The Cancer-Protective Potential of Protocatechuic Acid: A Narrative Review.

Cancer is one of the leading causes of death worldwide, making the search for alternatives for its control a critical issue. In this context, exploring alternatives from natural sources, such as certain vegetables containing a variety of secondary metabolites with beneficial effects on the body and that play a crucial role in the fight against cancer, is essential. Among the compounds with the greatest efficacy in controlling this disease, those with antioxidant activity, particularly phenolic com-pounds, stand out. A remarkable example of this group is protocatechuic acid (PCA), which has been the subject of various revealing research on its activities in different areas. These studies sustain that protocatechuic acid has anti-inflammatory, antimutagenic, antidiabetic, antiulcer, antiviral, antifibrogenic, antiallergic, neuroprotective, antibacterial, anticancer, antiosteoporotic, anti-aging, and analgesic properties, in addition to offering protection against metabolic syndrome and con-tributing to the preservation of hepatic, renal, and reproductive functionality. Therefore, this paper aims to review the biological activities of PCA, focusing on its anticancer potential and its in-volvement in the control of various molecular pathways involved in tumor development, sup-porting its option as a promising alternative for cancer treatment.

IDO2-siRNA Carried by Salmonella Combined with Nifuroxazide Attenuates Melanoma Growth.

BACKGROUND: Melanoma, a highly malignant skin cancer, is a hot topic in oncology treatment research. Nowadays, tumor immunotherapy, especially immunotherapy combined with other therapies, has attracted more and more attention. Indoleamine 2,3-dioxygenase 2 (IDO2), a ratelimiting enzyme of the tryptophan metabolism pathway in the urine of dogs with immunosuppression, is highly expressed in melanoma tissue. Additionally, IDO2 significantly inhibits the anti-tumor immunity of the body and has become a novel target of melanoma treatment. Nifuroxazide, as an intestinal antibacterial agent, was found to be able to inhibit Stat3 expression and exert an anti-tumor effect. Therefore, the present study aimed to examine the therapeutic effect of a self-designed IDO2-small interfering RNA (siRNA) delivered by attenuated Salmonella combined with nifuroxazide on melanoma- bearing mice, as well as determine its underlying mechanism. METHODS: The effect of nifuroxazide on melanoma was detected by flow cytometry, CCK-8 and colony- forming ability assays, respectively, in vitro. The plasmid of siRNA-IDO2 was constructed, and the mice-bearing melanoma model was established. After the treatment, the tumor growth and survival rate were monitored, and the morphological changes of tumor tissue were detected by HE staining. The expression of related proteins was detected by Western blotting, and the expression of CD4 and CD8 positive T cells in tumor tissue was detected by IHC and IF, and the proportion of CD4 and CD8 positive T cells in spleen was detected by flow cytometry. RESULTS: The results demonstrated that the combination therapy effectively inhibited the phosphorylation of Stat3 and the expression level of IDO2 in melanoma cells, which effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice. The mechanistic study revealed that, compared with control groups and monotherapy groups, the combination treatment group reduced the atypia of tumor cells, increased the apoptotic rate, enhanced the infiltration of T lymphocytes in tumor tissue and increased the CD4+ and CD8+ T lymphocytes in the spleen, suggesting that the mechanism may be associated with the inhibition of tumor cell proliferation, the increase of apoptosis and the enhancement of the cellular immunity. CONCLUSION: In conclusion, IDO2-siRNA combined with nifuroxazide therapy could serve a significant role in the treatment of melanoma-bearing mice, enhance the tumor immunity and provide an experimental basis for identifying a novel combination method for the treatment of melanoma clinically.

Nifuroxazide inhibits the growth of glioblastoma and promotes the infiltration of CD8 T cells to enhance antitumour immunity.

INTRODUCTION: Glioblastoma is a primary intracranial tumour with extremely high disability and fatality rates among adults. Existing diagnosis and treatment methods have not significantly improved the overall poor prognosis of patients. Nifuroxazide, an oral antibiotic, has been reported to act as a tumour suppressor in a variety of tumours and to participate in the process of antitumour immunity. However, whether it can inhibit the growth of glioma is still unclear. METHODS: We explored the potential mechanism of nifuroxazide inhibiting the growth of glioblastoma cells through in vitro and in vivo experiments. RESULTS: nifuroxazide can inhibit the proliferation of glioblastoma cells, promote G2 phase arrest, induce apoptosis, and inhibit epithelial-mesenchymal transition through the MAP3K1/JAK2/STAT3 pathway. Similarly, clinical sample analysis confirmed that MAP3K1 combined with STAT3 can affect the prognostic characteristics of patients with glioma. In addition, nifuroxazide can drive the M1 polarization of microglioma cells, inhibit the expression of CTLA4 and PD-L1 in tumour cells, and promote the infiltration of CD8 T cells to exert antitumour effects. Combination treatment with PD-L1 inhibitors can significantly prolong the survival time of mice. CONCLUSION: we found that nifuroxazide can inhibit the growth of glioblastoma and enhance antitumour immunity. Thus, nifuroxazide is an effective drug for the treatment of glioblastoma and has great potential for clinical application.

Nifuroxazide in combination with CpG ODN exerts greater efficacy against hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumour in China that remains a major challenge to the medical community, and effective treatment is urgently needed. Due to complex tumorigenesis, monotherapy shows poor therapeutic effects, and combined treatment becomes a necessary option. YW002, a CpG ODN-containing sequence, has been proven to enhance antitumor effects in tumour-bearing mouse models. Moreover, as a broad-spectrum antimicrobial drug, nifuroxazide exhibited an anti-HCC effect through activation of p-Stat3. Here, we tested the effect of nifuroxazide on HCC in vitro and then explored the therapeutic effect of combined nifuroxazide and CpG ODN on HCC in vivo. Nifuroxazide inhibited proliferation, induced apoptosis and suppressed migration and invasion in HepG2 cells in vitro. The combination therapy using nifuroxazide and CpG ODN significantly suppressed the growth of tumours in tumour-bearing mice with few side effects and achieved better therapeutic effects on HCC than monotherapy. Moreover, combined nifuroxazide and CpG ODN therapy significantly induced apoptosis, enhanced the infiltration of CD4+ and CD8+ T lymphocytes and macrophages in tumour tissue, and increased the ratio of CD4+ and CD8+ T lymphocytes in the spleens of tumour-bearing mice. The introduction of this combination therapy combining nifuroxazide and CpG ODN provided a new strategy for HCC treatment.

Protocatechuic acid protects mice from influenza A virus infection.

Influenza A virus (IAV) H1N1 infection remains great challenge to public health and causes great burden over the world. Although there are anti-viral agents available, searching for effective agents to treat H1N1 infection is still in urgent because of the emergence of resistant strain. Protocatechuic acid (PCA) is a biological agent with multiple functions. In present study, we explored the effects of PCA on H1N1 infection. Mice infected with mouse adapted influenza strain A/Font Monmouth were administrated with PCA. The body weight change, mortality, lung index, viral titer, immune cell infiltration, and cytokine production in the lung were monitored. The activation of toll-like receptor 4 (TLR4) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) pathway was investigated. PCA treatment prevented H1N1 infection-induced mice body weight loss and death. PCA reduced the lung index, viral titer, infiltration of immune cells, and cytokine level in the lung, as well as suppressed H1N1-induced TLR4/NF-κB activation. PCA protects mice against H1N1 infection and could be a potential therapeutic agent to treat influenza.

Inhibitory effect of polyphenols (phenolic acids, lignans, and stilbenes) on cancer by regulating signal transduction pathways: a review.

Natural products, especially polyphenols (phenolic acids, lignans, and stilbenes) are suggested to be more potent anticancer drugs because of their no or less adverse effects, excess availability, high accuracy, and secure mode of action. In the present review, potential anticancer mechanisms of action of some polyphenols including phenolic acids, lignans, and stilbenes are discussed based on clinical, epidemiological, in vivo, and in vitro studies. The emerging evidence revealed that phenolic acids, lignans, and stilbenes induced apoptosis in the treatment of breast (MCF-7), colon (Caco-2), lung (SKLU-1), prostate (DU-145 and LNCaP), hepatocellular (hepG-2), and cervical (A-431) cancer cells, cell cycle arrest (S/G2/M/G1-phases) in gastric (MKN-45 and MKN-74), colorectal (HCT-116), bladder (T-24 and 5637), oral (H-400), leukemic (HL-60 and MOLT-4) and colon (Caco-2) cancer cells, and inhibit cell proliferation against the prostate (PC-3), liver (LI-90), breast (T47D and MDA-MB-231), colon (HT-29 and Caco-2), cervical (HTB-35), and MIC-1 cancer cells through caspase-3, MAPK, AMPK, Akt, NF-κB, Wnt, CD95, and SIRT1 pathways. Based on accumulated data, we suggested that polyphenols could be considered as a viable therapeutic option in the treatment of cancer cells in the near future.

Nifuroxazide Mitigates Angiogenesis in Ehlrich's Solid Carcinoma: Molecular Docking, Bioinformatic and Experimental Studies on Inhibition of Il-6/Jak2/Stat3 Signaling.

Nifuroxazide is an antidiarrheal medication that has promising anticancer activity against diverse types of tumors. The present study tested the anticancer activity of nifuroxazide against Ehrlich's mammary carcinoma grown in vivo. Furthermore, we investigated the effect of nifuroxazide on IL-6/jak2/STAT3 signaling and the possible impact on tumor angiogenesis. The biological study was supported by molecular docking and bioinformatic predictions for the possible effect of nifuroxazide on this signaling pathway. Female albino mice were injected with Ehrlich carcinoma cells to produce Ehrlich's solid tumors (ESTs). The experimental groups were as follows: EST control, EST + nifuroxazide (5 mg/kg), and EST + nifuroxazide (10 mg/kg). Nifuroxazide was found to reduce tumor masses (730.83 ± 73.19 and 381.42 ± 109.69 mg vs. 1099.5 ± 310.83) and lessen tumor pathologies. Furthermore, nifuroxazide downregulated IL-6, TNF-α, NFk-ß, angiostatin, and Jak2 proteins, and it also reduced tumoral VEGF, as indicated by ELISA and immunohistochemical analysis. Furthermore, nifuroxazide dose-dependently downregulated STAT3 phosphorylation (60% and 30% reductions, respectively). Collectively, the current experiment shed light on the antitumor activity of nifuroxazide against mammary solid carcinoma grown in vivo. The antitumor activity was at least partly mediated by inhibition of IL-6/Jak2/STAT3 signaling that affected angiogenesis (low VEGF and high angiostatin) in the EST. Therefore, nifuroxazide might be a promising antitumor medication if appropriate human studies will be conducted.

A Review of the Health Protective Effects of Phenolic Acids against a Range of Severe Pathologic Conditions (Including Coronavirus-Based Infections).

Phenolic acids comprise a class of phytochemical compounds that can be extracted from various plant sources and are well known for their antioxidant and anti-inflammatory properties. A few of the most common naturally occurring phenolic acids (i.e., caffeic, carnosic, ferulic, gallic, p-coumaric, rosmarinic, vanillic) have been identified as ingredients of edible botanicals (thyme, oregano, rosemary, sage, mint, etc.). Over the last decade, clinical research has focused on a number of in vitro (in human cells) and in vivo (animal) studies aimed at exploring the health protective effects of phenolic acids against the most severe human diseases. In this review paper, the authors first report on the main structural features of phenolic acids, their most important natural sources and their extraction techniques. Subsequently, the main target of this analysis is to provide an overview of the most recent clinical studies on phenolic acids that investigate their health effects against a range of severe pathologic conditions (e.g., cancer, cardiovascular diseases, hepatotoxicity, neurotoxicity, and viral infections-including coronaviruses-based ones).

Targeting HMGB1/TLR4/NF-κB signaling pathway by protocatechuic acid protects against l-arginine induced acute pancreatitis and multiple organs injury in rats.

Acute pancreatitis (AP) is a common pancreatic inflammation associated with substantial morbidity and mortality. AP may be mild or severe which can spread systemically causing multiple organs failure (MOF) and even death. In the current study, protocatechuic acid (PCA), a natural phenolic acid, was investigated for its possible protective potential against L-arginine induced AP and multiple organs injury (MOI) in rats. AP was induced by L-arginine (500 mg/100 g, ip). Two dose levels of PCA were tested (50 and 100 mg/kg, oral, 10 days before L-arginine injection). PCA successfully protected against L-arginine induced AP and MOI that was manifested by normalizing pancreatic, hepatic, pulmonary, and renal tissue architecture and restoring the normal values of pancreatic enzymes (amylase and lipase), serum total protein, liver enzymes (alanine transaminase (ALT) and aspartate transaminase (AST)) and kidney function biomarkers (blood urea nitrogen (BUN) and serum creatinine (Cr)) that were significantly elevated upon L-arginine administration. Additionally, PCA restored balanced oxidant/antioxidants status that was disrupted by L-arginine and normalized pancreatic levels of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) content. Moreover, PCA significantly decreased L-arginine induced elevation in pancreatic high motility group box protein 1 (HMGB1), toll like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF-κB), tumor necrosis factor- α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) expression. PCA significantly ameliorated L-arginine-induced AP and MOI through its anti-inflammatory and antioxidant effects. HMGB1/TLR4/NF-κB was the major pathway involved in the observed protective potential.

Phenolic Compounds of Red Wine Aglianico del Vulture Modulate the Functional Activity of Macrophages via Inhibition of NF-κB and the Citrate Pathway.

Phenolic compounds of red wine powder (RWP) extracted from the Italian red wine Aglianico del Vulture have been investigated for the potential immunomodulatory and anti-inflammatory capacity on human macrophages. These compounds reduce the secretion of IL-1ß, IL-6, and TNF-α proinflammatory cytokines and increase the release of IL-10 anti-inflammatory cytokine induced by lipopolysaccharide (LPS). In addition, RWP restores Annexin A1 levels, thus involving activation of proresolutive pathways. Noteworthy, RWP lowers NF-κB protein levels, promoter activity, and nuclear translocation. As a consequence of NF-κB inhibition, reduced promoter activities of SLC25A1-encoding the mitochondrial citrate carrier (CIC)-and ATP citrate lyase (ACLY) metabolic genes have been observed. CIC, ACLY, and citrate are components of the citrate pathway: in LPS-activated macrophages, the mitochondrial citrate is exported by CIC into the cytosol where it is cleaved by ACLY in oxaloacetate and acetyl-CoA, precursors for ROS, NO·, and PGE2 inflammatory mediators. We identify the citrate pathway as a RWP target in carrying out its anti-inflammatory activity since RWP reduces CIC and ACLY protein levels, ACLY enzymatic activity, the cytosolic citrate concentration, and in turn ROS, NO·, PGE2, and histone acetylation levels. Overall findings suggest that RWP potentially restores macrophage homeostasis by suppressing inflammatory pathways and activating proresolutive processes.

Neuroprotective and Anti-Inflammatory Effects of Evernic Acid in an MPTP-Induced Parkinson's Disease Model.

Oxidative stress, mitochondrial dysfunction, and neuroinflammation are strongly associated with the pathogenesis of Parkinson's disease (PD), which suggests that anti-oxidative and anti-inflammatory compounds might provide an alternative treatment for PD. Here, we evaluated the neuroprotective effects of evernic aid (EA), which was screened from a lichen library provided by the Korean Lichen Research Institute at Sunchon National University. EA is a secondary metabolite generated by lichens, including Ramalina, Evernia, and Hypogymnia, and several studies have described its anticancer, antifungal, and antimicrobial effects. However, the neuroprotective effects of EA have not been studied. We found that EA protected primary cultured neurons against 1-methyl-4-phenylpyridium (MPP+)-induced cell death, mitochondrial dysfunction, and oxidative stress, and effectively reduced MPP+-induced astroglial activation by inhibiting the NF-κB pathway. In vivo, EA ameliorated MPTP-induced motor dysfunction, dopaminergic neuronal loss, and neuroinflammation in the nigrostriatal pathway in C57BL/6 mice. Taken together, our findings demonstrate that EA has neuroprotective and anti-inflammatory effects in PD models and suggest that EA is a potential therapeutic candidate for PD.

Isolation and characterization of anti-inflammatory and analgesic compounds from Uapaca staudtii Pax (Phyllanthaceae) stem bark.

ETHNOPHARMACOLOGICAL RELEVANCE: Uapaca species including Uapacastaudtii Pax (Phyllanthaceae) are used in West Africa ethnomedicine to treat diverse ailments including pile, rheumatism, oedema and wound healing. However, the anti-inflammatory and analgesic potential as well as constituents of the Uapacastaudtii stem bark has not been investigated. AIM OF THE STUDY: The study was designed to evaluate the anti-inflammatory, analgesic, and antioxidant activities of extract and fractions ofU. staudtii stem bark, and to isolate the bioactive constituents. MATERIALS AND METHODS: The anti-inflammatory, analgesic and antioxidant activities of the ethanol extract, dichloromethane, ethyl acetate, butanol, and aqueous fractions of U. staudtii stem bark, as well as protocatechuic acid and betulinic acid isolated from the bioactive ethyl acetate fraction were evaluated in different mice models of inflammation and pain; furthermore, antioxidant assays were carried out. Chemical structures of isolated compounds were established based on spectroscopic studies and comparison with literature data. RESULTS: The ethanol extract and ethyl acetate fraction exhibited good anti-inflammatory, analgesic, and antioxidant capacity in all studied models, comparable with those of the standard drugs used. Protocatechuic acid also gave significant (p < 0.05) anti-inflammatory (83%and 88% inhibition for egg-albumin induced and xylene induced oedema, respectively), analgesic (56% inhibition and 22 s of pain suppression for acetic acid-induced and hot plate-induced pain, respectively), and antioxidant effects (97% inhibition and absorbance of 2.516 at 100 µg/mL for DPPH and FRAP assay, respectively) in all the models, whereas betulinic acid only exhibited significant (p < 0.05) anti-inflammatory and antioxidant activity. CONCLUSIONS: The result supports the medicinal uses of the U. staudtii stem bark in the management of pain and inflammatory disease. This is the first report on the biological activities and characterization of compounds inU. staudtii, and presence of protocatechuic acid in Uapaca genus.

Effects of Corchorus olitorius and protacatechuic acid on diabetic rat testis tissue / Efectos de Corchorus olitorius y ácido protocatéquico en el tejido testicular de rata diabética

SUMMARY: The aim of this study is to investigate the effects of Protocatechuic acid and Corchorus olitorius on streptozotocin (STZ) induced diabetic rat testis tissue. Randomly selected Wistar Albino rats were divided into five groups as; Diabetes Mellitus, Diabetes Mellitus treated with Corchorus Olitorus (STZ+CO), Diabetes Mellitus treated with Protacatechuic acid (STZ+PCA), Corchorus olitorius (CO), Protocatechuic acid (PCA) and Control. Diabetic model was generated by intraperitoneal injection of 60 mg/kg Streptozotosin. After 48 hours of the STZ injection, blood samples were collected from tail vein in order to measure blood glycose levels. Over 250 mg/dL accepted as diabetic subjets and fed with 250 mg/kg Corchorus olitorius or 20 mg/kg PCA by oral gavage for three weeks. At the end of the experiment, right testes were removed and fixed in 10 % neutral formaldehyde for paraffine embedding. Sections were stained by HE, Masson trichrome, PAS and TUNEL for microscopic evaluation. Control, PCA-only and Corchorus olitorius-only treated group testes tissues showed a normal tissue organization, when degeneration in seminiferous tubules, the vacuolization, seperations in spermatogenic cell series, outpouring of cell groups in the lumen, vesicular body formation, liquid accumulation in the interstitial region and edema were observed in STZ induced diabetic models and untreated groups. Besides, higher amount of TUNEL (+) stained cells were determined in STZ group. On the other hand, blood glucose level and number of TUNEL (+) stained cells were decreased as a result of PCA and Corchorus olitorius treatment. Because of the reduction of blood glucose level and apoptotic cell numbers, PCA and Corchorus olitorius decreace the complications of diabetes mellitus induced rat testis.

RESUMEN: El objetivo de este estudio fue investigar los efectos del ácido protocatéquico y Corchorus olitorius sobre el tejido testicular de rata diabética inducida por estreptozotocina (STZ). Las ratas Wistar Albino fueron seleccionadas al azar y se dividieron en cinco grupos; Diabetes Mellitus, Diabetes Mellitus tratada con Corchorus olitorius (STZ + CO), Diabetes Mellitus tratada con ácido protocatéquico (STZ + PCA), Corchorus olitorius (CO), ácido protocatéquico (PCA) y Control. El modelo diabético se generó por inyección intraperitoneal de 60 mg/kg de estreptozotosina. Después de 48 horas de la inyección de STZ, se recogieron muestras de sangre de la vena de la cola para medir los niveles de glucosa. Niveles mayores a 250 mg/dL fueron considerados como especímenes diabéticos y alimentados con Corchorus olitorius de 250 mg/kg o PCA de 20 mg/kg por sonda oral durante tres semanas. Al final del experimento, se extirparon los testículos derechos y se fijaron en formaldehído neutro al 10 % para la inclusión en parafina. Las secciones se tiñeron con HE, tricromo de Masson, PAS y TUNEL para evaluación microscópica. Los tejidos de los testículos de los grupos control, tratados solo con PCA y con Corchorus olitorius mostraron una organización tisular normal. En cambio en modelos diabéticos inducidos por STZ y grupos no tratados se observó degeneración en los túbulos seminíferos, vacuolización, separaciones en series de células espermatogénicas, efusión de grupos celulares en la luz, formación del cuerpo vesicular, acumulación de líquido en la región intersticial y edema. Además, se determinó una mayor cantidad de células teñidas con TUNEL (+) en el grupo STZ. Por otro lado, el nivel de glucosa en sangre y el número de células teñidas con TUNEL (+) disminuyeron como resultado del tratamiento con PCA y Corchorus olitorius. Debido a la reducción del nivel de glucosa en sangre y el número de células apoptóticas, se observó que PCA y Corchorus olitorius disminuyen las complicaciones de los testículos de rata inducidos por diabetes mellitus.

Mitochondrial Dysfunction in Diabetic Cardiomyopathy: The Possible Therapeutic Roles of Phenolic Acids.

As the powerhouse of the cells, mitochondria play a very important role in ensuring that cells continue to function. Mitochondrial dysfunction is one of the main factors contributing to the development of cardiomyopathy in diabetes mellitus. In early development of diabetic cardiomyopathy (DCM), patients present with myocardial fibrosis, dysfunctional remodeling and diastolic dysfunction, which later develop into systolic dysfunction and eventually heart failure. Cardiac mitochondrial dysfunction has been implicated in the development and progression of DCM. Thus, it is important to develop novel therapeutics in order to prevent the progression of DCM, especially by targeting mitochondrial dysfunction. To date, a number of studies have reported the potential of phenolic acids in exerting the cardioprotective effect by combating mitochondrial dysfunction, implicating its potential to be adopted in DCM therapies. Therefore, the aim of this review is to provide a concise overview of mitochondrial dysfunction in the development of DCM and the potential role of phenolic acids in combating cardiac mitochondrial dysfunction. Such information can be used for future development of phenolic acids as means of treating DCM by alleviating the cardiac mitochondrial dysfunction.

Protocatechuic acid modulates reproductive dysfunction linked to furan exposure in rats.

The reproductive toxicity associated with furan exposure in both animals and humans has been documented. Protocatechuic acid (PCA), a dietary polyphenolic chemical, reportedly elicits beneficial effects on the male reproductive system. However, the influence of PCA on the reproductive toxicity related to furan exposure is unavailable in the literature. The current study evaluated the effects of PCA on the dysfunctional reproductive axis caused by furan exposure in rats. Experimental animals were exposed to furan (8 mg/kg) or co-treated with furan (8 mg/kg) and PCA (25 or 50 mg/kg) for twenty-eight successive days. Results revealed that PCA treatment significantly alleviated furan-mediated declines in sperm production and characteristic qualities as well as in serum levels of prolactin, luteinizing hormone, follicle-stimulating hormone, and testosterone. Further, PCA attenuated furan-induced reduction in antioxidant enzyme activities and testicular function marker enzymes, namely lactate dehydrogenase, glucose-6-phosphate dehydrogenase, acid phosphatase, and alkaline phosphatase. PCA effectively mitigated furan-mediated increases in myeloperoxidase activity, levels of reactive oxygen and nitrogen species, nitric oxide, tumour necrosis factor-alpha, and interleukin-1ß in testes, epididymis, and hypothalamus of rats. Moreover, PCA increased anti-inflammatory cytokine interleukin-10 but suppressed caspase-9 and caspase-3 activities and ameliorated injuries in the testes, epididymis, and hypothalamus of furan-treated rats. In conclusion, PCA ameliorated deficits in the hypothalamic-pituitary-gonadal axis function in furan-exposed rats by suppressing oxido-inflammatory stress and apoptosis.

Protocatechuic acid supplement alleviates allergic airway inflammation by inhibiting the IL-4Rα-STAT6 and Jagged 1/Jagged2-Notch1/Notch2 pathways in allergic asthmatic mice.

OBJECTIVE AND DESIGN: To clarify the effects of dietary supplementation of protocatechuic acid (PCA) and in-depth mechanisms on allergic asthma in ovalbumin (OVA)-induced mice. MATERIALS: Female BALB/c mice were randomly divided into three groups (n = 10 in each group): control group, OVA-induced allergic asthma group, and OVA plus PCA group. TREATMENT: Dietary supplementation of PCA was achieved by adding 50 mg/kg PCA to AIN 93G diet for 25 days. METHODS: Peripheral blood cells, pulmonary inflammatory cell infiltration, the levels of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid (BALF), the mRNA levels of Th2-related genes in the lungs, and the protein expressions of the IL-4Rα-STAT6 and the Jagged1/Jagged2-Notch1/Notch2 signaling pathways were measured. RESULTS: Significantly reduced inflammatory cells infiltration and mucosal hypersecretion in the lung tissues, repaired levels of interleukin IL-4, IL-5, and IL-13 in the BALF, and decreased mRNA expression of IL-4, IL-5, and GATA3 were observed in OVA plus PCA group. Moreover, PCA treatment down-regulated the protein levels of IL-4Rα-STAT6 and Jagged1/Jagged2-Notch1/Notch2 signaling pathways. CONCLUSIONS: Dietary supplement of PCA alleviated allergic asthma partly through suppressing the IL-4Rα-STAT6 and Jagged1/Jagged2-Notch1/Notch2 signaling pathways in mice. Our study provided the theoretic basis of PCA used as functional food in preventing allergic asthma.

Protective effects of protocatechuic acid against cognitive impairment in an amyloid beta-induced Alzheimer's disease mouse model.

In this study, we investigated the protective effects of protocatechuic acid (PA) against cognitive impairment in an amyloid-beta (Aß)-induced Alzheimer's disease (AD) mouse model. PA was administered orally for 14 days at 100 and 200 mg/kg/day. To examine effects on cognition, we conducted behavior tests including the T-maze test, novel object recognition, and the Morris water maze test. In addition, we measured lipid peroxidation, nitric oxide (NO) production, and inflammation-related protein expression in mice tissues. The PA-administered group showed more use of novel routes, better novel object recognition, and learning and memory ability compared to the Aß25-35-injected mice in the behavior tests. The results indicated that the administration of higher PA protected against cognitive impairment. In addition, the PA-administered groups showed significantly decreased lipid peroxidation and NO production in the brain, kidney, and liver tissues. Furthermore, the PA-administered groups showed attenuated Aß25-35-induced neuroinflammation by downregulating inflammatory mediators, inducible nitric oxide synthase and cyclooxygenase-2 in the brain. The results of the present study suggest that PA may be a protective agent against AD.

Black Raspberries and Protocatechuic Acid Mitigate DNFB-Induced Contact Hypersensitivity by Down-Regulating Dendritic Cell Activation and Inhibiting Mediators of Effector Responses.

Contact hypersensitivity (CHS) is the most common occupational dermatological disease. Dendritic cells (DCs) mediate the sensitization stage of CHS, while T-cells facilitate the effector mechanisms that drive CHS. Black raspberry (Rubus occidentalis, BRB) and BRB phytochemicals possess immunomodulatory properties, but their dietary effects on CHS are unknown. We examined the effects of diets containing BRB and protocatechuic acid (PCA, a constituent of BRB and an anthocyanin metabolite produced largely by gut microbes), on CHS, using a model induced by 2,4-dinitrofluorobenze (DNFB). Mice were fed control diet or diets supplemented with BRB or PCA. In vitro bone-marrow derived DCs and RAW264.7 macrophages were treated with BRB extract and PCA. Mice fed BRB or PCA supplemented diets displayed decreased DNFB-induced ear swelling, marked by decreased splenic DC accumulation. BRB extract diminished DC maturation associated with reduced Cd80 expression and Interleukin (IL)-12 secretion, and PCA reduced IL-12. Dietary supplementation with BRB and PCA induced differential decreases in IL-12-driven CHS mediators, including Interferon (IFN)-γ and IL-17 production by T-cells. BRB extracts and PCA directly attenuated CHS-promoting macrophage activity mediated by nitric oxide and IL-12. Our results demonstrate that BRB and PCA mitigate CHS pathology, providing a rationale for CHS alleviation via dietary supplementation with BRB or BRB derived anthocyanins.

The interplay of the inhibitory effect of nifuroxazide on NF-κB/STAT3 signaling attenuates acetic acid-induced ulcerative colitis in rats.

Ulcerative colitis (UC) is a disease of increased worldwide prevalence. UC progression is associated with serious complications that leave the patient with considerable health burdens. Nifuroxazide is an oral nitrofuran antibiotic used as antidiarrheal medication. The current study places an emphasis on investigating the potential therapeutic effectiveness of nifuroxazide (10 mg/kg) and (20 mg/kg) against acetic acid (AA)-induced UC. Intra-rectal AA induced a significant colonic injury and impairment of colonic biochemical and functional incidences. Nifuroxazide in a dose-dependent manner significantly corrected UC associated injury. Macroscopic scoring of UC, serum lactate dehydrogenase (LDH) activity, C-reactive protein (CRP) titer, colon malondialdehyde (MDA) and total nitric oxide (NOx) contents significantly declined. Meanwhile, serum total antioxidant capacity (TAC) and colon catalase, superoxide dismutase (SOD) and glutathione transferase (GST) activities and reduced glutathione (GSH) concentration significantly increased in a dose-dependent way. Ultimately, histopathological, immunohistochemical and ultramicroscopic analysis of colon specimen revealed significant improvement. To pinpoint the mechanistic pathway underlying the curative effect of nifuroxazide, colon expression of NF-κB, caspase-3 was evaluated along with STAT-3 activation. Nifuroxazide induced a dose-dependent significant suppression of NF-κB and caspase-3 signaling together with STAT3 signaling. In conclusion; nifuroxazide can be proposed as a therapeutic candidate to attenuate UC and its associated symptoms. The potential underlying mechanism involves suppression of NF-κB/STAT-3/caspase- signaling.

Tetradecyl 2,3-dihydroxybenzoate alleviates oligodendrocyte damage following chronic cerebral hypoperfusion through IGF-1 receptor.

Currently, there is no effective therapy for chronic cerebral hypoperfusion-induced subcortical ischemic vascular dementia (SIVD), which displays cognitive deficits and progressive white matter damage. Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from gentisides with neuritogenic activity. In this report, we intended to investigate the effect of ABG-001 on the SIVD experimental model through right unilateral common carotid arteries occlusion (rUCCAO) in mice. We found that ABG-001 remarkably alleviated white matter damage and cognitive deficits after cerebral hypoperfusion induced by rUCCAO. The protection of ABG-001 on the white matter was related to an amelioration of the oligodendrocyte apoptosis and demyelination rather than promoting remyelination. Molecular docking study showed that ABG-001 possesses a high affinity for insulin-like growth factor-1 receptor (IGF-1R), but not for tropomyosin receptor kinase A (TrkA). The protection of ABG-001 against oligodendrocyte damage was abrogated by IGF-1R antagonist or knockdown of IGF-1R through shRNA, but not TrkA antagonist. Moreover, ABG-001 did not induce hematological, renal or hepatic toxicity after chronic treatment. The present study indicates that ABG-001 protects oligodendrocytes through IGF-1R to relieve demyelination following chronic cerebral hypoperfusion, which could be represented as an encouraging treatment for SIVD.