Novel silicene-mesoporous silica nanoparticles conjugated gemcitabine induced cellular apoptosis via upregulating NF-κB p65 nuclear translocation suppresses pancreatic cancer growthin vitroandin vivo.

Pancreatic cancer's high fatality rates stem from its resistance to systemic drug delivery and aggressive metastasis, limiting the efficacy of conventional treatments. In this study, two-dimensional ultrathin silicene nanosheets were initially synthesized and near-infrared-responsive two-dimensional silicene-mesoporous silica nanoparticles (SMSNs) were successfully constructed to load the clinically-approved conventional pancreatic cancer chemotherapeutic drug gemcitabine. Experiments on nanoparticle characterization show that they have excellent photothermal conversion ability and stability. Then silicene-mesoporous silica nanoparticles loaded with gemcitabine nanoparticles (SMSN@G NPs) were employed in localized photothermal therapy to control pancreatic tumor growth and achieve therapeutic effects. Our research confirmed the functionality of SMSN@G NPs through immunoblotting and apoptotic assays, demonstrating its capacity to enhance the nuclear translocation of the NF-κB p65, further affect the protein levels of apoptosis-related genes, induce the apoptosis of tumor cells, and ultimately inhibit the growth of the tumor. Additionally, the study assessed the inhibitory role of SMSN@G NPs on pancreatic neoplasm growthin vivo, revealing its excellent biocompatibility. SMSN@G NPs have a nice application prospect for anti-pancreatic tumors.

The protective effect of apolipoprotein H in paediatric sepsis.

BACKGROUND: Sepsis is a severe condition characterized by acute organ dysfunction resulting from an imbalanced host immune response to infections. Apolipoprotein H (APOH) is a critical plasma protein that plays a crucial role in regulating various biological processes. However, the precise role of APOH in the immunopathology of paediatric sepsis remains unclear. METHODS: In this study, we evaluated the concentration of APOH in paediatric patients with sepsis and healthy individuals. In an experimental sepsis model of caecal ligation and puncture (CLP), the impact of APOH on survival, organ injury, and inflammation was measured. Furthermore, the anti-inflammatory effects of APOH were investigated across diverse immune cell types, encompassing peripheral blood mononuclear cells (PBMCs), peritoneal macrophages (PMs), bone marrow-derived macrophages (BMDMs), and RAW 264.7 macrophages. RESULTS: In the pilot cohort, the relative abundance of APOH was found to be decreased in patients with sepsis (2.94 ± 0.61) compared to healthy controls (1.13 ± 0.84) (p < 0.001), non-survivors had lower levels of APOH (0.50 ± 0.37) compared to survivors (1.45 ± 0.83) (p < 0.05). In the validation cohort, the serum concentration of APOH was significantly decreased in patients with sepsis (202.0 ± 22.5 ng/ml) compared to healthy controls (409.5 ± 182.9 ng/ml) (p < 0.0001). The application of recombinant APOH protein as a therapeutic intervention significantly lowered the mortality rate, mitigated organ injury, and suppressed inflammation in mice with severe sepsis. In contrast, neutralizing APOH with an anti-APOH monoclonal antibody increased the mortality rate, exacerbated organ injury, and intensified inflammation in mice with non-severe sepsis. Intriguingly, APOH exhibited minimal effects on the bacterial burden, neutrophil, and macrophage counts in the sepsis mouse model, along with negligible effects on bacterial phagocytosis and killing during Pseudomonas aeruginosa infection in PMs, RAW 264.7 cells, and PBMCs. Mechanistic investigations in PMs and RAW 264.7 cells revealed that APOH inhibited M1 polarization in macrophages by suppressing toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signalling pathway. CONCLUSION: This proof-of-concept study demonstrated that APOH has a protective role in the host defense response to sepsis, highlighting the potential therapeutic value of APOH in sepsis treatment.

Serine deficiency exacerbates psoriatic skin inflammation by regulating S-adenosyl methionine-dependent DNA methylation and NF-κB signalling activation in keratinocytes.

BACKGROUND: Serine metabolism is crucial for tumour oncogenesis and immune responses. S-adenosyl methionine (SAM), a methyl donor, is typically derived from serine-driven one-carbon metabolism. However, the involvement of serine metabolism in psoriatic skin inflammation remains unclear. OBJECTIVES: To investigate the association between serine metabolism and psoriatic skin inflammation. METHODS: Clinical samples were collected from patients with psoriasis and the expression of serine biosynthesis enzymes was evaluated. The HaCaT human keratinocyte cell line was transfected with small interfering RNA (siRNA) of key enzyme or treated with inhibitors. RNA sequencing and DNA methylation assays were performed to elucidate the mechanisms underlying serine metabolism-regulated psoriatic keratinocyte inflammation. An imiquimod (IMQ)-induced psoriasis mouse model was established to determine the effect of the SAM administration on psoriatic skin inflammation. RESULTS: The expression of serine synthesis pathway enzymes, including the first rate-limiting enzyme in serine biosynthesis, phosphoglycerate dehydrogenase (PHGDH), was downregulated in the epidermal lesions of patients with psoriasis compared with that in healthy controls. Suppressing PHGDH in keratinocytes promoted the production of proinflammatory cytokines and enrichment of psoriatic-related signalling pathways, including the tumour necrosis factor-alpha (TNF-α) signalling pathway, interleukin (IL)-17 signalling pathway and NF-κB signalling pathway. In particular, PHGDH inhibition markedly promoted the secretion of IL-6 in keratinocytes with or without IL-17A, IL-22, IL-1α, oncostatin M and TNF-α (mix) stimulation. Mechanistically, PHGDH inhibition upregulated the expression of IL-6 by inhibiting SAM-dependent DNA methylation at the promoter and increasing the binding of myocyte enhancer factor 2A. Furthermore, PHGDH inhibition increased the secretion of IL-6 by increasing the activation of NF-κB via SAM inhibition. SAM treatment effectively alleviated IMQ-induced psoriasis-like skin inflammation in mice. CONCLUSIONS: Our study revealed the crucial role of PHGDH in antagonising psoriatic skin inflammation and indicated that targeting serine metabolism may represent a novel therapeutic strategy for treating psoriasis.

Antiviral effect of palmatine against infectious bronchitis virus through regulation of NF-κB/IRF7/JAK-STAT signalling pathway and apoptosis.

1. Infectious bronchitis virus (IBV), a gamma-coronavirus, can infect chickens of all ages and leads to an acute contact respiratory infection. This study evaluated the anti-viral activity of palmatine, a natural non-flavonoid alkaloid, against IBV in chicken embryo kidney (CEK) cells.2. The half toxic concentration (CC50) of palmatine was 672.92 µM, the half inhibitory concentration (IC50) of palmatine against IBV was 7.76 µM and the selection index (SI) was 86.74.3. Mode of action assay showed that palmatine was able to directly inactivate IBV and inhibited the adsorption, penetration and intracellular replication of IBV.4. Palmatine significantly upregulated TRAF6, TAB1 and IKK-ß compared with the IBV-infected group, leading to the increased expressions of pro-inflammatory cytokines IL-1ß and TNF-α in the downstream NF-κB signalling pathway.5. Palmatine significantly up-regulated the levels of MDA5, MAVS, IRF7, IFN-α and IFN-ß in the IRF7 pathway, inducing type I interferon production. It up-regulated the expression of 2'5'-oligoadenylate synthase (OAS) in the JAK-STAT pathway.6. IBV infection induced cell apoptosis and palmatine-treatment delayed the process of apoptosis by regulation of the expression of apoptosis-related genes (BAX, BCL-2, CASPASE-3 and CASPASE-8).7. Palmatine could exert anti-IBV activity through regulation of NF-κB/IRF7/JAK-STAT signalling pathways and apoptosis, providing a theoretical basis for the utilisation of palmatine to treat IBV infection.

Decreased TMIGD1 aggravates colitis and intestinal barrier dysfunction via the BANF1-NF-κB pathway in Crohn's disease.

BACKGROUND: Disrupted intestinal epithelial barrier is one of the major causes of Crohn's disease (CD). Novel molecular targets for intestinal epithelial barrier are essential to treatment of CD. Transmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) is an adhesion molecule that regulates cell adhesion, migration, and enterocyte differentiation. However, the function and mechanism of TMIGD1 in CD and intestinal epithelial barrier has rarely been studied. Furthermore, the association between TMIGD1 and the clinical features of CD remains unclear. METHODS: Transcriptome analysis on colonic mucosa from CD patients and healthy individuals were performed to identify dysregulated genes. Multi-omics integration of the 1000IBD cohort including genomics, transcriptomics of intestinal biopsies, and serum proteomics identified the association between genes and characteristics of CD. Inflammation was assessed by cytokine production in cell lines, organoids and intestinal-specific Tmigd1 knockout (Tmigd1INT-KO) mice. Epithelial barrier integrity was evaluated by trans-epithelium electrical resistance (TEER), paracellular permeability, and apical junction complex (AJC) expression. Co-immunoprecipitation, GST pull-down assays, mass spectrometry, proteomics, and transcriptome analysis were used to explore downstream mechanisms. RESULTS: Multi-omics integration suggested that TMIGD1 was negatively associated with inflammatory characteristics of CD. TMIGD1 was downregulated in inflamed intestinal mucosa of patients with CD and mice colitis models. Tmigd1INT-KO mice were more susceptible to chemically induced colitis. In epithelial cell lines and colonic organoids, TMIGD1 knockdown caused impaired intestinal barrier integrity evidenced by increased paracellular permeability and reduced TEER and AJC expression. TMIGD1 knockdown in intestinal epithelial cells also induced pro-inflammatory cytokine production. Mechanistically, TMIGD1 directly interacted with cytoplasmic BAF nuclear assembly factor 1 (BANF1) to inhibit NF-κB activation. Exogenous expression of TMIGD1 and BANF1 restored intestinal barrier function and inhibited inflammation in vitro and in vivo. TMIGD1 expression predicted response to anti-TNF treatment in patients with CD. CONCLUSIONS: Our study demonstrated that TMIGD1 maintained intestinal barrier integrity and inactivated inflammation, and was therefore a potential therapeutic target for CD.

Dl-3-n-Butylphthalide Protects against Memory Deficits in Vascular Dementia Rats by Attenuating Pyroptosis via TLR-4/NF-κB Signaling Pathway.

INTRODUCTION: Inflammation is closely associated with the pathogenesis of vascular dementia (VD). Dl-3-n-butylphthalide (NBP) is a small molecule compound extracted from the seeds of Chinese celery, which have anti-inflammatory properties in animal models of acute ischemia and patients with stroke. In this experiment, we studied the protective effects of NBP in a rat model of VD induced by permanent bilateral occlusion of the common carotid arteries and investigated the role of the TLR-4/NF-κB inflammatory signaling pathway in the pathology of VD. METHODS: The Morris water maze test was used to evaluate cognitive deficits in the VD rats. Western blot, immunohistochemistry, and PCR analyses were used to analyze the molecular basis of the inflammatory response. RESULTS: NBP significantly improved the learning and memory ability of VD rats. With regard to the protective mechanism, the results showed that NBP significantly downregulated the relative expression of Cleaved Cas-1/Cas-1 and Cleaved GSDMD/GSDMD. Moreover, NBP decreased the levels of the TLR-4 and NF-κB (P65) protein and phosphorylation of P65 in the hippocampus of VD rats via the TLR-4/NF-κB signaling pathway. CONCLUSION: These findings demonstrate that NBP protects against memory deficits in permanent bilateral common carotid artery occlusion-induced VD rats by attenuating pyroptosis via the TLR-4/NF-κB signaling pathway.

Multifaceted role of NF-κB in hepatocellular carcinoma therapy: Molecular landscape, therapeutic compounds and nanomaterial approaches.

The predominant kind of liver cancer is hepatocellular carcinoma (HCC) that its treatment have been troublesome difficulties for physicians due to aggressive behavior of tumor cells in proliferation and metastasis. Moreover, stemness of HCC cells can result in tumor recurrence and angiogenesis occurs. Another problem is development of resistance to chemotherapy and radiotherapy in HCC cells. Genomic mutations participate in malignant behavior of HCC and nuclear factor-kappaB (NF-κB) has been one of the oncogenic factors in different human cancers that after nuclear translocation, it binds to promoter of genes in regulating their expression. Overexpression of NF-κB has been well-documented in increasing proliferation and invasion of tumor cells and notably, when its expression enhances, it induces chemoresistance and radio-resistance. Highlighting function of NF-κB in HCC can shed some light on the pathways regulating progression of tumor cells. The first aspect is proliferation acceleration and apoptosis inhibition in HCC cells mediated by enhancement in expression level of NF-κB. Moreover, NF-κB is able to enhance invasion of HCC cells via upregulation of MMPs and EMT, and it triggers angiogenesis as another step for increasing spread of tumor cells in tissues and organs. When NF-κB expression enhances, it stimulates chemoresistance and radio-resistance in HCC cells and by increasing stemness and population of cancer-stem cells, it can provide the way for recurrence of tumor. Overexpression of NF-κB mediates therapy resistance in HCC cells and it can be regulated by non-coding RNAs in HCC. Moreover, inhibition of NF-κB by anti-cancer and epigenetic drugs suppresses HCC tumorigenesis. More importantly, nanoparticles are considered for suppressing NF-κB axis in cancer and their prospectives and results can also be utilized for treatment of HCC. Nanomaterials are promising factors in treatment of HCC and by delivery of genes and drugs, they suppress HCC progression. Furthermore, nanomaterials provide phototherapy in HCC ablation.

Evening primrose oil attenuates oxidative stress, inflammation, fibrosis, apoptosis, and ultrastructural alterations induced by metanil yellow in the liver of rat: a histological, immunohistochemical, and biochemical study.

The food color metanil yellow (Myl) is hazardous to several body systems. Evening primrose oil (EPO) was reported to have anti-inflammatory and anti-oxidant properties. The present work investigated the impact of Myl on the hepatic structure and function of rats and evaluated the protective effect of EPO. Forty adult male rats were divided into four groups: control, EPO (5 g/kg/day), Myl (200 mg/kg/day), and EPO- Myl group. Myl significantly increased liver enzymes, advanced glycation end products (AGE), oxidative stress parameters, pro-inflammatory cytokines, nuclear factor kappa B (NF-κB), and inducible nitric oxide synthase (iNOS). Blood vessels in the liver were dilated and congested, with cellular infiltration around them and associated with fibrosis. The hepatocytes were vacuolated and had dark nuclei. The immunohistochemical expression of iNOS, glial fibrillary acidic protein (GFAP), and Bax was significantly elevated. Ultrastructurally, the hepatocytes showed lipid droplets, irregular condensed nuclei with widened perinuclear space, dilated rER, mitochondria with destructed cristae, and multiple vacuoles. Dilated congested blood sinusoids and collagen fiber bundles were seen between hepatocytes. Interestingly, these alterations were less pronounced in rats co-administrated with EPO and Myl. In conclusion, EPO can protect liver against the toxic effects of Myl due to its anti-inflammatory and anti-oxidant activities.

Ellagic acid alleviates TNBS-induced intestinal barrier dysfunction by regulating mucin secretion and maintaining tight junction integrity in rats.

In the present study, the mechanism of ellagic acid (EA) in alleviated ulcerative colitis (UC) was investigated. Twenty-four SD rats were randomly distributed into three treatment groups: (1) control group, (2) UC group, and (3) UC + EA group. Samples were collected for analysis after a 15-day trial period. We found that EA mitigated the colitis symptoms in TNBS-treated rats. Besides, EA decreased the expression of cytokines by inhibiting NF-κB signalling. TNBS-induced reduction in tight junction proteins was restored by EA supplementation via regulating RhoA/ROCK/MLC signalling. Further, persistent colonic inflammation destroyed the activity of goblet cells by inhibiting the expression of KLF4 and TFF3. EA also enhanced the expression of MUC2, AGR2, ST6GAL1 and B3GNT6. In summary, our findings demonstrated that dietary supplementation with EA ameliorated TNBS-induced colitis by maintaining intestinal barrier function, which proves its potential role as a therapeutic agent in the attenuation of UC.

Pharmacogenetic analysis of canonical versus noncanonical pathway of NF-kB in Crohn's disease patients under anti-tumor necrosis factor-α treatment.

OBJECTIVES: This study explores the potential of gene polymorphisms in the canonical and noncanonical NF-kB signaling pathway as a prediction biomarker of anti-tumor necrosis factor (TNF)α response in Crohn's patients. MATERIALS AND METHODS: A total of 109 Greek patients with Crohn's disease (CD) were recruited, and the genotype of TLR2 rs3804099, LTA rs909253, TLR4 rs5030728, and MAP3K14/NIK rs7222094 single nucleotide polymorphisms was investigated for association with response to anti-TNFα therapy. Patient's response to therapy was based on the Crohn's Disease Activity Index, depicting the maximum response within 24 months after initiation of treatment. RESULTS: Seventy-three patients (66.7%) were classified as responders while 36 as nonresponders (33.3%). Comparing allelic frequencies between responders and nonresponders, the presence of TLR2 rs3804099 T allele was associated with nonresponse (P = 0.003), even after stratification by anti-TNFα drugs (infliximab: P = 0.032, adalimumab: P = 0.026). No other association was identified for the rest of the polymorphisms under study. Haplotype analysis further enhanced the association of rs3804099 T allele with loss of response, even though the results were NS (P = 0.073). CONCLUSION: Our results suggest that polymorphisms in the canonical NF-kB pathway genes could potentially act as a predictive biomarker of anti-TNFα response in CD.

The nonopioid cholinergic agonist GTS-21 mitigates morphine-induced aggravation of burn injury pain together with inhibition of spinal microglia activation in young rats.

BACKGROUND: Repetitive opioid use does not always alleviate basal pain, procedural pain, or both after burn injury. Mitigation of burn injury-site pain can be achieved by GTS-21 stimulation of α7-acetylcholine nicotinic receptors (α7AChRs) and reduced microglia activation in rat. We tested the hypothesis that morphine exaggerates burn injury-site pain and GTS-21 alleviates both morphine-induced aggravated burn injury pain and microglia activation. METHODS: Young rats with dorsal paw burn injury or sham-burn received intraperitoneal saline, morphine, GTS-21, or a combination twice daily for 14 days. Ipsilateral plantar pain thresholds were tested every other day before morning drugs from days 0-20. Spinal microglia activation, evidenced as pain-transducer (tumour necrosis factor-α [TNF-α], interleukin [IL]-6, IL-1ß, nuclear factor kappa B [NF-κB], Toll-like receptor 4 [TLR4]) expression, was examined using immunohistochemistry and immunoblot. In cultured microglia, morphine-induced cytokine expression was measured (quantitative polymerase chain reaction/enzyme-linked immunosorbent assay [qPCR/ELISA]). RESULTS: Morphine aggravated allodynia at day 5 in sham-burn (P=0.039, n=8-11) but significantly aggravated burn injury site allodynia by day 3 (P=0.010, n=8-11). Microgliosis paralleled nociceptive behaviour changes where burn injury with morphine had highest microgliosis compared with burn injury, morphine alone, or controls (number of cells per field [SD]: 33.8 [2.4], 18.0 [4.1], 8.2 [1.9], and 4.8 [2.0], respectively; P<0.001, n=4-5]. GTS-21 reversed the morphine-induced pain component in sham-burn and burn injury rats together with reduced microgliosis and spinal pain-transducer expression (TNF-α, IL-6, IL-1ß, NF-κB, and TLR4). Morphine-exposed microglial cells showed increased cytokine expression, which was mitigated by GTS-21. CONCLUSIONS: Morphine or burn injury alone increases pain together with microgliosis and pain-transducer expression. Morphine administration augments burn injury-site nociception sooner and aggravated spinal microgliosis and inflammatory pain-transducer expression. GTS-21 has the potential to treat morphine-induced pain in burn injury.

miR-452-3p Targets HDAC3 to Inhibit p65 Deacetylation and Activate the NF-κB Signaling Pathway in Early Brain Injury after Subarachnoid Hemorrhage.

OBJECTIVES: Subarachnoid hemorrhage (SAH) is a subtype of stroke, and early brain injury (EBI) is a contributor to its unfavorable outcome. microRNA (miRNA) is abundantly expressed in the brain and participates in brain injury. This study investigated the effect of miR-452-3p on EBI after SAH. METHODS: The murine model of SAH was established. miR-452-3p expression was detected 48 h after the model establishment. Neurobehavioral function, blood-brain barrier permeability, brain water content, neuronal apoptosis, and inflammatory factors were evaluated. The cell model of SAH was induced by oxygen hemoglobin. Apoptosis rate, lactate dehydrogenase, and reactive oxygen species were detected. The targeting relationship between miR-452-3p and histone deacetylase 3 (HDAC3) was verified. The acetylation of p65 and the binding of HDAC3 to p65 were detected. The inhibitory protein of the nuclear factor κB pathway (IκBα) was detected. Suberoylanilide hydroxamic acid was injected into the SAH mice treated with miR-452-3p inhibitor. RESULTS: SAH mice showed upregulated miR-452-3p expression; reduced the neurological score; increased blood-brain barrier permeability, brain water content, and neuronal apoptosis; elevated pro-inflammatory factors; and reduced anti-inflammatory factors. SAH increased the apoptosis rate, lactate dehydrogenase release, and reactive oxygen species levels in oxygen-hemoglobin-treated neuron cells. Inhibition of miR-452-3p reversed the above trends. miR-452-3p targeted HDAC3. SAH upregulated p65 acetylation. miR-452-3p inhibitor promoted the binding of HDAC3 to p65, decreased p65 acetylation, and upregulated IκBα. Suberoylanilide hydroxamic acid reversed the protective effect of miR-452-3p inhibitor on SAH mice and aggravated brain injury. CONCLUSIONS: miR-452-3p targeted HDAC3 to inhibit the deacetylation of p65 and activate the nuclear factor κB pathway, thus aggravating EBI after SAH.

ß-Carotene inhibits NF-κB and restrains diethylnitrosamine-induced hepatic inflammation in Wistar rats.

ß-Carotene exhibits antioxidant and hepatoprotective activities via a multitude of biochemical mechanisms. However, the action mechanism involved in antioxidant and anti-inflammatory effects of this carotene in chronic liver diseases is not fully understood. In the present investigation, we have attempted to outline a plausible mechanism of ß-carotene action against liver fibrosis in albino Wistar rats. To induce hepatic fibrosis, diethylnitrosamine (DEN) was administered in experimental rats for two weeks. DEN treated rats were divided into four groups, wherein each group comprised of five rats. ß-Carotene supplement attenuated DEN-induced elevation in LFT markers (P < 0.05); averted depletion of glycogen (24%, P < 0.05) and, increased nitrite (P < 0.05), hydroxyproline (~67%, P < 0.05) and collagen levels (~65%, P < 0.05). Confocal microscopy of tissue sections stained with picrosirius red revealed accrued collagen in DEN-administered group, which was found to be reduced by ß-carotene supplementation. Furthermore, ß-carotene decreased the expression of iNOS/NOS-2 and NF-κB, as revealed by immunohistochemistry and Western immunoblotting. Collectively, these results demonstrate that ß-carotene mitigates experimental liver fibrosis via inhibition of iNOS and NF-κB in-vivo. Thus, ß-carotene may be suggested as a possible nutraceutical to curb experimental liver fibrosis.

Fenofibrate diminishes the self-renewal and metastasis potentials of oral carcinoma stem cells through NF-κB signaling.

BACKGROUND/PURPOSE: NF-κB family of transcription factors are the major contributors to malignant tumor progression, maintenance of cancer stemness, and enhancement of chemoresistance. Fenofibrate, a lipid-lowering drug, has been considered as a candidate for repurposing in the treatment of cancer through various pathways involved in apoptosis, cell cycle, migration, and invasion, including NF-κB. Nevertheless, whether fenofibrate possesses the potential to inhibit cancer stemness remained to be examined. METHODS: Cytotoxicity of fenofibrate was estimated by MTT assay. The cells expressing stemness marker were detected by flow cytometry using ALDEFLUOR™ Kit. The secondary sphere formation assay was used to assess the self-renewal ability. Transwell system was used to evaluate migration and invasion capacities. NF-κB expression was measured by the immunoblotting system. RESULTS: In the present study, we demonstrated that fenofibrate inhibited cell viability, expression of stemness marker, self-renewal, migration, and invasion capacities in a dose-dependent manner. Of note, fenofibrate targeted cancer stem cells of oral squamous cell carcinoma (OSCC-CSCs) and had minimal effects on normal cells. Moreover, administration of fenofibrate at a lower concentration was sufficient to diminish the expression of NF-κB p50 and p65. CONCLUSION: This study demonstrated that the inhibitory effects of fenofibrate on OSCC-CSCs properties may be associated with downregulation of NF-κB. These results indicated that administration of fenofibrate may serve as an alternative strategy for OSCC therapy.

Curcumin and rheumatoid arthritis: A systematic review of literature.

BACKGROUND: Curcumin is a natural polyphenol and the main compound from the rhizome of Turmeric (Curcuma longa) and other Curcuma species. It has been widely used for different medical purposes, such as improvement of pain and inflammatory conditions in various diseases. PURPOSE: This systematic review was aimed to assess all studies regarding the efficacy of the pure form of curcumin (unformulated curcumin) on rheumatoid arthritis (RA). METHODS: The comprehensive search of the literature was done until September 2020 on the MEDLINE, Embase, Scopus and Web of Knowledge databases. Out of 2079 initial records, 51 articles (13 in vitro and 37 animal and one human) were met our inclusion criteria. RESULTS: Most studies have shown the curative effects of curcumin on clinical and inflammatory parameters of RA and reported different mechanisms; inhibition of mitogen-activated protein kinase family, extracellular signal-regulated protein kinase, activator protein-1 and nuclear factor kappa B are the main mechanisms associated with the anti-inflammatory function of curcumin in RA. The results of the only human study showed that curcumin significantly improved morning stiffness, walking time and joint swelling. CONCLUSION: In conclusion, curcumin seems to be useful, and it is recommended that more human studies be performed to approve the cellular and animal results and determine the effective and optimal doses of curcumin on RA patients.

Anti-inflammatory effect of glycyrrhizin with Equisetum arvense extract.

Periodontal disease is the most prevalent infectious disease, and inflammatory mediators play critical roles in its progression. Therefore, controlling pro-inflammatory cytokine production, especially at initial disease stages, is essential to maintaining gingival and periodontal health. Glycyrrhizin (GL) has an anti-inflammatory effect and has been added to toothpaste and mouth rinse to prevent periodontal disease. However, there is a maximum dose for the use of GL. The aim of the present study is to screen plant extracts which can effectively enhance the effects of GL. The effects of extracts from six different plants on GL-suppressed TNF-α expression in Aggregatibacter actinomycetemcomitans (A.a.)-LPS-stimulated human oral keratinocytes (RT7) were examined. Results demonstrated that Equisetum arvense (EA) extract had the strongest additive effect on the suppression of TNF-α by GL at both mRNA and protein levels. In addition, GL downregulated the production of TNF-α by suppressing NF-κB p65 phosphorylation, but not JNK or p38 phosphorylation. In contrast, EA decreased JNK phosphorylation but not NF-κB p65 or p38 phosphorylation. The combination of GL and EA effectively attenuated A.a.-LPS-induced phosphorylation of NF-κB p65 and JNK. Furthermore, an LPS-induced periodontitis rat model showed that GL with EA supplementation significantly downregulated TNF-α mRNA in the gingival tissue. These results indicate that EA can suppress A.a.-LPS-induced pro-inflammatory cytokine production by inhibiting JNK activation and can promote the anti-inflammatory effects of GL. Our findings suggest that a combination of GL and EA may improve the development of new oral hygiene products aimed at enhancing periodontal health.

Proteasome Inhibitors in Multiple Myeloma: Biological Insights on Mechanisms of Action or Resistance Informed by Functional Genomics.

During the last 20 years, proteasome inhibitors have been a cornerstone for the therapeutic management of multiple myeloma (MM). This review highlights how MM research has evolved over time in terms of our understanding of the mechanistic basis for the pronounced clinical activity of proteasome inhibitors in MM, compared with the limited clinical applications of this drug class outside the setting of plasma cell dyscrasias.

2-Arachidonoylglycerol Activity in Over Ischemia Reperfusion Damage: Can Endocannabinoids Protect Ovarian Reserve?

Objective: The present study aimed to demonstrate the possible effects of increased 2-arachidonoylglycerol (2-AG) by applying the monoacylglycerol lipase inhibitor KML-29 on rats with ovarian ischemia-reperfusion (IR) model. Methods: Forty-eight female Wistar albino rats were divided into six groups. Group 1: Sham, Group 2: Ischemia, Group 3: IR, Group 4: IR + KML-29 (2 mg/kg), Group 5: IR + KML-29 (20 mg/kg), and Group 6: IR + vehicle (dimethyl sulfoxide). Three hours of ischemia followed by 3 h of reperfusion. Two different doses of KML-29 (2 and 10 mg/kg) were administered intraperitoneally in Groups 4 and 5, 30 min before reperfusion. Ovarian IR injury and ovarian reserve were evaluated histopathological and by using nuclear factor (NF)-κB, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1, superoxide dismutase, glutathione peroxidase pre-/postoperative blood antimullerian hormone, and inhibin B. Results: In the KML-1 and KML-2 groups, this damage was significantly reduced compared to the ischemia group. NF-κB, IL-1ß, TNF-α, and TGF-ß1 immunoreactivities increased statistically significantly in the ischemia group compared to the control group (p<0.001). Immunoreactivities of these proteins were significantly decreased in the KML-1 and KML-2 groups (p<0.001). It was observed that the number of these apoptotic cells decreased significantly in the KML-1 and KML-2 groups compared to the ischemia group (p<0.001). The postoperative inhibin level showed a significant decrease in the ischemia group compared to the sham group, while a significant increase was observed in the KML-1 and KML-2 groups compared to the ischemia group. Conclusion: It was seen that anti-inflammatory, antioxidant, and antiapoptotic activity was formed, and the ovarian reserve was preserved with 2-AG in ovarian IR damage. The protective effect of endocannabinoids on the ovaries may create a promising new treatment strategy for many pathologies that will affect the ovarian reserve.

Cluster of Differentiation-44-Targeting Prussian Blue Nanoparticles Onloaded with Colchicine for Atherosclerotic Plaque Regression in a Mice Model.

Atherosclerosis management heavily relies on the suppression of the inflammatory response of macrophages. Colchicine's potent anti-inflammatory properties make it a promising candidate for secondary prevention against cardiovascular disease. However, its high toxicity and numerous adverse effects limit its clinical use. To address this, there is an urgent need for specific drug delivery systems to boost the level of accumulation of colchicine within atherosclerotic plaques. In this study, the cluster of differentiation-44 receptor was verified to be overexpressed in inflammatory macrophages within plaques both in vitro and in vivo. Subsequently, a Prussian blue-based nanomedical loading system with hyaluronic acid (HA) coating was constructed, and its effects were observed on the atherosclerosis regression. Colchicine and Cy5.5 were encapsulated within Prussian blue nanoparticles through self-assembly, followed by conjugation with hyaluronic acid to create col@PBNP@HA. The formulated col@PBNP@HA displayed a cubic shape and scattered distribution. Importantly, col@PBNP@HA demonstrated specific cellular uptake into lipopolysaccharide-stimulated macrophages. In vitro experiments showed that col@PBNP@HA more effectively inhibited expression of inflammatory factors and scavenged reactive oxygen species compared with the control group, which were treated with colchicine. Furthermore, col@PBNP@HA exhibited its specific and higher accumulation in aortic plaque analysis via fluorescence imaging of aortas. After 4 weeks, administration of col@PBNP@HA resulted in significant atherosclerosis regression in the mice model, with therapeutic effects superior to those of free colchicine. Similar to colchicine, col@PBNP@HA inhibited the secretion of inflammation factors and scavenged ROS through the regulation of the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (Myd88)/nuclear factor kappa-B (NF-κB) and peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) signaling pathway. In summary, col@PBNP@HA demonstrated specific targeting ability to inflammatory plaques and exerted beneficial effects on atherosclerosis regression through TLR4/Myd88/NF-κB and PGC-1α modulation.

MUC1-EGFR crosstalk with IL-6 by activating NF-κB and MAPK pathways to regulate the stemness and paclitaxel-resistance of lung adenocarcinoma.

BACKGROUND: The chemotherapy resistance often leads to chemotherapy failure. This study aims to explore the molecular mechanism by which MUC1 regulates paclitaxel resistance in lung adenocarcinoma (LUAD), providing scientific basis for future target selection. METHODS: The bioinformatics method was used to analyse the mRNA and protein expression characteristics of MUC1 in LUAD. RT-qPCR and ELISA were used to detect the mRNA and protein expression, flow cytometry was used to detect CD133+ cells, and cell viability was detected by CCK-8 assay. The mRNA-seq was performed to analyse the changes in expression profile, GO and KEGG analysis were used to explore the potential biological functions. RESULTS: MUC1 is highly expressed in LUAD patients and is associated with a higher tumour infiltration. In paclitaxel resistance LUAD cells (A549/TAX cells), the expression of MUC1, EGFR/p-EGFR and IL-6 were higher than that of A549 cells, the proportion of CD133+ cells was significantly increased, and the expression of cancer stem cell (CSCs) transcription factors (NANOG, OCT4 and SOX2) were significantly up-regulated. After knocking down MUC1 in A549/Tax cells, the activity of A549/Tax cells was significantly decreased. Correspondingly, the expression of EGFR, IL-6, OCT4, NANOG, and SOX2 were significantly down-regulated. The mRNA-seq showed that knocking down MUC1 affected the gene expression, DEGs mainly enriched in NF-κB and MAPK signalling pathway. CONCLUSION: MUC1 was highly expressed in A549/TAX cells, and MUC1-EGFR crosstalk with IL-6 may be due to the activation of NF-κB and MAPK pathways, which promote the enrichment of CSCs and lead to paclitaxel resistance.