Novel insights into the protective effects of leonurine against acute kidney injury: Inhibition of ER stress-associated ferroptosis via regulating ATF4/CHOP/ACSL4 pathway.

Acute kidney injury (AKI) is a common and serious global health problem with high risks of mortality and the development of chronic kidney diseases. Leonurine is a unique bioactive component from Leonurus japonicus Houtt. and exerts antioxidant, antiapoptotic or anti-inflammatory properties. This study aimed to explore the benefits of leonurine on AKI and the possible mechanisms involved, with a particular foc on the regulation of ferroptosis and endoplasmic reticulum (ER) stress. Our results showed that leonurine exhibited prominent protective effects against AKI, as evidenced by the amelioration of histopathological alterations and reduction of renal dysfunction. In addition, leonurine significantly suppressed ferroptosis in AKI both in vivo and in vitro by effectively restoring ultrastructural abnormalities in mitochondria, decreasing ASCL4 and 4-HNE levels, scavenging reactive oxygen species (ROS), as well as increasing GPX4 and GSH levels. In parallel, leonurine also markedly mitigated ER stress via down-regulating PERK, eIF-2α, ATF4, CHOP and CHAC1. Further studies suggested that ER stress was closely involved in erastin-induced ferroptosis, and leonurine protected tubular epithelial cells in vitro by inhibiting ER stress-associated ferroptosis via regulating ATF4/CHOP/ASCL4 signalling pathway. Mechanistically, ATF4 silencing in vitro regulated CHOP and ACSL4 expressions, ultimately weakening both ER stress and ferroptosis. Notably, analyses of single-cell RNA sequencing data revealed that ATF4, CHOP and ASCL4 in renal tubular cells were all abnormally upregulated in patients with AKI compared to healthy controls, suggesting their contributions to the pathogenesis of AKI. Altogether, these findings suggest that leonurine alleviates AKI by inhibiting ER stress-associated ferroptosis via regulating ATF4/CHOP/ASCL4 signalling pathway, thus providing novel mechanisms for AKI treatment.

Protective effects of gallic acid against nickel-induced kidney injury: impact of antioxidants and transcription factor on the incidence of nephrotoxicity.

Nickel (Ni) is a common metal with a nephrotoxic effect, damaging the kidneys. This study investigated the mechanism by which gallic acid (GA) protects mice kidneys against renal damage induced by Nickel oxide nanoparticles (NiO-NPs). Forty male Swiss albino mice were randomly assigned into four groups, each consisting of ten mice (n = 10/group): Group I the control group, received no treatment; Group II, the GA group, was administrated GA at a dosage of 110 mg/kg/day body weight; Group III, the NiO-NPs group, received injection of NiO-NPs at a concentration of 20 mg/kg body weight for 10 consecutive days; Group IV, the GA + NiO-NPs group, underwent treatment with both GA and NiO-NPs. The results showed a significant increase in serum biochemical markers and a reduction in antioxidant activities. Moreover, levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), phosphorylated nuclear factor kappa B (p65), and protein carbonyl (PC) were significantly elevated in group III compared with group I. Furthermore, the western blot analysis revealed significant high NF-κB p65 expression, immunohistochemistry of the NF-κB and caspase-1 expression levels were significantly increased in group III compared to group I. Additionally, the histopathological inspection of the kidney in group III exhibited a substantial increase in extensive necrosis features compared with group I. In contrast, the concomitant coadministration of GA and NiO-NPs in group IV showed significant biochemical, antioxidant activities, immunohistochemical and histopathological improvements compared with group III. Gallic acid has a protective role against kidney dysfunction and renal damage in Ni-nanoparticle toxicity.

A multifunctional CaCO3 bioreactor coated with coordination polymers enhances cancer immunotherapy.

Designing effective nanomedicines to induce durable anti-tumor immunity represents a promising strategy for improving moderate immune stimulation. In this study, we engineered a multifunctional nanoreactor (named SCGFP NPs) for remodeling the tumor microenvironment (TME) to improve the therapeutic efficacy of immunotherapy. The core of SCGFP NPs consists of CaCO3 loaded with SN38, prepared by the gas diffusion method, and coated with a significant amount of gallic acid-Fe3+-PEG coordination polymer on the surface. In the acidic TME, SCGFP NPs explosively release exogenous Ca2+ and SN38. The SN38-induced intracellular Ca2+ accumulation and exogenous Ca2+ synergistically trigger immunogenic cell death (ICD) through sustained Ca2+ overload. The ablation of tumors with high-intensity photothermal therapy (PTT) by near-infrared (NIR) irradiation of GA-Fe3+ induces tumor cell necrosis, further enhancing ICD activation. Additionally, SN38 upregulates PD-L1, amplifying tumor responsiveness to immune checkpoint inhibitors (ICIs). This study indicates that SCGFP NPs, through the integration of a trimodal therapeutic strategy, hold enormous potential for various types of tumor immunotherapy through distinct mechanisms or synergistic effects.

Engineered Multifunctional Zinc-Organic Framework-Based Aggregation-Induced Emission Nanozyme for Accelerating Spinal Cord Injury Recovery.

Functional recovery following a spinal cord injury (SCI) is challenging. Traditional drug therapies focus on the suppression of immune responses; however, strategies for alleviating oxidative stress are lacking. Herein, we developed the zinc-organic framework (Zn@MOF)-based aggregation-induced emission-active nanozymes for accelerating recovery following SCI. A multifunctional Zn@MOF was modified with the aggregation-induced emission-active molecule 2-(4-azidobutyl)-6-(phenyl(4-(1,2,2-triphenylvinyl)phenyl)amino)-1H-phenalene-1,3-dione via a bioorthogonal reaction, and the resulting nanozymes were denoted as Zn@MOF-TPD. These nanozymes gradually released gallic acid and zinc ions (Zn2+) at the SCI site. The released gallic acid, a scavenger of reactive oxygen species (ROS), promoted antioxidation and alleviated inflammation, re-establishing the balance between ROS production and the antioxidant defense system. The released Zn2+ ions inhibited the activity of matrix metalloproteinase 9 (MMP-9) to facilitate the regeneration of neurons via the ROS-mediated NF-κB pathway following secondary SCI. In addition, Zn@MOF-TPD protected neurons and myelin sheaths against trauma, inhibited glial scar formation, and promoted the proliferation and differentiation of neural stem cells, thereby facilitating the repair of neurons and injured spinal cord tissue and promoting functional recovery in rats with contusive SCI. Altogether, this study suggests that Zn@MOF-TPD nanozymes possess a potential for alleviating oxidative stress-mediated pathophysiological damage and promoting motor recovery following SCI.

Evaluation of the antiparasitic and antifibrotic effects of gallic acid on experimental hepatic schistosomiasis mansoni.

Schistosomiasis afflicts approximately 120 million individuals globally. The hepatic pathology that occurs due to egg-induced granuloma and fibrosis is commonly attributed to this condition. However, there is currently no efficacious treatment available for either of these conditions.Our study aimed to investigate the potential antifibrotic and antiparasitic properties of different doses of gallic acid (GA) in experimental schistosomiasis mansoni. In addition, we investigated the outcomes of co-administering it with the standard anti-schistosomiasis treatment, praziquantel (PZQ).In experiment I, Schistosoma mansoni-infected mice were administered GA at doses of 10, 20, or 40 mg/kg. Their effectiveness was evaluated through parasitological (worm and egg loads, granuloma number and diameter), pathological (fibrosis percentage and H-score of hepatic stellate cells (HSCs)), and functional (liver enzymes) tests. In experiment II, we investigated the optimal dosage that yielded the best outcomes. This dosage was administered in conjunction with PZQ and was evaluated regarding the parasitological, pathological, functional, and immunological (fibrosis-regulating cytokines) activities.Our findings indicate that the administration of 40 mg/kg GA exhibited the highest level of effectiveness in experiment I. In experiment II, it exhibited lower antiparasitic efficacy in comparison to PZQ. However, it surpassed PZQ in other tests. It showed enhanced outcomes when combined with PZQ.In conclusion, our findings reveal that GA only slightly increased the antischistosomal activity of PZQ. However, it was linked to decreased fibrosis, particularly when administrated with PZQ. Our pilot study identifies GA as a natural antifibrotic agent, which could be administered with PZQ to mitigate the development of fibrosis.

The anticancer/cytotoxic effect of a novel gallic acid derivative in non-small cell lung carcinoma A549 cells and peripheral blood mononuclear cells from healthy individuals and lung cancer patients.

Gallic acid (GA) is a naturally occurring polyphenol with a strong antioxidant capacity. GA stimulates the apoptosis of cancer cells, thereby suppressing cancer cell invasion. However, the low oral permeability of GA limits its therapeutic use. In order to enhance the antioxidant capacity and oral permeability of GA, a series of compounds analogous to GA were synthesized: 4-methoxybenzenesulfonamide (MBS), 3,4-dimethoxybenzenesulfonamide (DMBS) and 3,4,5-trimethoxybenzenesulfonamide (TMBS). In the new compounds, hydroxyl groups were replaced with various numbers of methoxy groups (stronger electron-donating groups), to increase hydrophobicity and oral permeability compared to GA. In addition, the carboxylic group was replaced with a sulfonyl group (a stronger electron-withdrawing group), to increase the molecular polarity and antioxidative activities of the compounds. The cell counting kit-8 (CCK-8) assay was used to detect the effect of GA, MBS, DMBS, and TMBS on cell proliferation and apoptosis in peripheral blood mononuclear cells (PBMCs) from healthy individuals and non-small cell lung carcinoma A549 cells. Additionally, the comet assay was used to assess the genotoxicity of these compounds in PBMCs from healthy individuals, lung cancer patients, and A549 cells. Compared to untreated cells, TMBS reduced DNA damage more effectively than GA in PBMCs from lung cancer patients and healthy donors. Furthermore, in comparison to GA, TMBS was more cytotoxic in A549 cells. Moreover, TMBS was not cytotoxic in healthy PBMCs, suggesting that TMBS demonstrates therapeutic potential in cancer.

Skin irritation assessment and potential mechanism of Capparis spinosa L. fruits.

ETHNOPHARMACOLOGICAL RELEVANCE: In China, Capparis spinosa L. fruits (CSF) are often used topically in Uyghur folk medicine in treating rheumatic diseases with remarkable efficacy. However, it has noticed severe skin irritation after a short time application with high dose of CSF, which limited long-term clinical use. To date, there is almost no research related to skin irritation of CSF. AIM OF THE STUDY: This study was intended to perform the first systematic assessment of morphological and histological changes in skin after stimulation with CSF. Furthermore, potential irritant components in CSF and related mechanisms were explored by in vitro transdermal techniques, network pharmacology, molecular docking, and experimental validation. MATERIALS AND METHODS: Skin changes after single and multiple stimulations with CSF were observed and subjected to skin irritation response scoring, irritation strength assessment, and histopathological analysis. In addition, in vitro transdermal technology, liquid chromatography-mass spectrometry (LC-MS) method, network pharmacology, molecular docking, and experimental validation were used to further exploit underlying skin irritant components and possible mechanisms of action. RESULTS: CSF induced significant morphological (erythema and edema) and histological (epidermal thickening and inflammatory infiltration) changes in skin of mice, which were similar to the clinical presentation of irritation contact dermatitis (ICD). The ethyl acetate fraction of CSF (CFEAF) was the main source of CSF-induced skin irritation. Kaempferol, flazin, and gallic acid were potential major irritant compounds. Moreover, CFEAF, kaempferol, flazin, and gallic acid could increase the levels of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and interleukin-17A (IL-17A) to promote skin inflammation. The potential mechanism of CSF-induced skin irritation may be activation of the nuclear factor kappa-B (NF-κB) signaling pathway, including phosphorylation of NF-κB p65 (p65) and nuclear factor-kappa B inhibitor alpha (IκBα). CONCLUSION: Kaempferol, flazin, and gallic acid are potential skin irritant components from CSF. Altogether, they induce skin irritation responses through promoting the release of the inflammatory factors TNF-α and ICAM-1, as well as activating the NF-κB signaling pathway. In addition, IL-17A may be an important pro-inflammatory factor in skin irritation.

Gallic acid alleviates lipopolysaccharide-induced renal injury in rats by inhibiting cell pro-death and inflammatory response and its mechanism.

The mechanism of gallic acid in improving lipopolysaccharide-induced renal injury in rats was investigated by studying the pro-death and inflammatory response of cells. SPF rats were randomly divided into 4 groups with n=10 in each group. Blank control group: normal saline injection; The model group was injected with LPS induced model (LPS group); Low dose gallic acid group (LPS+L-GA group); Middle dose gallic acid group (LPS+M-GA group). The expression of serum inflammatory factors IL-1, IL-1ß, IL-18, and MCP-1 were detected by Elisa. Western blot assay was used to detect the expression of inflammation-related proteins. The contents of BUN, Scr, SUA, Serum cystatinALB, and ACR were determined by the biochemical analyzer. The pathological tissue sections were used to observe the kidney injury in each group. The renal expressions of NLRP3, Caspase-1, GSDMD, and IL-1ß were detected by immunohistochemistry. The activation of the AMPK/SIRT1 signaling pathway was detected by Western blot assay. The LPS-induced mouse kidney injury model was established successfully. Compared with the model group, different doses of gallic acid can improve the expression of renal biochemical indexes (P<0.05); At the same time, gallic acid can activate AMPK/SIRT1 and reduce kidney injury in mice (P<0.05); Compared with the model group, the expression of pyroptosis gene, the expression of genes related to inflammatory factors and the expression of inflammatory factors were decreased in the gallic acid injection group (P<0.05). By activating the AMPK/SIRT1 signaling pathway, gallic acid can inhibit the scorch death and validation effect in mice, thereby protecting the kidneys of mice.

Gallic acid ameliorates behavioral dysfunction, oxidative damage, and neuronal loss in the prefrontal cortex and hippocampus in stressed rats.

Gallic acid (GA) is known to be a natural phenolic compound with antioxidant and neuroprotective effects. This study aims to investigate the impact of GA against restraint stress-induced oxidative damage, anxiety-like behavior, neuronal loss, and spatial learning and memory impairment in male Wistar rats. The animals were divided into four groups (n = 8) and subjected to restraint stress for 4 h per day for 14 consecutive days or left undisturbed (control without inducing stress). In the treatment group, the animals were treated with 2 mL normal saline plus 100 mg/kg GA per day for 14 consecutive days (STR + GA group). The animals received the drug or normal saline by gavage 2 h before inducing restraint stress. ELISA assay measured oxidative stress factors. Elevated-plus maze and Morris water maze tests assessed anxiety-like behavior and spatial learning and memory, respectively. Also, neuronal density was determined using Nissl staining. Restraint stress significantly increased MDA and reduced the activities of GPX and SOD in the stressed rats, which were reserved by treatment with 100 mg/kg GA. Restraint stress markedly enhanced the anxiety-like behavior and spatial learning and memory impairment that were reserved by GA. In addition, treatment with GA reduced the neuronal loss in the stressed rats in the hippocampus and prefrontal cortex (PFC) regions. Taken together, our findings suggest that GA has the potential to be used as a good candidate to attenuate neurobehavioral disorders as well as neuronal loss in the hippocampus and PFC induced by restraint stress via reducing oxidative damage.

How gallic acid regulates molecular signaling: role in cancer drug resistance.

Cancer is one of the deadliest and most heterogeneous diseases. Cancers often develop drug resistance, which can lead to treatment failure or recurrence. Accordingly, anticancer compounds are essential for chemotherapy-resistant cancer cells. Phenolic compounds are of interest in the development of cancer drugs due to their medicinal properties and ability to target different molecular pathways. Gallic acid (GA), as one of the main components of phenol, which is abundantly present in plant compounds such as walnut, sumac, grapes, tea leaves, oak bark, and other plant compounds, has antitumor properties. GA can prevent cancer progression, cell invasion, and metastasis by targeting molecular pathways and is an effective complement to chemotherapy drugs and combating multidrug resistance (MDR). In this review, we discuss various mechanisms related to cancer, the therapeutic potential of GA, the antitumor properties of GA in various cancers, and the targeted delivery of GA with nanocarriers.

Gallic acid improves the metformin effects on diabetic kidney disease in mice.

OBJECTIVES: Metformin is an antidiabetic agent that is used as the first-line treatment of type 2 diabetes mellitus. Gallic acid is a type of phenolic acid that has been shown to be a potential drug candidate to treat diabetic kidney disease, an important complication of diabetes. We aimed to test whether a combination of gallic acid and metformin can exert synergetic effect on diabetic kidney disease in diabetic mice model. METHODS: Streptozotocin (65 mg/kg) intraperitoneal injection was used to induce diabetic kidney disease in mice. The diabetic mice were treated with saline (Vehicle), gallic acid (GA) (30 mg/kg), metformin (MET) (200 mg/kg), or the combination of gallic acid (30 mg/kg) and metformin (200 mg/kg) (GA + MET). RESULTS: Our results demonstrated that compared to the untreated diabetic mice, all three strategies (GA, MET, and GA + MET) exhibited various effects on improving renal morphology and functions, reducing oxidative stress in kidney tissues, and restoring AMP-activated protein kinase (AMPK)/silent mating type information regulation 2 homolog 1 (SIRT1) signaling in kidney tissues of diabetic mice. Notably, the combination strategy (GA + MET) provided the most potent renal protection effects than any single strategies (GA or MET). CONCLUSION: Our results support the hypothesis that gallic acid might serve as a potential supplement to metformin to enhance the therapeutical effect of metformin.

Gallic acid as a Sestrin (SESN2) activator and potential obesity therapeutic agent: A molecular docking study.

Sestrins (SESNs) are a family of evolutionarily conserved proteins among mammals. They have several body homeostatic functions such as antioxidant, metabolic, and anti-aging, and are required to regenerate hyperoxidized forms of peroxiredoxins and reactive oxygen species. Sestrin 2 has been studied as a therapeutic agent in obesity treatment. Gallic acid (GA) is a triphenolic compound with beneficial biological activities including anti-inflammatory, antidiabetic, antihypertensive, and antioxidant effects. Recent studies demonstrated the GA's ability to reduce body weight gain and improve glycemic parameters. In this sense, the present study aims to investigate the GA activating potential of Sestrin using the molecular docking method. The 3D structure of gallic acid was retrieved from the NCBI PubChem database and the chemical structure of the Sestrin2 protein from the RCSB Protein Data Bank (5DJ4). The docking calculus was performed via UCSF Chimera and AutoDock Vinaprograms. The results showed that amino acids Arg390, Glu451, Trp444, Thr386, Arg448, Thr374, Tyr375, Asn376, Thr377, Leu389, His454, Ser450, His86, and Val455 are very important for GA stabilization, resembling the interactions that permit Leucine to activate SESN2. In this context, the obesity therapeutic property of GA can be understood from a Sestrin activating process through amino acid metabolism.

Anticonvulsant potential of Grewia tiliaefolia in pentylenetetrazole induced epilepsy: insights from in vivo and in silico studies.

Epilepsy, a chronic neurological condition, impacts millions of individuals globally and remains a significant contributor to both illness and mortality. Available antiepileptic drugs have serious side effects which warrants to explore different medicinal plants used for the management of epilepsy reported in Traditional Indian Medicinal System (TIMS). Therefore, we explored the antiepileptic potential of the Grewia tiliaefolia (Tiliaeceae) which is known for its neuroprotective properties. Aerial parts of G. tiliaefolia were subjected to extraction with increasing order of polarity viz. hexane, chloroform and methanol. Antioxidant potential of hexane, chloroform and methanol extracts of G. tiliaefolia was evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) assay, total antioxidant capacity (TAC) assay, reducing power assay (RPA) and DNA nicking assay. Additionally, quantitative antioxidant assays were also conducted to quantify total phenolic (TPC) and total flavonoid content (TFC). As revealed by in vitro assays, methanol extract was found to contain more phenolic content. Hence, the methanol extract was further explored for its anticonvulsant potential in pentylenetetrazole (PTZ) induced acute seizures in mice. The methanol extract (400 mg/kg) significantly increased the latency to occurrence of myoclonic jerks and generalized tonic clonic seizures (GTCS). Additionally, it also reduced duration and seizure severity score associated with GTCS. The Grewia tiliaefolia methanol extract was further screened by Ultra High-Performance Liquid Chromatography (UHPLC) for presence of polyphenolic compounds, among which gallic acid and kaempferol were present in higher amount and were further analysed by in silico study to predict their possible binding sites and type of interactions these compounds show with gamma amino butyric acid (GABA) receptor and glutamate α amino-3- hydroxyl-5-methyl-4-isoxazolepropionic acid (Glu-AMPA) receptor. It was revealed that gallic acid and kaempferol had shown agonistic interaction for GABA receptor and antagonistic interaction for Glu-AMPA receptor. We concluded that G. tiliaefolia showed anticonvulsant potential possibly because of gallic acid and kaempferol possibly mediated through GABA and Glu-AMPA receptor.

Gallic acid improves liver cirrhosis by reducing oxidative stress and fibrogenesis in the liver of rats induced by bile duct ligation.

Disturbance in the production and excretion of bile acid causes cholestatic liver disease. Liver cirrhosis is a disease that occurs if cholestasis continues. This study evaluated the protective effect of gallic acid (GA) on liver damage caused by biliary cirrhosis. Rats were randomly divided into 4 groups, each with 8 subjects: 1) control, 2) BDL, 3) BDL + GA 20, and 4) BDL + GA 30. The rats were anesthetized 28 days after the BDL, followed by collecting their blood and excising their liver. Their serum was used to measure liver enzymes, and the liver was used for biochemical analysis, gene expression, and histopathological analysis. Serum levels of liver enzymes, total bilirubin, liver Malondialdehyde level (MDA), expression of inflammatory cytokines and caspase-3, necrosis of hepatocytes, bile duct proliferation, lymphocytic infiltration, and liver fibrosis showed an increase in the BDL group compared to the control group (p < 0.05). In addition, BDL decreased the activity of liver antioxidant enzymes and glutathione (GSH) levels compared to the control group (p < 0.05). The groups receiving GA indicated a decrease in liver enzymes, total bilirubin, MDA, the expression of inflammatory cytokines and caspase-3, and a reduction in liver tissue damage compared to the BDL group (p < 0.05). The level of GSH in the BDL + GA 20 group showed a significant increase compared to the BDL group (p < 0.05). Moreover, it was found that GA, with its anti-fibrotic and anti-inflammatory properties, reduces liver damage caused by biliary cirrhosis.

Gallic acid treatment protects intestinal tissue against ischaemia-reperfusion.

BACKGROUND: This study aimed to investigate the protective effects of gallic acid (GA) in the rat intestine against ischaemia-reperfusion (IR) injury. MATERIALS AND METHODS: Thirty male Wistar albino rats with a mean weight of 200-250 g were used. Animals were categorized into the sham, IR, and IR+GA groups. Ischaemia of the intestine was induced for 3 h by occluding the superior mesenteric artery (SMA) and then left for 3 h of reperfusion. In the IR+GA group, after ischaemia induction, 50 mg/kg GA was orally administered to the animals. Blood samples were collected for biochemical assays. Intestinal tissues were excised for histopathologic and immunohistochemical processing. RESULTS: Malondialdehyde (MDA) levels were increased, and catalase (CAT) and glutathione (GSH) levels were decreased in the IR group compared to the sham group. After GA treatment, MDA levels decreased and CAT and GSH levels increased in the GA-treated group compared to the IR group. In the sham group, normal intestinal histology was observed. In the IR group, the villi structures were completely degenerated. In the IR+GA group, histology was improved after GA treatment. In the sham group, the caspase-3 reaction was generally negative in the epithelium and glands. In the IR group, the caspase-3 reaction increased in apoptotic bodies and inflammatory cells. The caspase-3 reaction was negative in goblet cells and the epithelium. A moderate caspase-3 reaction was observed in the IR+GA group. The beclin-1 reaction was negative in epithelial cells and goblet cells in villi in the sham group. In the IR group, the beclin-1 reaction was positive in the degenerated villi. An intense beclin-1 reaction was also observed in some inflammatory cells. After GA treatment, the beclin-1 reaction was positive in a few cells. In general, moderate beclin-1 positivity was observed. CONCLUSIONS: Gallic acid, with its antioxidative effect, inhibited the apoptotic pathway (caspase-3) through beclin-1 regulation.

Effects of Gallic Acid on Memory Deficits and Electrophysiological Impairments Induced by Cerebral Ischemia/Reperfusion in Rats Following Exposure to Ambient Dust Storm.

We aimed to investigate the probable protective effects of gallic acid (GA) on cognitive deficits, hippocampal long term potentiation (LTP) impairments, and molecular changes induced by cerebral ischemia/reperfusion (I/R) in rats following exposure to ambient dust storm. After pretreatment with GA (100 mg/kg), or vehicle (Veh) (normal saline, 2 ml/kg) for ten days, and 60 minutes' exposure to dust storm including PM (PM, 2000-8000 g/m3) every day, 4-vessel occlusion (4VO) type of I/R was induced. Three days after I/R induction, we evaluated behavioral, electrophysiological, histopathological, molecular and brain tissue inflammatory cytokine changes. Our findings indicated that pretreatment with GA significantly reduced cognitive impairments caused by I/R (P < 0.05) and hippocampal LTP impairments caused by I/R after PM exposure (P < 0.001). Additionally, after exposure to PM, I/R significantly elevated the tumor necrosis factor α content (P < 0.01) and miR-124 level (P < 0.001) while pre-treatment with GA reduced the level of miR-124 (P < 0.001). Histopathological results also revealed that I/R and PM caused cell death in the hippocampus CA1 area (P < 0.001) and that GA decreased the rate of cell death (P < 0.001). Our findings show that GA can prevent brain inflammation, and thus cognitive and LTP deficits caused by I/R, PM exposure, or both.

Gallic acid and/or cerium oxide nanoparticles synthesized by gamma-irradiation protect cisplatin-induced nephrotoxicity via modulating oxidative stress, inflammation and apoptosis.

Cisplatin is one of the most significant anticancer. However, its use is associated with numerous toxicities especially nephrotoxicity. The main aim of this work was to examine the protective effect of Gallic acid (GA) and/or cerium oxide nanoparticles (CONPs) synthesized by gamma-irradiation on cisplatin-induced nephrotoxicity in rats. To do that, 48 adult male albino rats were separated into eight groups and received GA (100 mg/kg orally) and/or CONPs (15 mg/kg i. p.) for 10 days before injection with a single dose of cisplatin (7.5 mg/kg i. p.). The findings showed that cisplatin treatment impaired kidney functioning as shown by elevated serum levels of urea and creatinine. Additionally, the oxidative stress indicators (MDA and NO), levels of NF-kB, pro-inflammatory cytokines (IL1-and TNF-) and pro-apoptotic proteins (BAX and caspase-3) were raised after cisplatin injection, while levels of intrinsic anti-oxidants (CAT, SOD, and GSH) and anti-apoptotic protein (Bcl-2) were reduced. Moreover, renal toxicity was confirmed by alteration in normal histological architecture of the kidneys. On the other hand, pretreatment with CONPs and/or GA ameliorated cisplatin-induced nephrotoxicity as evidenced by improvement of renal function parameters and levels of oxidative stress, inflammatory and apoptotic markers in renal tissue along with the renal histopathological changes. This study clarifies how GA and CONPs protect against cisplatin-induced nephrotoxicity and demonstrates any potential synergism between them. Therefore, they can be considered as promising nephroprotective agents during chemotherapy.

Effects of gallic acid on gingival wounds.

OBJECTIVE: Our aim in this study was to investigate the effect of Gallic acid (GA) on gingival tissue injury. MATERIALS AND METHODS: Twenty rats were categorized into two groups. In the burn group, an excisional wound area was created by removing a 4 mm diameter flap from the left molar region in the mucoperiosteal region of the gingiva. In the Burn+gallic acid group, 1.2 mg/ml GA was administered as irrigation for 1 week. Animals were sacrificed under anesthesia at the end of experiment. Malondialdehyde (MDA), myeloperoxidase (MPO) and glutathione (GSH) levels were measured. Hematoxylin Eosin, fibroblast growth factor (FGF) and epidermal growth factor (EGF) immunostaining was applied to tissues. RESULTS: MDA and MPO levels increased, and GSH, epithelization, FGF and EGF expression levels were decreased. Gallic acid treatment improved these scores. Degenerated gingival epithelium, disintegrity in epithelial and connective tissue fibers, edema and inflammatory cells were observed in the burn group. Gallic acid treatment after burn improved the pathologies. After burn injury, FGF and EGF activity was increased in Gallic acid-treated groups. CONCLUSIONS: We suggest that GA has the potential for better healing outcomes in oral wounds. GA seems to have promising therapeutic efficacy in enhancing oral wound healing.

Co-drug development of gallic acid and metformin targeting the pro-inflammatory cytokines for the treatment of breast cancer.

It is well-documented that pro-inflammatory cytokines and inflammation play a significant role in the expansion of cancer disease. Gallic acid (GA), a natural compound, and metformin (Met), a synthetic drug exhibit potent anticancer potential via the distinct molecular mechanism. However, whether both these compounds can act synergistically to preclude and treat cancer is still unknown. This prompted us to scrutinize, the synergism between GA and Met, and that of a new co-drug synthesizing of GA and Met (GA-Met) and investigated the chemo-protective effect against breast cancer with possible intervention of cytokines. In vivo studies were based on chemical carcinogenesis, challenging breast tissue by dimethylbenz[α]anthracene (DMBA). Tumour incidence, tumour burden, pro-inflammatory cytokines in serum, breast, hepatic tissue, macroscopically and histological analysis of mammary tumours were carried out and estimated. GA, Met and GA-Met co-drug exhibited the inhibition of cell proliferation; higher reduction of cell proliferation was observed by GA-Met. The inhibitory effect of GA-Met was linked to cell cycle arrest at G0/G1 phase, along with induction of apoptosis and accumulation in the sub-G1 phase. GA-Met significantly inhibited the cytokines production along with protection against DMBA-induced hyperplasia. Taken altogether, the current result suggests that GA-Met co-drug endows a safe and protective effect against cancer metastasis and can possibly use for the treatment of human breast cancer.

Gallic Acid Improves Comorbid Chronic Pain and Depression Behaviors by Inhibiting P2X7 Receptor-Mediated Ferroptosis in the Spinal Cord of Rats.

Ferroptosis is an inflammatory programmed cell death process that is dependent on iron deposition and lipid peroxidation. The P2X7 receptor not only is involved in the pain process but also is closely related to the onset of depression. Gallic acid (3,4,5-trihydroxybenzoic acid), which is naturally found in a variety of plants, exhibits anti-inflammatory, antioxidant, and analgesic effects. This study established a rat model with the comorbidity of chronic constrictive injury (CCI) plus chronic unpredictable mild stress (CUMS) to explore the role and mechanism of gallic acid in the treatment of pain and depression comorbidity. Our experimental results showed that pain and depression-like behaviors were more obvious in the chronic constriction injury (CCI) plus chronic unpredictable mild stimulation (CUMS) group than they were in the sham operation group, and the P2X7-reactive oxygen species (ROS) signaling pathway was activated. The tissue iron concentration was increased, and mitochondrial damage was observed in the CCI plus CUMS group. These results were alleviated with gallic acid treatment. Therefore, we speculate that gallic acid inhibits the ferroptosis of the spinal microglia by regulating the P2X7-ROS signaling pathway and relieves the behavioral changes in rats with comorbid pain and depression.