The meta-analysis of nine studies (1611 patients) analyzing the effects of statins on serum ferritin levels that were included showed a significant decrease in circulating ferritin levels caused by statins. The results did not suggest any significant association between the changes in concentrations of serum ferritin and the duration of treatment with statins., Conclusions: Statin therapy decreases the circulating concentrations of ferritin, which might be beneficial for the prevention and/or progression of ASCVD. This effect might be explained by the anti-inflammatory effects and maybe some other pleiotropic effects of statins and not by their lipid-lowering effects.

Salvia officinalis is a medicinal plant used to treat some diseases, including microbial infections and diabetes. Different studies showed the biological and pharmacological properties of this species. The aim of this study was the determination of the chemical compounds of S. officinalis essential oils and the investigation of their antimicrobial, antioxidant, antidiabetic, and anti-inflammatory properties. The chemical compounds of S. officinalis were determined by GC-MS analysis. The antioxidant activity was assessed by DPPH, ABTS, H 2 O 2 , and FRAP assays. The in vitro antidiabetic effect was evaluated by the inhibition of α-amylase, α-glucosidase, and lipase activities, and the anti-inflammatory effect was evaluated using the 5-lipoxygenase assay. Moreover, antibacterial activity was assessed against six bacterial strains using agar well diffusion assay and microdilution method. The main compounds in essential oils of S. officinalis at three phenological stages were naphthalenone, camphor, 1.8-cineole, and α-thujone. The full flowering stage essential oil showed the best antioxidant activity with different IC 50 values according to the used tests. This oil also exhibited important inhibitory effects at the full flowering stage against α-amylase (IC 50 = 69.23 ± 0.1 μg/mL), α-glucosidase (IC 50 = 22.24 ± 0.07 μg/mL), and lipase (IC 50 = 37.3 ± 0.03 μg/mL). The 5-lipoxygenase inhibitory effect was the best at the full flowering stage (IC 50 = 9.24 ± 0.03 μg/mL). The results of the antibacterial evaluation revealed that, at three seasonal periods, S. officinalis essential oil demonstrated strong antibacterial activity. Although the full flowering stage had the best antibacterial activity, there were no significant differences between the three stages. Additionally, the essential oils showed bactericidal effects on Listeria monocytogenes , Staphylococcus aureus , Bacillus subtilis , Proteus mirabilis , Escherichia coli , and Salmonella typhimurium , respectively. The findings of this work showed remarkably that S. officinalis synthesizes essential oils according to different developmental stages. Moreover, it has exhibited interesting biological and pharmacological properties justifying its medicinal effects and suggesting it as a very important source of natural drugs.

Osteoarthritis (OA) is a progressive joint disease. The etiology of OA is considered to be multifactorial. Currently, there is no definitive treatment for OA, and the existing treatments are not very effective. Hypercholesterolemia is considered a novel risk factor for the development of OA. Statins act as a competitive inhibitor of the β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase and are widely used to manage hypercholesterolemia. Inhibition of HMG-CoA reductase results in reduced synthesis of a metabolite named mevalonate, thereby reducing cholesterol biosynthesis in subsequent steps. By this mechanism, statins such as atorvastatin and simvastatin could potentially have a preventive impact on joint cartilage experiencing osteoarthritic deterioration by reducing serum cholesterol levels. Atorvastatin can protect cartilage degradation following interleukin-1β-stimulation. Atorvastatin stimulates the STAT1-caspase-3 signaling pathway that was shown to be responsible for its anti-inflammatory effects on the knee joint. Simvastatin had chondroprotective effects on OA in vitro by reducing matrix metalloproteinases expression patterns. In this study, we tried to review the therapeutic effects of statins on OA., (© 2022 Wiley Periodicals LLC.)

There have been significant advances, particularly over the last 20 years, in the identification of non-coding RNAs (ncRNAs) and their pathophysiological role in a wide range of disease states, particularly cancer and other chronic conditions characterized by excess inflammation and oxidative stress such as atherosclerosis, diabetes, obesity, multiple sclerosis, osteoporosis, liver and lung fibrosis. Such discoveries have potential therapeutic implications as a better understanding of the molecular mechanisms underpinning the effects of ncRNAs on critical homeostatic control mechanisms and biochemical pathways might lead to the identification of novel druggable targets. In this context, increasing evidence suggests that several natural compounds can target ncRNAs at different levels and, consequently, influence processes involved in the onset and progression of disease states. The natural phenol resveratrol has been extensively studied for therapeutic purposes in view of its established anti-inflammatory and antioxidant effects, particularly in disease states such as cancer and cardiovascular disease that are associated with human aging. However, increasing in vitro and in vivo evidence also suggests that resveratrol can directly target various ncRNAs and that this mediates, at least in part, its potential therapeutic effects. This review critically appraises the available evidence regarding the resveratrol-mediated modulation of different ncRNAs in a wide range of disease states characterized by a pro-inflammatory state and oxidative stress, the potential therapeutic applications, and future research directions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Giordo, Wehbe, Posadino, Erre, Eid, Mangoni and Pintus.)

Cadmium, a ubiquitous environmental toxicant, disrupts testicular function and fertility. The dipeptidyl peptidase-4 inhibitor linagliptin has shown pronounced anti-inflammatory and anti-apoptotic features; however, its effects against cadmium-evoked testicular impairment have not been examined. Herein, the present study investigated targeting inflammation, apoptosis, and autophagy by linagliptin for potential modulation of cadmium-induced testicular dysfunction in rats. After 60 days of cadmium chloride administration (5 mg/kg/day, by gavage), testes, epididymis, and blood were collected for analysis. The present findings revealed that linagliptin improved the histopathological lesions, including spermatogenesis impairment and germ cell loss. Moreover, it improved sperm count/motility and serum testosterone. The favorable effects of linagliptin were mediated by curbing testicular inflammation seen by dampening of HMGB1/TLR4 pathway and associated lowering of nuclear NF-κBp65. In tandem, linagliptin suppressed the activation of NLRP3 inflammasome/caspase 1 axis with consequent lowering of the pro-inflammatory IL-1β and IL-18. Jointly, linagliptin attenuated testicular apoptotic responses seen by Bax downregulation, Bcl-2 upregulation, and suppressed caspase 3 activity. With respect to autophagy, linagliptin enhanced the testicular autophagy flux seen by lowered accumulation of p62 SQSTM1 alongside upregulation of Beclin 1. The observed autophagy stimulation was associated with elevated AMPK (Ser487) phosphorylation and lowered mTOR (Ser2448) phosphorylation, indicating AMPK/mTOR pathway activation. In conclusion, inhibition of testicular HMGB1/TLR4/NLRP3 pro-inflammatory axis and apoptosis alongside stimulation of autophagy were implicated in the favorable actions of linagliptin against cadmium-triggered testicular impairment.

The evolving view of gut microbiota has shifted toward describing the colonic flora as a dynamic organ in continuous interaction with systemic physiologic processes. Alterations of the normal gut bacterial profile, known as dysbiosis, has been linked to a wide array of pathologies. Of particular interest is the cardiovascular-metabolic disease continuum originating from positive energy intake and high-fat diets. Accumulating evidence suggests a role for sex hormones in modulating the gut microbiome community. Such a role provides an additional layer of modulation of the early inflammatory changes culminating in negative metabolic and cardiovascular outcomes. In this review, we will shed the light on the role of sex hormones in cardiovascular dysfunction mediated by high-fat diet-induced dysbiosis, together with the possible involvement of insulin resistance and adipose tissue inflammation. Insights into novel therapeutic interventions will be discussed as well. SIGNIFICANCE STATEMENT: Increasing evidence implicates a role for dysbiosis in the cardiovascular complications of metabolic dysfunction. This minireview summarizes the available data on the sex-based differences in gut microbiota alterations associated with dietary patterns leading to metabolic impairment. A role for a differential impact of adipose tissue inflammation across sexes in mediating the cardiovascular detrimental phenotype following diet-induced dysbiosis is proposed. Better understanding of this pathway will help introduce early approaches to mitigate cardiovascular deterioration in metabolic disease., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Human exposure to bisphenol A (BPA) is mainly due to migration from plastic packaging into food and beverages. Studies reported BPA endocrine disruptions through interactions with different nuclear receptors, including the arylhydrocarbon receptor (AhR). AhR mediates xenobiotic responses and regulates expression of drug-metabolizing enzymes (DMEs), including many CYP450s. This study aimed to assess the effects of BPA maternal exposure on CYP450s expression in fetal brain. Sprague-Dawley dams were exposed to BPA concentrations of 0, 0.5, 5, and 50 mg/L in drinking water, individually, and with nicotine. Fetal brains were isolated at gestational days GD14 and GD19, and protein expression was assessed by Western blotting. Results showed a BPA-induced significant decrease in CYP1B1 expression levels at GD14 (p = 0.001), and CYP19A1 (aromatase) expression at both mid- and late-stage development (p < 0.001). In addition, nicotine individually decreased expression levels of all examined protein targets, significantly for CYP1B1 (p < 0.001), CYP19A1 (p = 0.010), AhRR (p = 0.042), and ARNT (p < 0.001), compared to control. When combined with BPA, nicotine suppressive effects were attenuated at both GD14 and GD19. In conclusion, BPA suppresses CYP1B1 and CYP19A1 expression in fetal brain, and attenuates the suppressive effects of nicotine. Observed effects may be mediated by AhR-ARNT independent mechanisms that need further examination., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Breast cancer is the leading cause of cancer-related deaths among women. Among breast cancer types, triple negative breast cancer (TNBC) is the most aggressive, and is resistant to hormonal and chemotherapeutic treatments. As such, alternative approaches that may provide some benefit in fighting this debilitating pathology are critically needed; hence the utilization of herbal medicine. Origanum syriacum L., one of the most regularly consumed plants in the Mediterranean region, exhibits antiproliferative effect on several cancer cell lines. However, whether this herb modulates the malignant phenotype of TNBC remains poorly investigated. Here, we show that in MDA-MB-231, a TNBC cell line, Origanum syriacum L. aqueous extract (OSE) inhibited cellular viability, induced autophagy determined by the accumulation of lipidized LC3 II, and triggered apoptosis. We also show that OSE significantly promoted homotypic cell-cell adhesion while it decreased cellular migration, adhesion to fibronectin, and invasion of MDA-MB-231 cells. This was supported by decreased activity of focal adhesion kinase (FAK), reduced α2 integrin expression, and downregulation of secreted PgE 2 , MMP2 and MMP-9, in OSE-treated cells. Finally, we also show that OSE significantly inhibited angiogenesis and downregulated the level of nitric oxide (NO) production. Our findings demonstrate the ability of OSE to attenuate the malignant phenotype of the MDA-MB-231 cells, thus presenting Origanum syriacum L. as a promising potential source for therapeutic compounds for TNBC., Competing Interests: Author AA was employed by Kurome Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 AlKahlout, Fardoun, Mesmar, Abdallah, Badran, Nasser, Baydoun, Kobeissy, Shaito, Iratni, Muhammad, Baydoun and Eid.)

In addition to its well-established immunosuppressive actions, tryptophan 2,3-dioxygenase (TDO) appears to elicit direct effects on tumor cell function. Although TDO has been associated with cancer stemness, its involvement in melanoma stem cell biology remains largely unknown. Since we showed that by upregulating TDO, dexamethasone (dex) promotes proliferation and migration of SK-Mel-28 human melanoma cells, we sought to investigate dex effects on melanoma spherogenesis and stemness, and whether these events are mediated by TDO. We demonstrate here that dex significantly upregulates TDO in A375, a more aggressive melanoma cell line, confirming that dex effects are not limited to SK-Mel-28 cells. Moreover, dex stimulates spherogenesis of both cell lines, which is mediated by TDO, evident by its suppression with 680C91, a TDO inhibitor. The formed melanospheres appear to be enriched with embryonic stem cell marker mRNAs, the expression of which is potentiated by dex. Expression of cancer stem cell markers (CD133, CD44, ganglioside GD2) was significantly increased in A375 spheres, as detected by flow cytometry. Taken together, our results suggest that TDO could represent a promising target in the management of melanoma and that dex, routinely used as a co-medication also in advanced melanoma, may stimulate melanoma cell function/tumor-supporting properties, a rather debilitating and undesired side effect., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cecchi, Mannini, Lapucci, Silvano, Lulli, Luceri, D’Ambrosio, Chiarugi, Eid and Parenti.)

Background: Glycans play essential functional roles in the nervous system and their pathobiological relevance has become increasingly recognized in numerous brain disorders, but not fully explored in traumatic brain injury (TBI). We investigated longitudinal glycome patterns in patients with moderate to severe TBI (Glasgow Coma Scale [GCS] score ≤12) to characterize glyco-biomarker signatures and their relation to clinical features and long-term outcome., Methods: This prospective single-center observational study included 51 adult patients with TBI (GCS ≤12) admitted to the neurosurgical unit of the University Hospital of Pecs, Pecs, Hungary, between June 2018 and April 2019. We used a high-throughput liquid chromatography-tandem mass spectrometry platform to assess serum levels of N-glycans up to 3 days after injury. Outcome was assessed using the Glasgow Outcome Scale-Extended (GOS-E) at 12 months post-injury. Multivariate statistical techniques, including principal component analysis and orthogonal partial least squares discriminant analysis, were used to analyze glycomics data and define highly influential structures driving class distinction. Receiver operating characteristic analyses were used to determine prognostic accuracy., Findings: We identified 94 N-glycans encompassing all typical structural types, including oligomannose, hybrid, and complex-type entities. Levels of high mannose, hybrid and sialylated structures were temporally altered (p<0·05). Four influential glycans were identified. Two brain-specific structures, HexNAc5Hex3DeoxyHex0NeuAc0 and HexNAc5Hex4DeoxyHex0NeuAc1, were substantially increased early after injury in patients with unfavorable outcome (GOS-E≤4) (area under the curve [AUC]=0·75 [95%CI 0·59-0·90] and AUC=0·71 [0·52-0·89], respectively). Serum levels of HexNAc7Hex7DeoxyHex1NeuAc2 and HexNAc8Hex6DeoxyHex0NeuAc0 were persistently increased in patients with favorable outcome, but undetectable in those with unfavorable outcome. Levels of HexNAc5Hex4DeoxyHex0NeuAc1 were acutely elevated in patients with mass lesions and in those requiring decompressive craniectomy., Interpretation: In spite of the exploratory nature of the study and the relatively small number of patients, our results provide to the best of our knowledge initial evidence supporting the utility of glycomics approaches for biomarker discovery and patient phenotyping in TBI. Further larger multicenter studies will be required to validate our findings and to determine their pathobiological value and potential applications in practice., Funding: This work was funded by the Italian Ministry of Health (grant number GR-2013-02354960), and also partially supported by a NIH grant (1R01GM112490-08)., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Background: Doxorubicin as an anti-cancer drug causes cardiotoxicity, limiting its tolerability and use. The mechanism of toxicity is due to free radical production and cardiomyocytes injury. This research evaluated Rheum turkestanicum ( R.turkestanicum ) extract against doxorubicin cardiotoxicity due to its considerable in vitro antioxidant activity. Methods: Male Wistar rats received 2.5 mg/kg doxorubicin intraperitoneally every other day for 2 weeks to create an accumulative dose. R. turkestanicum was administrated at a dose of 100 and 300 mg/kg intraperitoneally from the second week for 7 days. On the 15th day, the animals were anesthetized and blood was collected from cardiac tissue for evaluation of alanine aminotransferase (ALT), cardiac muscle creatinine kinase (CK-MB), troponin T (cTn-T), lactate dehydrogenase (LDH), and B-type natriuretic peptide brain natriuretic peptide. A cardiac homogenate was also collected to determine superoxide dismutase (SOD), catalase Catalase Activity, malondialdehyde (MDA), and thiols. Histopathology was also performed. Results: Doxorubicin increased all cardiac enzymes and malondialdehyde, correlating with a reduction in SOD, catalase, and thiols. Histopathology revealed extracellular edema, moderate congestion, and hemorrhage of foci. In contrast, administration of R. turkestanicum ameliorated these doxorubicin-induced pathophysiological changes. Conclusion: This study revealed that the extract ameliorated doxorubicin-induced cardiac toxicity via modulation of oxidative stress-related pathways. Liquid chromatography-mass spectrometry analysis of R. turkestanicum indicated several components with potent pharmacological properties., Competing Interests: EG is employed by Isagenix International, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hosseini, Safari, Rajabian, Boroumand-Noughabi, Eid, Al Dhaheri, Gumpricht and Sahebkar.)

Hypertension is a major risk factor for cardiovascular disease (CVD) as well as a major contributor to all-cause mortality and disability worldwide. The pathophysiology of hypertension is highly attributed to a dysfunctional endothelium and vascular remodeling. Despite the wide use of pharmacological therapies that modulate these pathways, a large percentage of patients continue to have uncontrolled hypertension, and the use of non-pharmacological interventions is increasingly investigated. Among these, caloric restriction (CR) appears to be a promising nutritional intervention for the management of hypertension. However, the mechanisms behind this effect are not yet fully understood, although an evolving view supports a significant impact of CR on vascular structure and function, specifically at the level of vascular endothelial cells, vascular smooth muscle cells along with their extracellular matrix (ECM). Accumulating evidence suggests that CR promotes endothelium-dependent vasodilation through activating eNOS and increasing nitric oxide (NO) levels through multiple cascades involving modulation of oxidative stress, autophagy, and inflammation. Indeed, CR diminishes phenotypic shift, and suppresses proliferation and migration of VSMCs via pathways involving NO and mTOR. By regulating transforming growth factor-β and matrix metalloproteinases, CR appears to reduce ECM and collagen deposition in vascular walls. Here, we offer a detailed discussion of how these mechanisms contribute to CR's influence on reducing blood pressure. Such mechanisms could then provide a valuable foundation on which to base new therapeutic interventions for hypertension., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The metabolic syndrome comprises a family of clinical and laboratory findings, including insulin resistance, hyperglycemia, hypertriglyceridemia, low high-density lipoprotein cholesterol levels, and hypertension, in addition to central obesity. The syndrome confers a high risk of cardiovascular mortality. Indeed, metabolic dysfunction has been shown to cause a direct insult to smooth muscle and endothelial components of the vasculature, which leads to vascular dysfunction and hyperreactivity. This, in turn, causes cerebral vasoconstriction and hypoperfusion, eventually contributing to cognitive deficits. Moreover, the metabolic syndrome disrupts key homeostatic processes in the brain, including apoptosis, autophagy, and neurogenesis. Impairment of such processes in the context of metabolic dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer, Parkinson, and Huntington diseases. The aim of this review is to elucidate the role that the metabolic syndrome plays in the pathogenesis of the latter disorders, with a focus on the role of perivascular adipose inflammation in the peripheral-to-central transduction of the inflammatory insult. This review delineates common signaling pathways that contribute to these pathologies. Moreover, the role of therapeutic agents aimed at treating the metabolic syndrome, as well as their risk factors that interfere with the aforementioned pathways, are discussed as potential interventions for neurodegenerative diseases., (© 2022 The Obesity Society.)