Search Results (31)

Mercury exposure has been linked to male infertility. Given that mercury chloride (HgCl₂) may promote an oxido-inflammatory milieu associated with pathophysiological derangements, it is hypothesised that Thymoquinone (TQ), an antioxidant and anti-inflammatory agent, may mitigate the gradual harmful effects of mercury exposure on rat testes, epididymis, and hypothalamus, as these organs are vital to reproductive function. To test this hypothesis, 40 rats (strain: Wistar; sex: male) were randomly assigned to five cohorts of eight rats each. After a 7-day acclimation, treatments were dispensed for 28 consecutive days accordingly: Cohort I: distilled water only, as control; Cohort II: HgCl₂ only (20 µg/mL); Cohort III: TQ only (2.5 mg/kg); Cohort IV: HgCl₂ + TQ (20 µg/mL + 2.5 mg/kg); and Cohort V: HgCl₂ + TQ (20 µg/mL + 5 mg/kg). Co-treatment with TQ preserved the body and organ weight of the HgCl₂ exposed animals. However, TQ did not reduce HgCl₂-induced dysfunction in sperm function and morphology. The serum follicle-stimulating hormone (FSH), luteinising hormone (LH), and testosterone were increased significantly (p < 0.05) by TQ co-treatment, while decreasing the prolactin level. TQ administration also increased (p < 0.05) testicular enzymes, including alkaline phosphatase (ALP), lactate dehydrogenase (LDH), acid phosphatase (ACP), and glucose-6-phosphate dehydrogenase (G6PD) activities, which HgCl₂ decreased. TQ administration increased (p < 0.05) HgCl₂-induced decreases in catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione (GSH), glutathione-s-transferase (GST), and total sulfhydryl group (TSH) levels in the testes, epididymis, and hypothalamus of experimental rats. Further, TQ reduced HgCl₂-mediated increases in RONS-reactive oxygen and nitrogen species; LPO–lipid peroxidation; PC–protein carbonyl formation; and XO–xanthine oxidase activity. Furthermore, levels of inflammatory biomarkers, including tumour necrosis factor alpha (TNF-α), nitric oxide (NO), interleukin-1 beta (IL-1β), and myeloperoxidase (MPO), were decreased (p < 0.05) in the co-treated groups, with a higher dose of TQ (5.0 mg/kg) showing a more pronounced protective effect. Additionally, TQ co-administration increased Bax and decreased Bcl-2 and p53 protein levels (p < 0.05), thereby protecting the rats’ testes, epididymis, and hypothalamus from HgCl₂-induced apoptosis. Molecular docking simulation analysis revealed TQ interaction dynamics with PPAR-α and PPAR-δ to suppress NF-kB-mediated pro-inflammatory sequela as well as activate Nrf-2-mediated antioxidant defence system. These predicted biological effects of TQ resonate with the findings from the in vivo studies. Therefore, supplementation with TQ may help reduce chemical-induced toxicities, including HgCl₂‘s reproductive toxicity. Full article

Background: Inflammation plays an important role in the initiation of atrial fibrillation (AF) and the development of fibrosis following pulmonary vein isolation (PVI). We aimed to investigate whether early post-PVI levels of C-reactive protein (CRP), white blood cells, tumour necrosis factor alpha (TNF-α) and transforming growth factor beta 1 (TGF-ß1) are associated with long-term arrhythmia recurrence. Methods: This prospective observational study included 48 patients with paroxysmal AF undergoing PVI. Peripheral venous blood samples were collected on the day of hospitalisation (T0), immediately after the procedure (T1) and after 24 h (T2), seven days (T3) and one month (T4) following the procedure. Blood samples were obtained from the coronary sinus (CS) before and after PVI. CRP levels, leukocyte (LKc) and neutrophile (Neu) counts were determined. TGF-β1 and TNF-α were analysed using the enzyme-linked immunosorbent assay (ELISA). After discharge, follow-up visits were scheduled at seven days and one-, three-, six-, nine- and twelve-months post-ablation, with 24 h Holter monitoring at each visit. Results: Patients were allocated into a recurrent and a non-recurrent group. Baseline characteristics did not differ between the groups, except for the duration of AF, which was found to be a significant arrhythmia recurrence predictor. Patients in the non-recurrent group had statistically significantly higher LKc at all time points, and Neu at T2 and T3. CRP and TGF-β1 concentrations were significantly higher in the non-recurrent group, while TNF-α concentration was significantly higher in the recurrent group at the T2 time point. Significantly higher concentrations of CS TNF-α at T1 and TGF-β1 at T0 and T1 were documented in the non-recurrent group. Conclusions: The study shows that an enhanced inflammatory response early after PVI, characterised by increased CRP, WBC and TGF-β1 levels, may play a protective role against late arrhythmia recurrence. Full article

Inflammation is associated with the pathophysiology of type 2 diabetes and COVID-19. Phytochemicals have the potential to modulate inflammation, expression of SARS-CoV-2 viral entry receptors (angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2)) and glucose transport in the gut. This study assessed the impact of phytochemicals on these processes. We screened 12 phytochemicals alongside 10 pharmaceuticals and three plant extracts, selected for known or hypothesised effects on the SARS-CoV-2 receptors and COVID-19 risk, for their effects on the expression of ACE2 or TMPRSS2 in differentiated Caco-2/TC7 human intestinal epithelial cells. Genistein, apigenin, artemisinin and sulforaphane were the most promising ones, as assessed by the downregulation of TMPRSS2, and thus they were used in subsequent experiments. The cells were then co-stimulated with pro-inflammatory cytokines interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α) for ≤168 h to induce inflammation, which are known to induce multiple pathways, including the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Target gene expression (ACE2, TMPRSS2, SGLT1 (sodium-dependent glucose transporter 1) and GLUT2 (glucose transporter 2)) was measured by droplet digital PCR, while interleukin-1 (IL-6), interleukin-1 (IL-8) and ACE2 proteins were assessed using ELISA in both normal and inflamed cells. IL-1β and TNF-α treatment upregulated ACE2, TMPRSS2 and SGLT1 gene expression. ACE2 increased with the duration of cytokine exposure, coupled with a significant decrease in IL-8, SGLT1 and TMPRSS2 over time. Pearson correlation analysis revealed that the increase in ACE2 was strongly associated with a decrease in IL-8 (r = −0.77, p < 0.01). The regulation of SGLT1 gene expression followed the same pattern as TMPRSS2, implying a common mechanism. Although none of the phytochemicals decreased inflammation-induced IL-8 secretion, genistein normalised inflammation-induced increases in SGLT1 and TMPRSS2. The association between TMPRSS2 and SGLT1 gene expression, which is particularly evident in inflammatory conditions, suggests a common regulatory pathway. Genistein downregulated the inflammation-induced increase in SGLT1 and TMPRSS2, which may help lower the postprandial glycaemic response and COVID-19 risk or severity in healthy individuals and those with metabolic disorders. Full article

Piper nigrum L. (PN), which contains various bioactive compounds, is a plant with homologous medicine and food. Sleep deprivation (SD) profoundly impacts cognitive function and emotional health. However, the mechanisms by which PN improves cognitive function and depressive mood induced by SD remain unclear. In our study, network pharmacology and molecular docking techniques were used to predict the potential mechanisms by which PN regulates SD. In this study, 220 compounds were identified in PN, and 10 core targets were screened through network pharmacology. Animal experiments showed that PN ameliorated depressive mood and cognitive deficits in sleep-deprived mice, upregulated the serum activities of superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT), and downregulated malondialdehyde (MDA) levels. The ELISA assay showed that PN significantly decreased the tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) levels. Histopathological staining of brain tissue demonstrated that PN mitigates SD-induced hippocampal damage, enables the hippocampus to produce more neurotransmitters, including 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), and dopamine (DA), and reduces glutamate (Glu) levels. RT-qPCR and WB analyses further indicated that PN could exert anti-SD effects by inhibiting the over-activation of the JAK1/STAT3 signalling pathway. In the PC12 cell model, PN could reduce inflammation and prevent apoptosis, exerting neuroprotective effects. In summary, PN has positive effects on alleviating depressive symptoms and cognitive dysfunction induced by SD. Full article

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder traditionally characterised by the presence of amyloid beta (Aβ) plaques and neurofibrillary tau tangles in the brain. However, emerging research has highlighted additional metabolic hallmarks of AD pathology. These include the metabolic reprogramming of microglia in favour of glycolysis over oxidative phosphorylation. This shift is attributed to an ‘M1′-like pro-inflammatory phenotype, which exacerbates neuroinflammation and contributes to neuronal damage. The urea cycle also presents as an altered metabolic pathway in AD, due to elevated urea levels and altered expression of urea cycle enzymes, metabolites, and transporters in the brain. However, to date, these changes remain largely unexplored. Methods: This study focuses on understanding the effects of extracellular urea and urea transporter-B (UT-B) inhibition on inflammatory changes in lipoteichoic acid (LTA)-stimulated BV2 microglia and on the viability of SH-SY5Y neuronal cells under oxidative stress and neurotoxic conditions. Results: In BV2 microglia, UT-B inhibition demonstrated a notable anti-inflammatory effect by reducing the formation of nitric oxide (NO) and the expression of tumour necrosis factor α (TNFα) and CCL2 in response to stimulation with the toll-like receptor (TLR)2 agonist, lipoteichoic acid (LTA). This was accompanied by a reduction in extracellular urea and upregulation of UT-B expression. The application of exogenous urea was also shown to mediate the inflammatory profile of BV2 cells in a similar manner but had only a modest impact on UT-B expression. While exposure to LTA alone did not alter the microglial metabolic profile, inhibition of UT-B upregulated the expression of genes associated with both glycolysis and fatty acid oxidation. Conversely, neither increased extracellular urea nor UT-B inhibition had a significant impact on cell viability or cytotoxicity in SH-SY5Y neurones exposed to oxidative stressors tert-butyl hydroperoxide (t-BHP) and 6-hydroxydopamine (6-OHDA). Conclusions: This study further highlights the involvement of urea transport in regulating the neuroinflammation associated with AD. Moreover, we reveal a novel role for UT-B in maintaining microglial metabolic homeostasis. Taken together, these findings contribute supporting evidence to the regulation of UT-B as a therapeutic target for intervention into neuroinflammatory and neurodegenerative disease. Full article

Type 2 diabetes (T2D) is characterised by insulin resistance and leads to hyperglycaemia. Its prevalence and associated complications continue to rise exponentially, despite the existence of pharmaceutical drugs, and this has prompted research into exploring safer herbal remedies. Portulaca oleracea (purslane) has been investigated in animal and clinical trials to explore its effects on diabetes, yielding conflicting results. This study aimed to evaluate the effects of purslane on inflammation and oxidative stress in diabetes mellitus. We conducted a comprehensive literature search on Scopus PubMed, and through a manual bibliographical search to find relevant studies from inception to 13 September 2024. The search terms included purslane, portulaca oleracea, and type 2 diabetes mellitus. Of the 38 retrieved studies, 12 were considered relevant and underwent critical review. Evidence from rodent studies showed decreased inflammatory markers such as interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), nuclear factor kappa-beta (NF-κβ), and C-reactive (CRP), while interleukin-10 (IL-10) was increased after intervention with purslane. The markers of oxidative stress such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), and total antioxidant capacity (TAC) levels increased, thiobarbituric acid reactive substances (TBARS), reactive oxygen species (ROS) and malondialdehyde (MDA) decreased. Notably, the evidence from clinical trials showed a significant reduction in NF-κβ and CRP after purslane treatment; however, no effect was observed on MDA and TAC. The evidence gathered in this study suggests that purslane exerts anti-inflammatory properties by downregulating NF-κβ, thus suppressing the production of associated pro-inflammatory cytokines. Therefore, purslane may be used as an antioxidant and inflammatory agent for diabetes. However, further clinical evidence with a broader population is required to validate the therapeutic properties of purslane in diabetes. Full article

Background/Objectives: Metabolic syndrome (MS) is diagnosed when at least three out of five key risk factors are present: obesity, high blood pressure, insulin resistance, high triglycerides (TG) and low high-density lipoprotein (HDL). MS is often associated with chronic low-grade inflammation. Recent studies have shown that raw stingless bee honey (SBH) can alleviate MS risk factors. However, the high moisture content in raw SBH predisposes it to fermentation, which can degrade its quality. Therefore, dehydrating SBH is necessary to prevent the fermentation process. This study aimed to compare the effects of dehydrated (DeGT) and raw (RGT) SBH from Geniotrigona thoracica species on high-carbohydrate, high-fat diet (HCHF)-induced MS in rats. Methods: Twenty-four male Wistar rats were divided into four groups: control (C), HCHF-induced MS without treatment (MS), HCHF-induced MS treated with DeGT (MS+DeGT) and HCHF-induced MS treated with RGT (MS+RGT). Group C received standard rat chow, while the other groups were fed with HCHF diet for 16 weeks. In the final eight weeks, two HCHF-induced groups received their respective SBH treatments. Results: Both DeGT and RGT treatments reduced energy intake, fat mass, high blood pressure, inflammatory (tumour necrosis factor-alpha (TNF-α)) and obesity (the leptin/adiponectin (L/A) ratio, corticosterone, 11 beta-hydroxysteroid dehydrogenase type-1 (11βHSD1)) markers, as well as prevented histomorphometry changes (prevented adipocyte hypertrophy, increased the Bowman’s space area and glomerular atrophy). Additionally, DeGT increased serum HDL levels, while RGT reduced serum TG, leptin and other inflammatory markers (interleukin-6 (IL-6) and interleukin-1 beta (IL-1β)), as well as hepatosteatosis. Conclusions: While DeGT demonstrates potential as a preventive agent for MS, RGT exhibited more pronounced anti-MS effects in this study. Full article

A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). The study analysed articles published in JCR journals from 2019 to 2024. The search strategy comprised the MESH, free terms of “Neuroinflammation”, and selective searches for the following single biomarkers that had previously been selected from the relevant literature: “High mobility group box 1/HMGB1”, “Toll-Like-Receptor 4/TLR-4”, “Interleukin-1/IL-1”, “Interleukin-6/IL-6”, “Transforming growth factor beta/TGF-β”, and “Tumour necrosis factor-alpha/TNF-α”. These queries were all combined with the MESH terms “Epileptogenesis” and “Epilepsy”. We found 243 articles related to epileptogenesis and neuroinflammation, with 356 articles from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 55 evaluated by the authors. A total of 21 articles were included in the qualitative evaluation, including 18 case–control studies, 2 case series, and 1 prospective study. As conclusion, this systematic review provides acceptable support for five biomarkers, including TNF-α and some of its soluble receptors (sTNFr2), HMGB1, TLR-4, CCL2 and IL-33. Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control of epileptic seizures. Their value will be better defined by future studies. Full article

The immune system plays a crucial role in defending the body against foreign invaders, and the balance of various polyunsaturated fatty acids, such as alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), can impact immune cell functions and overall immune responses. This study aimed to assess the effectiveness of mussel oil extracts in modulating inflammatory responses by analysing their effects on immune cell lines and cytokine expression. Four different mussel oil extracts were obtained using two extraction methods (organic solvent and supercritical CO₂ extraction) from two tissue sources (fresh and commercial). These extracts were then tested at various concentrations on T lymphocyte (Jurkat) cells, monocytes, and macrophages (THP-1 and U-937). Cytokine levels were quantified using ELISA. The results showed that the solvent-extracted samples had a dose-dependent effect on tumour necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) cytokine secretion in THP-1 and U937 cells, with the extract from a commercial mussel powder being more efficient than the extract from fresh powder. However, supercritical CO₂ samples showed elevated cytokine secretion levels despite their high omega-3 content. Furthermore, 100 ug/mL extract from fresh powder successfully reduced interleukin-2 (IL-2) secretion while maintaining cell viability after stimulation. The study demonstrated that solvent-extracted mussel oil can effectively regulate cytokine secretion, modulate immune cell activation, and alleviate inflammation. These findings offer valuable insights into using mussel oil extracts to treat inflammatory disorders and enhance immune responses. Full article

Orphan nuclear receptor subfamily 4A (NR4A) are key regulators of inflammatory responses, largely by their interactions with NF-κB. Over the last decade, several NR4A modulators have been developed, and they are showing potential as therapeutics, although their widespread use in laboratory settings is limited. Here, we have examined, using myeloid cell line THP-1, whether the NR4A modulator 3-[(4-Chlorophenyl)-(1H-indol-3-yl)methyl]-1H-indole (C-DIM12) can alter the inflammatory outcome of six inflammatory ligands: lipopolysaccharide (LPS), tumour necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), flagellin (FL), lipoteichoic acid (LTA), and zymosan (ZY). We demonstrate that C-DIM12 (10 µM) selectively alters the secretion of inflammatory chemokine MCP-1 following exposure to distinct inflammatory ligands in a concentration-dependent manner. Furthermore, data obtained from THP-1 Lucia cell experiments show that 10 µM C-DIM12, and not 1 µM C-DIM12, can significantly attenuate the increased NF-κB transcriptional activity observed following the exposure to several inflammatory ligands (LPS, FL, TNFα, LTA, and ZY). Lastly, experimental analysis confirms that the cellular action(s) of C-DIM12 is independent of changes in metabolic parameters. Thus, these data contribute to the understanding of how the NR4A modulator C-DIM12 alters inflammatory responses in a myeloid cell following exposure to multiple ligands. Full article

Background: The evidence links chemotherapy to cognitive impairment in breast cancer patients. This study assessed the link between subjective chemotherapy-related cognitive impairment and neuroinflammation in breast cancer patients. Methods: In a correlational study, 113 patients aged 21 to 60 years on chemotherapy regimens completed the Functional Assessment of Cancer Therapy-Cognition Test (FACT-Cog) as a measure of subjective cognitive functioning at three time points (baseline- T₀, third cycle- T₁, and sixth cycle- T₂). The levels of inflammatory cytokines (interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumour necrosis factor-alpha (TNF-α)) were measured using an assay method and compared with the subjective cognitive impairment. Results: Midway through chemotherapy, higher levels of TNF-α were inversely linked with self-perceived cognitive performance, while higher levels of IL-1β were positively associated (p = 0.030). However, at the end of chemotherapy, only IL-8 (p = 0.50) was associated with higher self-perceived cognitive problems. Conclusions: The specific roles that various cytokines and their interactions may play in neuroinflammation or neuroprotection require further investigation. Full article

Background: Tumour heterogeneity in high-grade serous ovarian cancer (HGSOC) is a proposed cause of acquired resistance to treatment and high rates of relapse. Among the four distinct molecular subtypes of HGSOC, the mesenchymal subtype (MES) has been observed with high frequency in several study cohorts. Moreover, it exhibits aggressive characteristics with poor prognosis. The failure to adequately exploit such subtypes for treatment results in high mortality rates, highlighting the need for effective targeted therapeutic strategies that follow the idea of personalized medicine (PM). Methods: As a proof-of-concept, bulk and single-cell RNA data were used to characterize the distinct composition of the tumour microenvironment (TME), as well as the cell–cell communication and its effects on downstream transcription of MES. Moreover, transcription factor activity contextualized with causal inference analysis identified novel therapeutic targets with potential causal impact on transcription factor dysregulation promoting the malignant phenotype. Findings: Fibroblast and macrophage phenotypes are of utmost importance for the complex intercellular crosstalk of MES. Specifically, tumour-associated macrophages were identified as the source of interleukin 1 beta (IL1B), a signalling molecule with significant impact on downstream transcription in tumour cells. Likewise, signalling molecules tumour necrosis factor (TNF), transforming growth factor beta (TGFB1), and C-X-C motif chemokine 12 (CXCL12) were prominent drivers of downstream gene expression associated with multiple cancer hallmarks. Furthermore, several consistently hyperactivated transcription factors were identified as potential sources for treatment opportunities. Finally, causal inference analysis identified Yes-associated protein 1 (YAP1) and Nuclear Receptor Subfamily 2 Group F Member 6 (NR2F6) as novel therapeutic targets in MES, verified in an independent dataset. Interpretation: By utilizing a sophisticated bioinformatics approach, several candidates for treatment opportunities, including YAP1 and NR2F6 were identified. These candidates represent signalling regulators within the cellular network of the MES. Hence, further studies to confirm these candidates as potential targeted therapies in PM are warranted. Full article

Optic nerve head (ONH) cupping is a clinical feature of glaucoma associated with extracellular matrix (ECM) remodelling and lamina cribrosa (LC) fibrosis. Peripapillary atrophy (PPA) occurs commonly in glaucoma, and is characterised by the loss of retinal pigment epithelium (RPE) adjacent to the ONH. Under pro-fibrotic conditions, epithelial cells throughout the body can differentiate into fibroblast-like cells through epithelial-to-mesenchymal transition (EMT) and contribute to ECM fibrosis. This is investigated here in the context of glaucoma and PPA. Human-donor ONH sections were assessed for the presence of the RPE cell-specific marker RPE65 using immunofluorescence. We examined the EMT response of ARPE-19 cells to the following glaucoma-related stimuli: cyclic mechanical stretch, mechanical stiffness, transforming growth factor beta (TGFβ), and tumour necrosis factor alpha (TNFα). The gene expression was measured using the PCR of the epithelial tight junction marker zona occludens 1 (ZO-1) and the mesenchymal markers alpha smooth muscle actin (αSMA) and vimentin. A scratch assay was used to assess the ARPE-19 migration. Significant RPE-65 staining was demonstrated in the glaucomatous ONH. The cyclic stretching and substrate stiffness of the ARPE-19 cells caused a significant decrease in ZO-1 (p = 0.04), and an increase in αSMA (p = 0.04). The scratch assays demonstrated increased migration of ARPE19 in the presence of TNFα (p = 0.02). Furthermore, ARPE-19 cells undergo an EMT-like transition (gain of αSMA, loss of ZO-1 and increased migration) in response to glaucomatous stimuli. This suggests that during PPA, RPE cells have the potential to migrate into the ONH and differentiate into fibroblast-like cells, contributing to glaucomatous ONH cupping. Full article

Diabetic retinopathy (DR), a microvascular complication of diabetes, is associated with pronounced inflammation arising from the activation of a nucleotide-binding and oligomerization domain-like receptor (NLR) protein 3 (NLRP3) inflammasome. Cell culture models have shown that a connexin43 hemichannel blocker can prevent inflammasome activation in DR. The aim of this study was to evaluate the ocular safety and efficacy of tonabersat, an orally bioavailable connexin43 hemichannel blocker, to protect against DR signs in an inflammatory non-obese diabetic (NOD) DR mouse model. For retina safety studies, tonabersat was applied to retinal pigment epithelial (ARPE-19) cells or given orally to control NOD mice in the absence of any other stimuli. For efficacy studies, either tonabersat or a vehicle was given orally to the inflammatory NOD mouse model two hours before an intravitreal injection of pro-inflammatory cytokines, interleukin-1 beta, and tumour necrosis factor-alpha. Fundus and optical coherence tomography images were acquired at the baseline as well as at 2- and 7-day timepoints to assess microvascular abnormalities and sub-retinal fluid accumulation. Retinal inflammation and inflammasome activation were also assessed using immunohistochemistry. Tonabersat did not have any effect on ARPE-19 cells or control NOD mouse retinas in the absence of other stimuli. However, the tonabersat treatment in the inflammatory NOD mice significantly reduced macrovascular abnormalities, hyperreflective foci, sub-retinal fluid accumulation, vascular leak, inflammation, and inflammasome activation. These findings suggest that tonabersat may be a safe and effective treatment for DR. Full article

Targeted therapies are the most attractive options in the treatment of different tumours, including kidney cancers. Such therapies have entered a golden era due to advancements in research, breakthroughs in scientific knowledge, and a better understanding of cancer therapy mechanisms, which significantly improve the survival rates and life expectancy of patients. The use of tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) as an anticancer therapy has attracted the attention of the scientific community and created great excitement due to its selectivity in targeting cancerous cells with no toxic impacts on normal tissues. However, clinical studies disappointingly showed the emergence of resistance against TRAIL. This study aimed to employ curcumin to sensitise TRAIL-resistant kidney cancerous ACHN cells, as well as to gain insight into the molecular mechanisms of TRAIL sensitization. Curcumin deregulated the expression of apoptosis-regulating micro Ribonucleic Acid (miRNAs), most notably, let-7C. Transfecting ACHN cells with a let-7C antagomir significantly increased the expression of several cell cycle protein, namely beta (β)-catenin, cyclin dependent kinase (CDK)1/2/4/6 and cyclin B/D. Further, it overexpressed the expression of the two key glycolysis regulating proteins including hypoxia-inducible factor 1-alpha (HIF-1α) and pyruvate dehydrogenase kinase 1 (PDK1). Curcumin also suppressed the expression of the overexpressed proteins when added to the antagomir transfected cells. Overall, curcumin targeted ACHN cell cycle and cellular metabolism by promoting the differential expression of let-7C. To the best of our knowledge, this is the first study to mechanistically report the cancer chemosensitisation potential of curcumin in kidney cancer cells via induction of let-7C. Full article