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Obesity-induced type 2 diabetes (T2D) increases the risk of metabolic syndrome due to the high calorie intake. The role of sugar beet pulp (SBP) in T2D and the mechanism of its action remain unclear, though it is abundant in phenolics and has antioxidant activity. In this study, we isolated and purified ferulic acid from SBP, referred to as SBP-E, and studied the underlying molecular mechanisms in the regulation of glucose and lipid metabolism developing high glucose/high fat diet-induced diabetic models in vitro and in vivo. SBP-E showed no cytotoxicity and reduced the oxidative stress by increasing glutathione (GSH) in human liver (HepG2) and rat skeletal muscle (L6) cells. It also decreased body weight gain, food intake, fasting blood glucose levels (FBGL), glucose intolerance, hepatic steatosis, and lipid accumulation. Additionally, SBP-E decreased the oxidative stress and improved the antioxidant enzyme levels in high-fat diet (HFD)-induced T2D mice. Further, SBP-E reduced plasma and liver advanced glycation end products (AGEs), malondialdehyde (MDA), and pro-inflammatory cytokines, and increased anti-inflammatory cytokines in HFD-fed mice. Importantly, SBP-E significantly elevated AMPK, glucose transporter, SIRT1 activity, and Nrf2 expression and decreased ACC activity and SREBP1 levels in diabetic models. Collectively, our study results suggest that SBP-E treatment can improve obesity-induced T2D by regulating glucose and lipid metabolism via SIRT1/AMPK signalling and the AMPK/SREBP1/ACC1 pathway., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest regarding the content of this article., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Hypothyroidism is an endocrine disorder characterised by decreased T3, T4 and increased TSH levels. This study aims to examine the potential effects of Ferulic acid (FA) on rats with hypothyroidism induced by propylthiouracil through the estimation of biochemical parameters and histopathological studies., Methods: Twenty-five female wistar rats were allocated into five groups: Control group [1% CMC, p.o.], Disease group [PTU-50 mg/kg, p.o.], [Levothyroxine (LT4) group - 20 µg/kg, p.o. + PTU-50 mg/kg, p.o.], [FA -25 mg/kg, p.o. + PTU-50 mg/kg, p.o.] and [FA 50 mg/kg, p.o. + PTU-50 mg/kg, p.o.]. On 15th day blood was collected and serum was separated for estimation of biochemical parameters, liver and kidney homogenate was utilised for the estimation of oxidative stress markers and the thyroid gland was dissected to examine histological features., Results: PTU administration for 14 days showed a substantial decline in T3 and T4 and increases in TSH levels. PTU-administered rats significantly increased TC, TG and LDL levels, and decreased HDL levels. AST, ALT, urea, creatinine, and IL-6 were determined and these levels were significantly altered in PTU-induced hypothyroid group. In hypothyroid rats MDA, NO, GSH and SOD levels were significantly altered. However, treatment with FA for 14 days attenuated PTU-induced alterations. Furthermore, FA improves the histological changes of the thyroid gland., Conclusion: In conclusion, FA treatment showed a protective effect against hypothyroidism by stimulating the thyroid hormones through the activation of thyroid peroxidase enzyme and improving thyroid function. In addition, FA diminished the increase in lipids, liver and kidney markers, oxidative stress and inflammation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metabolic diseases are abnormal conditions that impair the normal metabolic process, which involves converting food into energy at a cellular level, and cause difficulties like obesity and diabetes. The study aimed to investigate how ferulic acid (FA) and its derivatives could prevent different metabolic diseases and disorders and to understand the specific molecular mechanisms responsible for their therapeutic effects. Information regarding FA associations with metabolic diseases and disorders was compiled from different scientific search engines, including Science Direct, Wiley Online, PubMed, Scopus, Web of Science, Springer Link, and Google Scholar. This review revealed that FA exerts protective effects against metabolic diseases such as diabetes, diabetic retinopathy, neuropathy, nephropathy, cardiomyopathy, obesity, and diabetic hypertension, with beneficial effects on pancreatic cancer. Findings also indicated that FA improves insulin secretion by increasing Ca 2+ influx through the L-type Ca 2+ channel, thus aiding in diabetes management. Furthermore, FA regulates the activity of inflammatory cytokines (TNF-α, IL-18, and IL-1β) and antioxidant enzymes (CAT, SOD, and GSH-Px) and reduces oxidative stress and inflammation, which are common features of metabolic diseases. FA also affects various signaling pathways, including the MAPK/NF-κB pathways, which play an important role in the progression of diabetic neuropathy and other metabolic disorders. Additionally, FA regulates apoptosis markers (Bcl-2, Bax, and caspase-3) and exerts its protective effects on cellular destruction. In conclusion, FA and its derivatives may act as potential medications for the management of metabolic diseases., Competing Interests: Declaration of competing interest The authors declared that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Population aging is a global reality driven by increased life expectancy. This demographic phenomenon is intrinsically linked to the epidemic of cognitive disorders such as dementia and Alzheimer's disease, posing challenges for elderly and their families. In this context, the search for new therapeutic strategies to prevent or minimize cognitive impairments becomes urgent, as these deficits are primarily associated with oxidative damage and increased neuroinflammation. Ferulic acid (FA), a natural and potent antioxidant compound, is proposed to be nanoencapsulated to target the central nervous system effectively with lower doses and an extended duration of action. Here, we evaluated the effects of the nanoencapsulated FA on d-galactose (d-Gal)- induced memory impairments. Male Wistar adult rats were treated with ferulic acid-loaded nanocapsules (FA-Nc) or non-encapsulated ferulic acid (D-FA) for 8 weeks concurrently with d-Gal (150 mg/kg s.c.) injection. As expected, our findings showed that d-Gal injection impaired memory processes and increased anxiety behavior, whereas FA-Nc treatment ameliorated these behavioral impairments associated with the aging process induced by d-Gal. At the molecular level, nanoencapsulated ferulic acid (FA-Nc) ameliorated the decrease in ACh and glutamate induced by d-galactose (d-Gal), and also increased GABA levels in the dorsal hippocampus, indicating its therapeutic superiority. Additional studies are needed to elucidate the mechanisms underlying our current promising outcomes. Nanoscience applied to pharmacology can reduce drug dosage, thereby minimizing adverse effects while enhancing therapeutic response, particularly in neurodegenerative diseases associated with aging. Therefore, the strategy of brain-targeted drug delivery through nanoencapsulation can be effective in mitigating aging-related factors that may lead to cognitive deficits., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Phenolic acids and their analogues in nature exist in many diseases of oxidative stress with beneficial effects on human health (such as cancer). Phenolic acids possess a variety of pharmacological activities, with anti-inflammatory, anticancer and cytotoxic, antioxidant, immunomodulatory, antimicrobial, insecticidal and other biological activities. Numerous in vitro and in vivo studies have shown that because phenolic acids have antioxidant capacity, they can reflect their strong anticancer potential by regulating cell growth and metastasis and promoting cancer cell death. Studies have shown that the consumption of natural polyphenols can significantly reduce the risk of cancer metastasis. A combination of phenolic acids with traditional chemoradiation or other polyphenols may be effective in reducing cancer spread.Ferulic acid is ubiquitous, and widely found in plants, such as angelica, chuanxiong, cohote, three, edge, reed root, tomato, sweet corn, and rice are produced by the metabolism of phenylalanine and tyrosine. It is the most abundant hydroxyl cassia bark-acid acid in the plant kingdom, with anti-inflammatory, antidiabetic, anticancer and antioxidant activity, and polyphenols composed of hydroxyl cassia bark-acid derivatives, flavone-3-alcohol and flavonol retain non-cancer-cells-and-significantly-inhibit glioblastoma viability in a dose-dependent manner, which deserves further investigation as potential anticancer drugs. This paper summarizes the role of ferulic acid in the PI3K / AKT pathway and its mechanism in glioblastoma resistance.

Di-(2-ethylhexyl) phthalate (DEHP) is the most abundant phthalate threatening public health-induced neurotoxicity. This neurotoxicity is associated with behavioral and biochemical deficits in male rats. Our study investigated the neuroprotective effect of ferulic acid (FA) on male rats exposed to DEHP. Thirty-two male Wistar rats were assigned to four groups. Group I control rats received corn oil, group II intoxicated rats received 300 mg/kg of DEHP, group III received 300 mg/kg of DEHP + 50 mg/kg of FA, and group IV received 50 mg/kg of FA, all agents administrated daily per os for 30 days. Anxiety-like behavior, spatial working memory, and recognition memory were assessed. Also, brain oxidative stress biomarkers, including brain malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), superoxide dismutase (SOD), brain-derived neurotrophic factor (BDNF) as well as heme oxygenase-1 (HO-1) were measured. Moreover, brain histopathology examinations associated with immunohistochemistry determination of brain caspase-3 were also evaluated. Furthermore, docking simulation was adapted to understand the inhibitory role of FA on caspase-3 and NO synthase. Compared to DEHP-intoxicated rats, FA-treated rats displayed improved cognitive memory associated with a reduced anxious state. Also, the redox state was maintained with increased BNDF levels. These changes were confirmed by restoring the normal architecture of brain tissue and a decrement in the immunohistochemistry caspase-3. In conclusion, FA has potent antioxidant and antiapoptotic properties that confirm the neuroprotective activity of FA, with a possible prospect for its therapeutic capabilities and nutritional supplement value., (© 2023. The Author(s).)

Introduction: Ferulic acid (FA) is a phenolic phytochemical that has garnered the attention of the research community due to its abundant availability in nature. It is a compound that has been explored for its multifaceted therapeutic potential and benefits in modern and contemporary healthcare., Areas Covered: This review furnishes a compilation of the molecular mechanisms underlying the anti-diabetic, anticancer, antioxidant, and anti-inflammatory effects of FA. We also aim to excavate an in-depth analysis of the role of nanoformulations to achieve release control, reduce toxicity, and deliver FA at specified target sites. To corroborate the safety and efficacy of FA, a multitude of pre-clinical studies have also been conducted by researchers and have been discussed comprehensively in this review. The various patented innovations and newer paradigms pertaining to FA have also been presented., Expert Opinion: Enormous research has been conducted and should still be continued to find the best possible novel drug delivery system for FA delivery. The utilization of nanocarriers and nanoformulations has intrigued the scientists for delivery of FA, but before that, it is necessary to shed light upon toxicity, safety, and regulatory concerns of FA.

Depression is a common but severe mood disorder with a very high prevalence across the general population. Depression is of global concern and poses a threat to human physical and mental health. Ferulic acid (FA) is a natural active ingredient that has antioxidative, anti-inflammatory, and free radical scavenging properties. Furthermore, studies have shown that FA can exert antidepressant effects through a variety of mechanisms. The aim of the review was to comprehensively elucidate the mechanisms in FA that alleviate depression using animal models. The in vivo (animal) studies on the mechanism of FA treatment of depression were searched in PubMed, Chinese National Knowledge Infrastructure, Baidu academic, and Wan fang databases. Thereafter, the literature conclusions were summarized accordingly. Ferulic acid was found to significantly improve the depressive-like behaviors of animal models, suggesting that FA is a potential natural product in the treatment of depression. The mechanisms are achieved by enhancing monoamine oxidase A (MOA) activity, inhibiting microglia activation and inflammatory factor release, anti-oxidative stress, promoting hippocampal nerve regeneration, increasing brain-derived neurotrophic factor secretion, regulating gut microbiome, and activating protein kinase B/collapsin response mediator protein 2 (AKT/CRMP2) signaling pathway. Ferulic acid produces significant antidepressant effects in animal depression models through various mechanisms, suggesting its potential value as a treatment of depression. However, clinical research trials involving FA are required further to provide a solid foundation for its clinical application., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Cancer is a significant disease that poses a major threat to human health. The main therapeutic methods for cancer include traditional surgery, radiotherapy, chemotherapy, and new therapeutic methods such as targeted therapy and immunotherapy, which have been developed rapidly in recent years. Recently, the tumor antitumor effects of the active ingredients of natural plants have attracted extensive attention. Ferulic acid (FA), (3-methoxy-4-hydroxyl cinnamic), with the molecular formula is C 10 H 10 O 4 , is a phenolic organic compound found in ferulic, angelica, jujube kernel, and other Chinese medicinal plants but is also, abundant in rice bran, wheat bran, and other food raw materials. FA has anti-inflammatory, analgesic, anti-radiation, and immune-enhancing effects and also shows anticancer activity, as it can inhibit the occurrence and development of various malignant tumors, such as liver cancer, lung cancer, colon cancer, and breast cancer. FA can cause mitochondrial apoptosis by inducing the generation of intracellular reactive oxygen species (ROS). FA can also interfere with the cell cycle of cancer cells, arrest most cancer cells in G 0 /G 1 phase, and exert an antitumor effect by inducing autophagy; inhibiting cell migration, invasion, and angiogenesis; and synergistically improving the efficacy of chemotherapy drugs and reducing adverse reactions. FA acts on a series of intracellular and extracellular targets and is involved in the regulation of tumor cell signaling pathways, including the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT), B-cell lymphoma-2 (Bcl-2), and tumor protein 53 (P53) pathways and other signaling pathways. In addition, FA derivatives and nanoliposomes, as platforms for drug delivery, have an important regulatory effect on tumor resistance. This paper reviews the effects and mechanisms of antitumor therapies to provide new theoretical support and insight for clinical antitumor therapy., (© 2023. The Author(s).)

Background: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes uncontrolled inflammation and ulcers in your digestive tract. The coumaric acid and syringic acid are phenolic derivative found in many fruits and vegetables and is widely recognized for the ability of anti-parasitic, anti-microbial, anti-viral, anti-inflammatory, and antioxidant. The purpose of this study was to investigate the anti-inflammatory and antioxidant properties of coumaric acid and syringic acid on acetic acid-induced colitis in rats., Methods: A total of 64 male Wistar rats were divided into eight equal groups (n = 8). Colitis was induced by intrarectal administration of acetic acid, and rats orally received coumaric acid (100 and 150 mg/kg), syringic acid (10, 25, and 50 mg/kg), and dexamethasone (2 mg/kg) once per day for four days after colitis induction. Then, HO-1, Nrf2, and NQO1 mRNA expression were quantified by real time-PCR. Finally, the tissue levels of TNF-α and IL-1β protein were measured by ELISA., Results: Colitis led to a decrease in HO-1, Nrf2, and NQO1 mRNA expression and an increase in the tissue levels of TNF-α and IL-1β protein in the colon tissue. Treatment with dexamethasone significantly increased HO-1, Nrf2, and NQO1 mRNA expression and decreased the tissue levels of TNF-α and IL-1β protein compared to the UC group. Treatment with 150 mg/kg of coumaric acid and 50 mg/kg of syringic acid significantly increased HO-1, Nrf2, and NQO1 mRNA expression compared to the UC group. Also, treatment with 100 and 150 mg/kg of coumaric acid and 10, 25, and 50 mg/kg of syringic acid significantly decreased the tissue levels of TNF-α and IL-1β protein compared to the UC group., Conclusion: The coumaric acid and syringic acid, especially at high doses, may be an alternative strategy for the treatment of UC by the reduction of TNF-α and IL-1β levels and upregulation of the Nrf2/HO-1 pathway., 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 Elsevier B.V. All rights reserved.)

Ferulic acid (FA), a prevalent dietary phytochemical, has many pharmacological effects, including anti-oxidation and anti-inflammation effects, and has been widely used in the pharmaceutical, food, and cosmetics industries. Many studies have shown that FA can significantly downregulate the expression of reactive oxygen species and activate nuclear factor erythroid-2-related factor-2/heme oxygenase-1 signaling, exerting anti-oxidative effects. The anti-inflammatory effect of FA is mainly related to the p38 mitogen-activated protein kinase and nuclear factor-kappaB signaling pathways. FA has demonstrated potential clinical applications in the treatment of pulmonary diseases. The transforming growth factor-β1/small mothers against decapentaplegic 3 signaling pathway can be blocked by FA, thereby alleviating pulmonary fibrosis. Moreover, in the context of asthma, the T helper cell 1/2 imbalance is restored by FA. Furthermore, FA ameliorates acute lung injury by inhibiting nuclear factor-kappaB and mitogen-activated protein kinase pathways via toll-like receptor 4, consequently decreasing the expression of downstream inflammatory mediators. Additionally, there is a moderate neuraminidase inhibitory activity showing a tendency to reduce the interleukin-8 level in response to influenza virus infections. Although the application of FA has broad prospects, more preclinical mechanism-based research should be carried out to test these applications in clinical settings. This review not only covers the literature on the pharmacological effects and mechanisms of FA, but also discusses the therapeutic role and toxicology of FA in several pulmonary diseases.

Introduction: Sciatica causes intense pain. No satisfactory therapeutic drugs exist to treat sciatica. This study aimed to probe the potential mechanism of ferulic acid in sciatica treatment., Methods: Thirty-two SD rats were randomly divided into 4 groups: sham operation, chronic constriction injury (CCI), mecobalamin, and ferulic acid. We conducted RNA sequencing, behavioral tests, ELISA, PCR, western blotting, and immunofluorescence analysis. TAK-242 and JSH23 were administered to RSC96 and GMI-R1 cells to explore whether ferulic acid can inhibit apoptosis and alleviate inflammation., Results: RNA sequencing showed that TLR4/NF-κB pathway is involved in the mechanism of sciatica. CCI induced cold and mechanical hyperalgesia; destroyed the sciatic nerve structure; increased IL-1β, IL-6, TNF-α, IL-8, and TGF-β protein levels and IL-1β, IL-6, TNF-α, TGF-β, TLR4, and IBA-1 mRNA levels; and decreased IL-10 and INF-γ protein levels and IL-4 mRNA levels. Immunohistochemistry showed that IBA-1, CD32, IL-1β, iNOS, nNOS, COX2, and TLR4 expression was increased while S100β and Arg-1 decreased. CCI increased TLR4, IBA-1, IL-1β, iNOS, Myd88, p-NF-κB, and p-p38MAPK protein levels. Treatment with mecobalamin and ferulic acid reversed these trends. Lipopolysaccharide (LPS) induced RSC96 cell apoptosis by reducing Bcl-2 and Bcl-xl protein and mRNA levels and increasing Bax and Bad mRNA and IL-1β, TLR4, Myd88, p-NF-κB, and p-p38MAPK protein levels, while ferulic acid inhibited cell apoptosis by decreasing IL-1β, TLR4, Myd88, p-NF-κB, and p-p38MAPK levels and increasing Bcl-2 and Bcl-xl levels. In GMI-R1 cells, Ferulic acid attenuated LPS-induced M1 polarization by decreasing the M1 polarization markers IL-1β, IL-6, iNOS, and CD32 and increasing the M2 polarization markers CD206, IL-4, IL-10 and Arg-1. After LPS treatment, IL-1β, iNOS, TLR4, Myd88, p-p38MAPK, and p-NF-κB levels were obviously increased, and Arg-1 expression was reduced, while ferulic acid reversed these changes., Conclusion: Ferulic acid can promote injured sciatic nerve repair by reducing neuronal cell apoptosis and inflammatory infiltration though the TLR4/NF-κB pathway., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Testicular torsion is twisting of the spermatic cord around its axis, which impairs blood flow and causes ischemia and formation of free radicals. Ferulic acid is a phenolic acid of the hydroxycinnamic family that is found in the seeds and leaves of plants; it is present in substantial amounts in fruits and vegetables. We investigated the protective effect of ferulic acid on experimental testicular torsion in rats. Animals were divided randomly into five groups: control, ethyl alcohol, torsion, torsion-detorsion, and torsion-detorsion + ferulic acid. Histopathology was assessed using hematoxylin and eosin, and periodic acid-Schiff staining. Tissues were assessed using TUNEL, active caspase-3, myeloperoxidase and inducible nitric oxide synthase immunostaining. Biochemical changes were assessed using assays for superoxide dismutase, malondialdehyde, glutathione peroxidase and glutathione. Ferulic acid reduced the levels of free radicals and increased the levels of antioxidants. Ferulic acid also reduced histopathological changes and germ cell differentiation in the testis following torsion-detorsion. Ferulic acid should be investigated further as a potential treatment for sequelae of torsion-detorsion injury.

Background and Aims: Increasing research evidence indicates that temporal lobe epilepsy (TLE) induced by kainic acid (KA) has high pathological similarities with human TLE. KA induces excitotoxicity (especially in the acute phase of the disease), which leads to neurodegeneration and epileptogenesis through oxidative stress and inflammation. Ferulic acid (FA) is one of the well-known phytochemical compounds that have shown potential antioxidant and anti-inflammatory properties and promise in treating several diseases. The current study set out to investigate the neuroprotective effects of FA in a rat model of TLE., Methods: Thirty-six male Wistar rats were divided into four groups. Pretreatment with FA (100 mg/kg/day p.o.) started one week before the intrahippocampal injection of KA (0.8 μg/μl, 5μl). Seizures were recorded and evaluated according to Racine's scale. Oxidative stress was assessed by measuring its indicators, including malondialdehyde (MDA), nitrite, and catalase. Histopathological evaluations including Nissl staining and immunohistochemical staining of cyclooxygenase-2 (COX-2), and neural nitric oxide synthases (nNOS) were performed for the CA3 region of the hippocampus., Results: Pretreatment with FA significantly attenuates the severity of the seizure and prevents neuronal loss in the CA3 region of the hippocampus in rats with KA-induced post-status epilepticus. Also, nitrite concentration and nNOS levels were markedly diminished in FA-pretreated animals compared to non-pretreated epileptic rats., Conclusion: Our findings indicated that neuroprotective properties of FA, therefore, could be considered a valuable therapeutic supplement in treating TLE., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Alzheimer's disease (AD) is one of the most common diseases in the elderly, with a high incidence of dementia. The pathogenesis of AD is complex, and there is no unified conclusion and effective treatment in the clinic. In recent years, with the development of traditional Chinese medicine (TCM), researchers put forward the idea of prevention and treatment of AD based on TCM according to the characteristics of multi- target of TCM. Ferulic acid (FA), also known as 3-methoxy-4-hydroxycinnamic acid, is an active ingredient in TCM that inhibits β-amyloid (Aβ) aggregation and has antioxidant and anti-inflammatory effects. FA derivatives have been reported to have low toxicity, high biological activity, and high blood-brain barrier permeability. However, the multitarget of FA in the treatment of AD has not been systematically elucidated., Objectives: In this systematic review, we aimed to comprehensively assess the neuroprotective effects of FA and its derivatives on in vitro and in vivo AD models., Methods: We searched PubMed, Chinese National Knowledge Infrastructure (CNKI), Baidu Academic, and Wanfang databases for relevant pre-clinical studies until November 2021., Results: We identified studies that evaluated the efficacy of FA and its derivatives using relevant keywords. 864 studies were included, of which 129 were found in PubMed, 111 in CNKI, 454 in Baidu Academic, and 170 in Wanfang. Due to duplication between databases, and after applying the exclusion and inclusion criteria, 43 articles were selected. Thereafter, the abstracts of the 43 articles were reviewed. Finally, 21 articles were included in this review, including 11 in vivo, 5 in vitro, and 5 in vivo and in vitro studies., Conclusion: Previous studies have shown that FA or its derivatives have multiple therapeutic effects on AD models and can improve the symptoms of AD and resistance of AD cell models. FA and its derivatives have anti-Aβ aggregation, antioxidant, antiinflammatory, and other effects and are potential drugs for the multi-targeted treatment of AD. The result of our study showed that FA and its derivatives have significant therapeutic effects on animal and cell models of AD, suggesting that they may be potential therapeutic drugs for patients with AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Despite the immense therapeutic advances in the field of health sciences, cancer is still to be found among the global leading causes of morbidity and mortality. Ethnomedicinally, natural bioactive compounds isolated from various plant sources have been used for the treatment of several cancer types and have gained notable attention. Ferulic acid, a natural compound derived from various seeds, nuts, leaves, and fruits, exhibits a variety of pharmacological effects in cancer, including its proapoptotic, cell-cycle-arresting, anti-metastatic, and anti-inflammatory activities. This review study presents a thorough overview of the molecular targets and cellular signaling pathways modulated by ferulic acid in diverse malignancies, showing high potential for this phenolic acid to be developed as a candidate agent for novel anticancer therapeutics. In addition, current investigations to develop promising synergistic formulations are also discussed.

Over the past thirty years, research has shown the huge potential of chitosan in biomedical applications such as drug delivery, tissue engineering and regeneration, cancer therapy, and antimicrobial treatments, among others. One of the major advantages of this interesting polysaccharide is its modifiability, which facilitates its use in tailor-made applications. In this way, the molecular structure of chitosan has been conjugated with multiple molecules to modify its mechanical, biological, or chemical properties. Here, we review the conjugation of chitosan with some bioactive molecules: hydroxycinnamic acids (HCAs); since these derivatives have been probed to enhance some of the biological effects of chitosan and to fine-tune its characteristics for its application in the biomedical field. First, the main characteristics of chitosan and HCAs are presented; then, the currently employed conjugation strategies between chitosan and HCAs are described; and, finally, the studied biomedical applications of these derivatives are discussed to present their limitations and advantages, which could lead to proximal therapeutic uses.

Alzheimer's Disease (AD) is a common neurodegenerative disorder characterized by memory loss and cognitive impairment. Its pathology has not been fully clarified and therefore highly effective treatments have not been obtained yet. Almost all the current treatment options aim to alleviate only the symptoms and not to eliminate the disease itself. Acetylcholinesterase inhibitors are the main therapeutic agents against AD, whereas oxidative stress and inflammation have been found to be of great significance for the development and progression of neurodegeneration. In this work, ethyl nipecotate (ethyl-piperidine-3-carboxylate), a heterocyclic carboxylic acid derivative, which acts as a GABA reuptake inhibitor and has been used in research for diseases involving GABAergic neurotransmission dysfunction, was amidated with various carboxylic acids bearing antioxidant and/or anti-inflammatory properties (e.g., ferulic acid, sinapic acid, butylated hydroxycinnamic acid). Most of our compounds have significant antioxidant potency as lipid peroxidation inhibitors (IC 50 as low as 20 μΜ), as oxidative protein glycation inhibitors (inhibition up to 57%), and act as DPPH reducing agents. Moreover, our compounds are moderate LOX inhibitors (up to 33% at 100 μΜ) and could reduce rat paw edema induced by carrageenan by up to 61%. Finally, some of them possessed inhibitory activity against acetylcholinesterase (IC 50 as low as to 47 μΜ). Our results indicate that our compounds could have the potentiality for further optimization as multi-targeting agents directed against AD., Competing Interests: The authors declare no conflict of interest.

Objective: Asthma is a chronic inflammatory airway disease associated with the airway narrowing and obstruction. Sinapic acid (SA), a hydroxycinnamic acid, possesses various pharmacological properties including antioxidant and anti-inflammatory activity. This research evaluated effects of different doses of SA on murine model of ovalbumin (OVA)-induced allergic asthma., Materials and Methods: Allergic asthma induced by sensitizing mice on days 1 and 14 by intraperitoneal injection of OVA. After initial sensitization, between days 21 and 23, mice were challenged for 30 min with an aerosol of 1 % (wt/vol) OVA. Treatment with dexamethasone (3 mg/kg) or SA (25, 50 or 100 mg/kg) were done by oral gavage on days 15-23. Inflammatory cells infiltration and interferon-γ (IFN-γ), interlukin-4 (IL-4), IL-5 and IL-13 levels were evaluated in the bronchoalveolar lavage fluid (BALF). Serum total and OVA-specific immunoglobulin E (IgE) and lung tissue nitric oxide (NO) levels were measured. Histological changes in lung tissue were examined by staining with hematoxylin and eosin (H&E) for cell infiltration, periodic acid-Schiff (PAS) for mucus production and Masson's trichrome for collagen deposition., Results: Treatment with SA significantly inhibited inflammatory cell infiltration, enhanced IFN-γ level and decreased IL-4, IL-5 and IL-13 levels in BALF. Serum total and OVA-specific IgE levels and NO level in lung tissue were significantly reduced by SA. Histological examination demonstrated that SA significantly attenuated inflammatory cell infiltration and mucus-producing cells in the lung., Conclusion: These data suggest that SA may be a new therapeutic potential to treat allergic asthma through suppressing T-helper 2 immune responses., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Neuroblastoma is the most common solid tumor in children. New treatment approaches are needed because of the harmful side effects and costs of the methods used in the treatment of neuroblastoma. Medicinal and aromatic plants are important for new treatment approaches due to their minimal side effects and economic advantages. Therefore, the present study was carried out to examine the cytotoxic effect of Chaerophyllum macropodum extract on human neuroblastoma (SH-SY5Y) and fibroblast (HDFa) cell lines. 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase release (LDH) assays were used to determine the cytotoxic effect of C. macropodum. The extracts were analyzed for their phenolic content by HPLC-PDA. Major components were determined as 63.600% o-coumaric acid, 15.606% catechine hydrate, 8.713% rosmarinic acid, 4.376% clorogenic acid, and 3.972% salicylic acid. The obtained results from cytotoxicity testing revealed that C. macropodum exerted a significant cytotoxic effect on human neuroblastoma cells at all tested concentrations (p < 0.05). But it did not lead to any cytotoxic potential on human fibroblasts. As a result, the obtained data clearly revealed C. macropodum exerted a selective cytotoxic action on neuroblastoma cells for the first time., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alzheimer's disease (AD) is a progressive degenerative disorder of the central nervous system, characterized by neuroinflammation, neurotransmitter deficits, and neurodegeneration, which finally leads to neuronal death. Emerging evidence highlighted that hyperglycemia and brain insulin resistance represent risk factors for AD development, thus suggesting the existence of an additional AD form, associated with glucose metabolism impairment, named type 3 diabetes. Owing to the limited pharmacological options, novel strategies, especially dietary approaches based on the consumption of polyphenols, have been addressed to prevent or, at least, slow down AD progression. Among polyphenols, ferulic acid is a hydroxycinnamic acid derivative, widely distributed in nature, especially in cereal bran and fruits, and known to be endowed with many bioactivities, especially antioxidant, anti-inflammatory and antidiabetic, thus suggesting it could be exploited as a possible novel neuroprotective strategy. Considering the importance of ferulic acid as a bioactive molecule and its widespread distribution in foods and medicinal plants, the aim of the present narrative review is to provide an overview on the existing preclinical and clinical evidence about the neuroprotective properties and mechanisms of action of ferulic acid, also focusing on its ability to modulate glucose homeostasis, in order to support a further therapeutic interest for AD and type 3 diabetes.

Aim: This study was done to investigate the anti-diabetic and anti-oxidative synergism between zinc(II) and ferulic acid through complexation., Methods: Zinc sulphate was complexed with ferulic acid in a 1:2 molar ratio. The complex was characterized using Fourier-transform infrared spectroscopy, proton NMR and high-resolution mass spectroscopy techniques and evaluated for cellular toxicity. In silico, in vitro, cell-based and tissue experimental models were used to test the anti-diabetic and anti-oxidant activities of the complex relative to its precursors., Results: A zinc(II)-biferulate.2H 2 O complex was formed. The in vitro radical scavenging, anti-lipid peroxidative and α-glucosidase and α-amylase inhibitory activity of the complex was 1.7-2.1 folds more potent than ferulic acid. Zn(II) complexation increased the anti-glycation activity of ferulic acid by 1.5 folds. The complex suppressed lipid peroxidation (IC 50  = 48.6 and 331 μM) and GHS depletion (IC 50  = 33.9 and 33.5 μM) in both Chang liver cells and isolated rat liver tissue. Its activity was 2.3-3.3 folds more potent than ferulic acid and statistically comparable to ascorbic acid. Zn(II) complexation afforded ferulic acid improved glucose uptake activity in L-6 myotube (EC 50  = 11.7 vs. 45.7 μM) and isolated rat muscle tissue (EC 50  = 501 and 1510 μM). Complexation increased muscle tissue zinc(II) uptake and hexokinase activity. Docking scores of the complex (-7.24 to -8.25 kcal/mol) and ferulic acid (-5.75 to 6.43 kcal/mol) suggest the complex had stronger interaction with protein targets related to diabetes, which may be attributed to the 2 ferulic acid moieties and Zn(II) in the complex. Moreover, muscle tissue showed increased phospho-Akt/pan-Akt ratio upon treatment with complex. The complex was not hepatotoxic and myotoxic at in vitro cellular level., Conclusion: Zn(II) complexation may be promising therapeutic approach for improving the glycaemic control and anti-oxidative potential of natural phenolic acids., (© 2022 Diabetes UK.)

p -Coumaric acid (pCA) is a hydroxycinnamic acid derivative commonly found in many natural products that has been extensively studied for its anticancer activity in multiple cell lines. In this report we investigated the effects of this phytochemical as adjuvant therapy to treat glioblastoma, an infaust brain tumour characterized by the acquired or innate resistance to the conventional chemotherapy temozolomide (TMZ). U87Mg glioblastoma cell growth and viability was assessed by growth rate curves and MTT assay incubating cells with 0.5 and 1 mM pCA for 24 h, 48 h and 72 h. Cell cycle analysis, performed by flow cytometry, showed that pCA led the accumulation of GBM cells in G2/M phase. Western blot analysis shows that pCA induced CDK4 cyclin-dependent kinase reduction and p53 increase, followed by induction of the CDK inhibitor p21. Furthermore, pCA treatment mediated the activation of apoptosis and the inhibition of migration of U87Mg cells. Finally, the treatment of glioblastoma cells in vitro with pCA concomitantly with the TMZ revealed a synergistic effect between the natural substance and the chemotherapy. In conclusion, our results demonstrated that pCA acts influencing the cell viability and cell cycle of U87Mg cells by promoting cell cycle arrest in G2/M phase and apoptosis.

Nature has provided therapeutic substances for millennia, with many valuable medications derived from plant sources. Multitarget drugs become essential in the management of various disorders, including hepatic disorders, neurological disorders, diabetes, and carcinomas. Ferulic acid is a significant potential therapeutic agent, which is easily available at low cost, possesses a low toxicity profile, and has minimum side effects. Ferulic acid exhibits various therapeutic actions by modulation of various signal transduction pathways such as Nrf2, p38, and mTOR. The actions exhibited by ferulic acid include anti-apoptosis, antioxidant, anti-inflammatory, antidiabetic, anticarcinogenic, hepatoprotection, cardioprotection, activation of transcriptional factors, expression of genes, regulation of enzyme activity, and neuroprotection, which further help in treating various pathophysiological conditions such as cancer, skin diseases, brain disorders, diabetes, Parkinson's disease, Alzheimer's disease, hypoxia, hepatic disorders, H1N1 flu, and viral infections. The current review focuses on the significance of natural products as sources of multitarget compounds, and a primary focus has been made on ferulic acid and its mechanism, role, and protective action in various ailments., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Hybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology, they were characterized for their ROCK2 inhibition, radical scavenging, effects on cell viability (MTT assay), and NRF2 induction (luciferase assay). One of the compounds ( 1d ) was selected in view of its good multitarget profile and good tolerability. It was able to induce the NRF2 signature, promoting the expression of the antioxidant response enzymes HO-1 and NQO1, via a KEAP1-dependent mechanism. Analysis of mRNA and protein levels of the NRF2 pathway showed that 1d induced the NRF2 signature in control and SOD1 -ALS lymphoblasts but not in sALS, where it was already increased in the basal state. These results show the therapeutic potential of this compound, especially for ALS patients with a SOD1 mutation.

Heart failure (HF), the main cause of death in patients with many cardiovascular diseases, has been reported to be closely related to the complicated pathogenesis of autophagy, apoptosis, and inflammation. Notably, Si-Miao-Yong-An decoction (SMYAD) is a traditional Chinese medicine (TCM) used to treat cardiovascular disease; however, the main active components and their relevant mechanisms remain to be discovered. Based on our previous ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) results, we identified angoriside C (AC) and 3,5-dicaffeoylquinic acid (3,5-DiCQA) as the main active components of SMYAD. In vivo results showed that AC and 3,5-DiCQA effectively improved cardiac function, reduced the fibrotic area, and alleviated isoproterenol (ISO)-induced myocarditis in rats. Moreover, AC and 3,5-DiCQA inhibited ISO-induced autophagic cell death by inhibiting the PDE5A/AKT/mTOR/ULK1 pathway and inhibited ISO-induced apoptosis by inhibiting the TLR4/NOX4/BAX pathway. In addition, the autophagy inhibitor 3-MA was shown to reduce ISO-induced apoptosis, indicating that ISO-induced autophagic cell death leads to excess apoptosis. Taken together, the main active components AC and 3,5-DiCQA of SMYAD inhibit the excessive autophagic cell death and apoptosis induced by ISO by inhibiting the PDE5A-AKT and TLR4-NOX4 pathways, thereby reducing myocardial inflammation and improving heart function to alleviate and treat a rat ISO-induced heart failure model and cell heart failure models. More importantly, the main active components of SMYAD will provide new insights into a promising strategy that will promote the discovery of more main active components of SMYAD for therapeutic purposes in the future., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Among the diseases of the digestive system, the incidence of acute pancreatitis (AP) has increased. Although the AP is primarily self-limited, mortality remains high when it progressed to severe acute pancreatitis (SAP). Despite significant advances in new drug development, treatments for AP are not ideal. Here, we discovered a novel hydroxycinnamic acid, sinapic acid (SA), which is widely distributed in plants and is an effective treatment for AP. Using in vitro and in vivo models, we demonstrated that pretreatment with SA ameliorated cerulein-induced pancreatic damage and inflammation and inhibited the activation of Caspase-1 and Caspase-11, which mediate pyroptosis of pancreatic acinar cells during AP. These effects may occur through the inhibition of AMPK phosphorylation and downregulation of NF-[Formula: see text]B. Our findings demonstrate the therapeutic effects and reveal the underlying mechanisms of SA, which warrants its further study as an effective treatment for AP.

Introduction: Diabetic nephropathy (DN), a global problem that threatens human health, is an important reason for chronic kidney disease and kidney failure. In our study, it was aimed to investigate the individual and combined effects of SA and EA in streptozotocin (STZ)-induced rats., Methods: The groups are as follows: Control, untreated diabetic, diabetic treated with Sinapic acid (SA), diabetic treated with Ellagic acid (EA), diabetic treated with SA and EA, treated with SA, treated with EA, and treated with SA and EA. Total kidney volume, total glomerulus volume, total filtration space volume, caspase-3, and 8-OHdG immunoreactivity, Malondialdehyde (MDA), Glutathione (GSH), Catalase (CAT), serum urea, and creatinine levels were evaluated by stereological, immunohistochemical, and biochemical methods., Results: The findings of the study showed that total kidney volume, total glomerulus volume, total filtration gap volume, caspase-3, and 8-OHdG immunoreactivity, MDA, serum urea, and creatinine levels significantly increased in the untreated diabetic group compared to the control group. Also, severe mesangial and glomerular enlargement, extracellular matrix accumulation, and glomerular and tubular basal membrane thickness were observed in the tubulointerstitial and glomerular of the diabetic rats. However, individual and combined treatments of SA and EA ameliorated these histological changes. Additionally, decreased GSH and CAT in the untreated diabetic group increased by SA and EA treatment., Conclusions: The findings suggest that treatment of SA and EA prevent apoptosis and DNA damage and structural changes in STZ-induced DN. However, the combined treatment of SA and EA were more effective than their individual treatments in all parameters except serum urea and creatinine.

Trans -ferulic acid (FA) is a derivative of 4-hydroxycinnamic acid, which is found in many food products, fruits and beverages. It has scientifically proven antioxidant, anti-inflammatory and antibacterial properties. However, its low ability to permeate through biological barriers (e.g., the blood-brain barrier, BBB), its low bioavailability and its fast elimination from the gastrointestinal tract after oral administration limit its clinical use, e.g., for the treatment of neurodegenerative diseases, such as Alzheimer's disease. Therefore, new nanotechnological approaches are developed in order to regulate intracellular transport of ferulic acid. The objective of this review is to summarize the last decade's research on biological properties of ferulic acid and innovative ways of its delivery, supporting pharmacological therapy.

Alzheimer's disease (AD) is a neurodegenerative disease with a high incidence in the elderly. Many preclinical studies show that a natural product, ferulic acid (FA), displays neuroprotective effects in AD models. This review aims to systematically review and meta-analyze published pre-clinical researches about the effects, mechanism, and clinical prospects of FA in the treatment of AD. According to the pre-determined search strategy and inclusion criteria, a total of 344 animals in 12 papers were included in the meta-analysis. We used the fixed effects model to analyze data and I 2 and p values to indicate heterogeneity. Results show that FA treatment can effectively improve rodents' spatial memory ability in MWM and Y maze experiments (I 2 ≥ 70, p < 0.005), and reduce the deposition of Aβ in the brains of various model animals (I 2 ≥ 50, p < 0.005). The potential mechanisms include anti-amyloidogenesis, anti-inflammation, anti-oxidation, mitochondrial protection, and inhibition of apoptosis. In conclusion, we systematically review and meta-analyze the literature reporting the effects of FA treatment on AD rodent models and solidify the benefits of FA in reducing Aβ deposition and improving memory in preclinical experiments. We also point out the limitations in the current research design and provide a strategy for the production research of FA in the future.

Alzheimer's disease (AD) is a severe multifactorial neurodegenerative disorder characterized by a progressive loss of neurons in the brain. Despite research efforts, the pathogenesis and mechanism of AD progression are not yet completely understood. There are only a few symptomatic drugs approved for the treatment of AD. The multifactorial character of AD suggests that it is important to develop molecules able to target the numerous pathological mechanisms associated with the disease. Thus, in the context of the worldwide recognized interest of multifunctional ligand therapy, we report herein the synthesis, characterization, physicochemical and biological evaluation of a set of five ( 1a - e ) new ferulic acid-based hybrid compounds, namely feroyl-benzyloxyamidic derivatives enclosing different substituent groups, as potential anti-Alzheimer's disease agents. These hybrids can keep both the radical scavenging activity and metal chelation capacity of the naturally occurring ferulic acid scaffold, presenting also good/mild capacity for inhibition of self-Aβ aggregation and fairly good inhibition of Cu-induced Aβ aggregation. The predicted pharmacokinetic properties point towards good absorption, comparable to known oral drugs.

Skin, our first interface to the external environment, is subjected to oxidative stress caused by a variety of factors such as solar ultraviolet, infrared and visible light, environmental pollution, including ozone and particulate matters, and psychological stress. Excessive reactive species, including reactive oxygen species and reactive nitrogen species, exacerbate skin pigmentation and aging, which further lead to skin tone unevenness, pigmentary disorder, skin roughness and wrinkles. Besides these, skin microbiota are also a very important factor ensuring the proper functions of skin. While environmental factors such as UV and pollutants impact skin microbiota compositions, skin dysbiosis results in various skin conditions. In this review, we summarize the generation of oxidative stress from exogenous and endogenous sources. We further introduce current knowledge on the possible roles of oxidative stress in skin pigmentation and aging, specifically with emphasis on oxidative stress and skin pigmentation. Meanwhile, we summarize the science and rationale of using three well-known antioxidants, namely vitamin C, resveratrol and ferulic acid, in the treatment of hyperpigmentation. Finally, we discuss the strategy for preventing oxidative stress-induced skin pigmentation and aging., (© 2021 Society of Cosmetic Scientists and the Société Française de Cosmétologie.)

In the present study, we aimed to investigate the effect of individual and combined treatment of sinapic acid (SA) and ellagic acid (EA) in streptozotocin (STZ)-induced diabetic rats. Rats were divided into eight groups (n = 7): Normal Control, Diabetic Control, Diabetic + Sinapic Acid, Diabetic + Ellagic Acid, Diabetic + Sinapic Acid + Ellagic Acid, Sinapic Acid, Ellagic Acid and Sinapic Acid + Ellagic Acid. Diabetic groups were injected with a single dose of 50 mg/kg STZ intraperitoneally. Rats received 20 mg/kg/day SA and 50 mg/kg/day EA intragastrically for 28 days. The numerical density of immunopositive β-cells and volume density of pancreatic islets were calculated. Additionally, glucose and insulin levels in serum, MDA, GSH, and CAT levels of pancreatic tissue were measured. While serum glucose levels increased, serum insulin levels decreased in STZ-induced diabetic rats. But these changes in glucose and insulin were restored by individual and combined treatments of SA and EA. Also, individual and combined treatments of SA and EA increased insulin expression of β-cells in STZ-induced diabetic rats. Moreover, these compounds improved deteriorating oxidative stress parameters in STZ-induced diabetic rats. Our study indicates that SA and EA, especially their combined treatments, can be used as an antihyperglycemic agent in diabetes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Ferulic acid (FA) is a natural polyphenol compound existing in many plants. The purpose of this study was to investigate the effect of FA on non-alcoholic steatohepatitis (NASH) induced by high-cholesterol and high-fat diet (HCHF) and its possible mechanism. Rats were fed HCHF for 12 weeks to establish NASH model. FA improved liver coefficients and had no effect on body weight changes. FA could reduce serum alanine transferase (ALT) and aspartate transferase (AST) activities. FA attenuated the increase of total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) levels caused by NASH, improved the liver pathological damage induced by NASH, and inhibited the progression of liver fibrosis. FA prevented the production of reactive oxygen species (ROS) and the increase of malondialdehyde (MDA) levels, and attenuated the decrease in superoxide dismutase (SOD) activity. Meanwhile, FA significantly restored the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α). In addition, we also found that FA inhibited the activity of ROCK and the activation of NF-κB signaling pathway in the liver of NASH rats. Overall, FA has a hepatoprotective anti-oxidative stress and anti-inflammatory effects in NASH rats, and its mechanism may be related to the inhibition of ROCK/NF-κB signaling pathway., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in this work., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

This study aimed to investigate the protective effect of sinapic acid (SA) on biochemical and histopathological changes in an experimental testicular torsion-detorsion rat model. Twenty-four rats were randomised into four groups: sham group, ischemia/reperfusion (IR) group subjected to testicular torsion for 2 hr and then detorsion for 4 hr, and two groups treated with SA1 and SA2 (10 mg/kg and 20 mg/kg, by single intraperitoneal injection, 30 min before reperfusion). Serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured by an autoanalyzer, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), protein carbonyl (PC), and nitric oxide (NO) oxidative stress parameters by spectrophotometric methods, and tumour necrosis factor (TNF-α), interleukin-1 beta (IL-1β), and interleukin 6 (IL-6) parameters by the Elisa method. In addition, immunohistochemical and histopathological examinations were performed on testicular tissues. There was no significant difference between the groups in terms of serum testosterone, FSH and LH levels (p > .05). SA significantly reduced increased testicular damage, oxidative stress, inflammation, cell death and also restored decreased antioxidant enzyme activities (p < .05). Pre-treatment of rats with SA reduced testicular dysfunction and morphological changes IRI. SA's antioxidant, anti-inflammatory, and antiapoptotic properties were found to be protective against testicular IR., (© 2021 Wiley-VCH GmbH.)

Aims: Intestinal injury is a clinical problem related to radiotherapy or accidental exposure to ionizing radiation. This study aimed to investigate the protective effect of p-coumaric acid (CA) against radiation induced intestinal injury., Main Methods: The present study orally administered CA to C57BL/6 male mice at 30 min before total body irradiation and continued for 3 days post irradiation. Then, the mice were sacrificed at day 3.5 or 14 after irradiation, respectively. The blood was collected to analyze the inflammatory cytokines. The antioxidant indexes of jejunum tissues were determined. Hematoxylin and eosin staining and apoptosis analysis was studied to investigate the pathological changes of the jejunum tissues. In addition, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were carried out to determine the changes in mRNA and protein levels of jejunum tissues., Key Findings: Compared with the only irradiated group, treatment with CA improved intestinal morphology and apoptosis, increased the villus height and the ratio of villus height to crypt depth. It also reduced the oxidative stress and inflammatory response. The molecular mechanism analysis showed that CA significantly inhibited the pyroptosis genes (Caspase-1, NLRP3 and AIM2) mRNA expression and improved the intestinal barrier genes expression., Significance: The results suggested that CA ameliorates ionizing radiation-induced intestinal injury by inhibition of oxidative stress, inflammatory response and pyroptosis., (Copyright © 2021. Published by Elsevier Inc.)

Rationale: Preclinical and clinical reports suggest that ferulic acid (FA), a plant-derived phenylpropanoid, is effective against mental health problems such as agitation, anxiety, and irritability in humans, without causing adverse side effects. However, the mechanism of action is unknown., Objective: The aim of the study is to investigate the mechanism underlying the ameliorative effects of FA on mental health problems such as agitation, anxiety, and irritability, using in vivo behavioral analysis, in vitro pharmacological analysis, and in silico binding analysis., Methods: The effects of FA (10 mg/kg, 50 mg/kg, and 250 mg/kg) on hyperactivity and aggressive behaviors of isolation-reared mice were examined. The effects of FA (50 mg/kg and 250 mg/kg) on extracellular levels of monoamines such as serotonin (5-HT), dopamine, and noradrenaline were analyzed by in vivo microdialysis. The effects of FA (10 -13 -10 -6 M) on 5-HT 1A and 5-HT 2A receptors were analyzed using a luciferase reporter gene assay. Binding of FA to the mouse 5-HT 1A receptor was evaluated by in silico analysis., Results: The behavioral analysis showed that administration of FA (50 mg/kg) 1 h before experiments significantly alleviated hyperactivity and aggressive behaviors in isolation-reared mice. These alleviative effects were abolished by pretreatment with the 5-HT 1A receptor antagonist WAY-100635 (1 mg/kg). In vivo microdialysis analysis showed that FA (50 mg/kg) did not change extracellular monoamine levels in the prefrontal cortex of mice. The luciferase reporter gene assay indicated that FA activated 5-HT 1A receptors, but not 5-HT 2A receptors, in a dose-dependent manner. The maximal response of 5-HT 1A receptors to FA was weaker than that to 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), a 5-HT 1A receptor full agonist. In silico binding analysis showed that FA binds to the orthosteric site of 5-HT 1A receptors., Conclusion: Taken together, these results suggest that FA ameliorates agitation-, anxiety-, and irritability-like behaviors such as hyperactivity and aggressive behaviors in isolation-reared mice via 5-HT 1A receptor partial agonist activity. These findings support the efficacy of FA on mental health problems that have been suggested in preclinical and clinical practice., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Previously the potential therapeutic action of ferulic acid, ligustrazine and tetrahydropalmatine (FLT) are discovered with unclear mechanism in rat autograft endometriosis. However, the effect of FLT on endometrial cells and allograft endometriosis is still unclear. This study is designed to elucidate the influence of FLT on epithelial-mesenchymal transformation in allograft endometriosis and endometrium cells. In vivo , fluorescent xenogeneic endometriosis model was established. In vitro , invasion and metastasis were analyzed after treating FLT. Epithelial-mesenchymal transformation and Wnt/β-catenin pathway were inspected in vitro and in vivo . Activator or inhibitor of Wnt/β-catenin signaling was performed to inspect mechanism of epithelial-mesenchymal transformation. In vivo , FLT not only decreased fluorescent intensity and volume of ectopic lesion, but also ameliorated pathological morphology. E 2 and PROG levels in serum were reduced by FLT. In endometrial cells, FLT significantly inhibited the invasion and metastasis. Meantime, epithelial-mesenchymal transformation was reversed, accompanied by suppression of Wnt/β-catenin pathway. In-depth study, activation of Wnt/β-catenin pathway lead to promotion of epithelial-mesenchymal transformation, which was reversed by FLT. FLT prevented fluorescent allograft endometriosis and endometrium cells, which was related to suppress epithelial-mesenchymal transformation through inactivating Wnt/β-catenin pathway. The findings disclose molecular mechanism of epithelial-mesenchymal transformation in endometriosis by FLT, and contribute to further application., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Ferulic acid is being screened in preclinical settings to combat various neurological disorders. It is a naturally occurring dietary flavonoid commonly found in grains, fruits, and vegetables such as rice, wheat, oats, tomatoes, sweet corn etc., which exhibits protective effects against a number of neurological diseases such as epilepsy, depression, ischemia-reperfusion injury, Alzheimer's disease, and Parkinson's disease. Ferulic acid prevents and treats different neurological diseases pertaining to its potent anti-oxidative and anti-inflammatory effects, beside modulating unique neuro-signaling pathways. It stays in the bloodstream for longer periods than other dietary polyphenols and antioxidants and easily crosses blood brain barrier. The use of novel drug delivery systems such as solid-lipid nanoparticles (SLNs) or its salt forms (sodium ferulate, ethyl ferulate, and isopentyl ferulate) further enhance its bioavailability and cerebral penetration. Based on reported studies, ferulic acid appears to be a promising molecule for treatment of neurological disorders; however, more preclinical (in vitro and in vivo) mechanism-based studies should be planned and conceived followed by its testing in clinical settings.

Prenatal and/or early postnatal exposure to lead (Pb) may be associated with deficits in cognitive function in the toddler offspring, and oxidative stress likely play a central role in mediating these adverse effects. Here, we tested the hypothesis that ameliorative effect of ferulic acid (FA) on lead-induced cognitive deficits attributed to its antioxidant properties in a nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent manner in the context of prenatal Pb exposure. To test this hypothesis, Nrf2 knockout and C57BL/6 wild type mouse dams were exposed/unexposed to PbAc (250 ppm) during gestation day 5 to postnatal day 14 via drinking water, and FA (50 mg/kg)/vehicle was administered orally to dams for 31 d. Spatial learning and memory in pups was assessed by Morris water maze. Biochemical assays, real-time PCR, western blot techniques were employed to evaluate oxidative stress and signaling pathways in the brain of pups. We report that lead acetate (PbAc) leads to deficits in cognitive functions in offspring, which were partially attenuated by FA (P<.05). In parallel, pretreatment with FA also significantly inhibited the PbAc-induced oxidative stress, as indicated by a change in NAD+/NADH ratio, glutathione (GSH) and malondialdehyde contents (all P<.05). Interestingly, FA significantly elevated the glutamate cysteine ligase and heme oxygenase 1 at levels of transcription and translation in both mice exposed and unexposed to Pb, increasing de novo synthesis of GSH (all P<.05). Furthermore, maternal FA administration activates extracellular signal-regulated kinases 1 and 2 and promotes more Nrf2 nuclear accumulation by increasing the Nrf2 total protein in brain of offspring mice (all P<.05). Conversely, FA failed to influence Pb-induced both memory deficits and oxidative stress in offspring of Nrf2 knockout mice (all P≥.05), suggesting that Nrf2 is essential in mediating the cognition-enhancing and antioxidant effects of FA. Overall, our results demonstrate that FA protects against Pb-induced offspring's cognitive deficits, suggesting that it is a promising candidate for the treatment of Pb toxicity., (Copyright © 2021. Published by Elsevier Inc.)

The structures of melatonin and ferulic acid were merged into tertiary amide-based histone deacetylase 6 (HDAC6) inhibitors to develop multi-target-directed inhibitors for neurodegenerative diseases to incorporate antioxidant effects without losing affinity and selectivity at HDAC6. Structure-activity relationships led to compound 10b as a hybrid molecule showing pronounced and selective inhibition of HDAC6 (IC50 = 30.7 nM, > 25-fold selectivity over other subtypes). This compound shows comparable DPPH radical scavenging ability to ferulic acid, comparable ORAC value to melatonin and comparable Cu 2+ chelating ability to EDTA. It also lacks neurotoxicity on HT-22 cells, exhibits a pronounced immunomodulatory effect, and is active in vivo showing significantly higher efficacy in an AD mouse model to prevent both Aβ25-35-induced spatial working and long-term memory dysfunction at lower dose (0.3 mg/kg) compared to positive control HDAC6 inhibitor ACY1215 and an equimolar mixture of the three entities ACY1215, melatonin and ferulic acid, suggesting potentially disease-modifying properties.

Distichochlamys benenica is a native black ginger that grows in Vietnam. In point of fact, there is limitation of available information in the literature making mention of the chemical constituents and bioactive properties of this plant. This study is aimed at isolating trans-o -coumaric acid ( 1 ), trans -cinnamic acid ( 2 ), and borneol ( 3 ) from the rhizomes of D. benenica Q.B.Nguyen & Škorničk and evaluate the anti-inflammatory and antimicrobial activities of 1-3 using the carrageenan paw edema model and the dilution broth method, respectively. This revealed that 1 was as effective as diclofenac in reducing the intensity of the edema development. The in silico research showed that the activity of 1 might be derived from inhibiting COX-2 by generating h-bonds at the positions of Arg 120, Tyr 355, and Arg 513 residues. The antimicrobial activities against Gram-positive strains ( Staphylococcus aureus and Bacillus subtilis ) were comparable, with the minimum inhibitory concentrations ranging from 1.52 to 3.37 mM. This is the first study of the bioactivity of compounds isolated from D. benenica Q.B.Nguyen & Škorničk. Our results suggest that 1 may be a nature-derived compound which demonstrates the anti-inflammatory properties and inhibit the proliferation of several Gram-positive bacteria., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Ty Viet Pham et al.)

Alzheimer's disease (AD) is an age-related multifactorial neurodegenerative disorder characterized by severe central cholinergic neuronal loss, gradually contributing to cognitive dysfunction and impaired motor activity, resulting in the brain's cell death at the later stages of AD. Although the etiology of AD is not well understood, however, several factors such as oxidative stress, deposition of amyloid-β (Aβ) peptides to form Aβ plaques, intraneuronal accumulation of hyperphosphorylated tau protein, and low level of acetylcholine are thought to play a major role in the pathogenesis of AD. There is practically no drug for AD treatment that can address the basic factors responsible for the neurodegeneration and slow down the disease progression. The currently available therapies for AD in the market focus on providing only symptomatic relief without addressing the aforesaid basic factors responsible for the neurodegeneration. Ferulic acid (FA) is a phenol derivative from natural sources and serves as a potential pharmacophore that exerts multiple pharmacological properties such as antioxidant, neuroprotection, Aβ aggregation modulation, and anti-inflammatory. Several FA based hybrid analogs are under investigation as a multi-target directed ligand (MTDLs) to develop novel hybrid compounds for the treatment of AD. In the present review article, we are focused on the critical pathogenic factors responsible for the onset of AD followed by the developments of FA pharmacophore-based hybrids compounds as a novel multifunctional therapeutic agent to address the limitations associated with available treatment for AD. The rationale behind the development of these compounds and their pharmacological activities in particular to their ChE inhibition (ChEI), neuroprotection, antioxidant property, Aβ aggregation modulation, and metal chelation ability, are discussed in detail. We have also discussed the discovery of caffeic and cinnamic acids based MTDLs for AD. This review paper provides an in-depth insight into the research progress and current status of these novel therapeutics in AD and prospects for developing a druggable molecule with desired pharmacological affinity and reduced toxicity for the management of AD., 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 © 2021 Elsevier Masson SAS. All rights reserved.)

Phenolic compounds, present in plants, are considered to be indispensable parts of human dietary sources. Sinapic acid, is a natural herbal compound containing phenolic acid. It is found in oranges, grapefruits, and cranberries and in herbs like canola, mustard seed and rapeseed. Sinapic acid is chemically studied as a cinnamic acid derivative that contains 3, 5-dimethoxyl and 4-hydroxyl substitutions in the phenyl group of cinnamic acid. Sinapic acid has been pharmacologically evaluated for its potent antioxidant, anti-inflammatory, anti-cancer, hepatoprotective, cardioprotective, renoprotective, neuroprotective, anti-diabetic, anxiolytic and anti-bacterial activities. In this review we have summarized the potential pharmacological and therapeutic effects of Sinapic acid in various models.

To explore the influence of sodium ferulate (SF) on miR-133a and left ventricle remodeling (LVR) in rats with myocardial infarction (MI). The left coronary artery was ligated to create 36 ischemia-reperfusion (IR) rat models that were randomly divided into mock surgical group (MSG) (not ligated), model group (MG), and sodium ferulate group (SFG). After the successful modeling, SFG was intravenously injected with SF at the dose of 10 mg/kg, and the other two groups were injected with the same volume of normal saline. After 28 days, cardiac hemodynamic indices of all groups were measured; the myocardial infarction size (MIS), left ventricular mass index (LVMI), and collagen volume fraction (CVF) were calculated, the content of serum malondialdehyde (MDA) and activities of catalase (CAT), superoxide dismutase (SOD) and glutathione catalase (GSH-px) were detected by ELISA, and miR-133a expression in myocardial tissues of the left ventricle (LV) was detected by RT-qPCR. SF improved the cardiac hemodynamic indices of rat model and reduced the MIS, LVMI and CVF. SF decreased the serum MDA level and increased the serum CAT, SOD and GSH-px levels in rat model. SF increased the expression of miR-133a in myocardial tissue of rat model. Therefore, SF could effectively reduce the myocardial injury of IR rats and improve the LVR. Its mechanism may be related to the antioxygenation and upregulation of miR-133a.

P-Coumaric acid (p-CA) is a hydroxycinnamic acid, an organic compound that is a hydroxyl derivative of cinnamic acid. P-CA is the most abundant isomer in nature and can be found in a wide variety of edible plants such as fungi, peanuts, navy beans, tomatoes, carrots, basil, and garlic. Recently, the therapeutic properties of p-CA have received a great deal of attention from scientific society. Here, we described the medicinal effects of p-CA on various pathological conditions. This review was performed via evaluating PubMed reported studies from January 2010 to January 2020. Also, reference lists were checked to find additional studies. All intermediation or complementarity of animal models, case-control and cohort studies, in vitro studies, and controlled trials (CTs) on p-CA were acceptable. However plant extract studies without indication of main active substances were excluded due to the considerable diversities and heterogeneities. According to recent evidence regarding the beneficial effects of p-CA, numerous diseases such as nephropathies, cardiovascular diseases, neuroinflammatory diseases, liver diseases, cancers, and some metabolic disorders could potentially be controlled by this natural herb. Interestingly, autophagy is a novel molecular mechanism involved in the crosstalk between classic effects of p-CA and introduces alternative therapeutic pathways for this compound. Much work remains in clarifying the main therapeutic properties among the various p-CA effects; these will be the subject of forthcoming work, resulting in presenting further mechanism of action., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The p-coumaric acid is a phenolic compound present in large quantities in the extract of Baccharis dracunculifolia DC, a Brazilian medicinal plant used to treat gastric ulcer. Given the necessity for finding new chemical components capable of accelerating gastric healing, in this study, the effects of the p-coumaric acid were evaluated in the acetic acid-induced ulcer model in rats, where histological, inflammatory, and oxidative parameters were analyzed. The healing property was also evaluated in the scratch assay on fibroblast cells (L929) and the cytotoxicity of p-coumaric acid was assessed in both L929 and human gastric adenocarcinoma (AGS) cells by MTT assay. The treatment with p-coumaric acid (10 mg/kg, p.o.) for 7 days, twice a day, decreased by 44.6% the acetic acid-induced gastric ulcer compared with the vehicle-treated group. The vehicle control-treated group showed a larger extension of the ulcer base and an extensive damage into the mucosa and submucosa layers, which were mitigated by the treatment with p-coumaric acid. This beneficial effect was also associated with increased levels of mucin and reduced glutathione, decreased amount of lipid hydroperoxides, and increased superoxide dismutase and catalase activities without interfering with the activity of myeloperoxidase in the gastric tissue. The compound promoted the restructuring of the cell monolayer in the scratch test and did not show toxicity in the L929 cell line, while reduced the viability of the AGS, a lineage of human gastric adenocarcinoma. Thus, p-coumaric acid may be considered a natural source for the treatment of gastric ulcers, by reinforcing protective factors of gastric mucosa and by accelerating gastric healing.

Bioactive compounds found in food and medicinal plants contribute to maintaining health and treating illnesses. For example, hydroxycinnamic acids, such as ferulic acid, are widely present in nature and have several pharmacological properties, including antioxidant, anti-inflammatory, and beneficial effects in parameters of diabetes and hyperlipidemia. The results of studies in animal models and in vitro experiments of ferulic acid suggest its high therapeutic and preventive potential against several pathological disorders, such as cardiovascular diseases. Therefore, in this review, the bioactivities of ferulic acid on the cardiovascular system are described, including the discussion of the mechanisms of action in the various components of the system. In this review, we discuss the pharmacological properties of this versatile natural product in aspects of cardiovascular health, including cardioprotective and antihypertensive actions, and on the metabolism of lipids, diabetes, and thrombosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA), a hydroxycinnamic acid derived from various seeds, nuts, leaves, and fruits, exists in a free form as well as is covalently conjugated with polysaccharides, glycoproteins, polyamines, lignin, and hydroxy fatty acids of plant cell walls. It exhibits a variety of pharmacological effects, such as antioxidant, anti-inflammatory, vasodilatory, antithrombotic, antimicrobial, anti-allergic, antiviral, hepatoprotective, and anticancer activities. FA induces the expression of cell cycle-related proteins, such as p53 and p21, and reduces cyclin D1 and cyclin E levels. Moreover, FA triggers apoptosis and autophagic cell death depending on intracellular reactive oxygen species production in various cancer cell lines. The potential apoptotic action of FA is mediated by altered expression of procaspase-3, procaspase-8, procaspase-9, poly (ADP ribose) polymerase, Bcl-2, and Bax. It blocks the activation of both the canonical Smad and noncanonical extracellular-signal-regulated kinase/Akt (protein kinase B) pathways in various cancer cells. However, due to low solubility and permeability, its availability to biological systems is limited. Therefore, encapsulation of FA into chitosan tripolyphosphate nanoparticles may enhance its cytocompatibility, solubility, and anticancer potential. The nanohybrids of FA and double layered hydroxide exhibit cellular delivery properties of intercalated molecules on cancer cell lines. This chapter summarizes the anticancer efficacy of FA with an emphasis on the role of apoptosis, and underlying molecular mechanisms involving various signaling pathways in tumor cells., (Copyright © 2021 Elsevier Inc. All rights reserved.)