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Scientific Reports Apr 2024Coumarins are heterocycles of great interest in the development of valuable active structures in chemistry and biological domains. The ability of coumarins to inhibit...
Coumarins are heterocycles of great interest in the development of valuable active structures in chemistry and biological domains. The ability of coumarins to inhibit biofilm formation of Gram positive bacterium (Staphylococcus aureus), Gram negative bacterium (Escherichia coli) as well as the methicillin-resistant S. aureus (MRSA) has been previously described. In the present work, new hybrid coumarin-heterocycles have been synthesized via the reaction of coumarin-6-sulfonyl chloride and 6-aminocoumarin with different small heterocycle moieties. The biological efficacy of the new compounds was evaluated towards their ability to inhibit biofilm formation and their anti-inflammatory properties. The antimicrobial activities of the newly synthesized compounds were tested against Gram positive bacterium (S. aureus ATCC 6538), Gram negative bacterium (E. coli ATCC 25922), yeast (Candida albicans ATCC 10231) and the fungus (Aspergillus niger NRRL-A326). Compounds 4d, 4e, 4f, 6a and 9 showed significant MIC and MBC values against S. aureus, E. coli, C. albicans, and methicillin-resistant S. aureus (MRSA) with especial incidence on compound 9 which surpasses all the other compounds giving MIC and MBC values of (4.88 and 9.76 µg/mL for S. aureus), (78.13 and 312.5 µg/mL for E. coli), (9.77 and 78.13 µg/mL for C. albicans), and (39.06 and 76.7 µg/mL for MRSA), respectively. With reference to the antibiofilm activity, compound 9 exhibited potent antibiofilm activity with IC of 60, 133.32, and 19.67 µg/mL against S. aureus, E. coli, and MRSA, (respectively) considering the reference drug (neomycin). Out of all studied compounds, the anti-inflammatory results indicated that compound 4d effectively inhibited nitric oxide production in lipopolysaccharide-(LPS-) stimulated RAW264.7 macrophage cells, giving NO% inhibition of 70% compared to Sulindac (55.2%).
Topics: Humans; Anti-Bacterial Agents; Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus; Escherichia coli; Gram-Positive Bacteria; Gram-Negative Bacteria; Coumarins; Inflammation; Biofilms; Anti-Inflammatory Agents; Microbial Sensitivity Tests
PubMed: 38643226
DOI: 10.1038/s41598-024-59072-w -
Current Issues in Molecular Biology Mar 2024Prostate cancer remains a significant public health concern in sub-Saharan Africa, particularly impacting South Africa with high mortality rates. Despite many years of...
Prostate cancer remains a significant public health concern in sub-Saharan Africa, particularly impacting South Africa with high mortality rates. Despite many years of extensive research and significant financial expenditure, there has yet to be a definitive solution to prostate cancer. It is not just individuals who vary in their response to treatment, but even different nodules within the same tumor exhibit unique transcriptome patterns. These distinctions extend beyond mere differences in gene expression levels to encompass the control and networking of individual genes. Escalating chemotherapy resistance in prostate cancer patients has prompted increased research into its underlying mechanisms. The heterogeneous nature of transcriptomic organization among men makes the pursuit of universal biomarkers and one-size-fits-all treatments impractical. This study delves into the expression of drug resistance-associated genes, ABCB1 and CYP1B1, in cancer cells. Employing bioinformatics, we explored the molecular pathways and cascades linked to drug resistance following upregulation of these genes. Samples were obtained from archived prostate cancer patient specimens through pre-treatment biopsies of two categories: good vs. poor responders, with cDNAs synthesized from isolated RNAs subjected to qPCR analysis. The results revealed increased ABCB1 and CYP1B1 expression in tumor samples of the poor responders. Gene enrichment and network analysis associated ABCB1 with ABC transporters and LncRNA-mediated therapeutic resistance (WP3672), while CYP1B1 was linked to ovarian steroidogenesis, tryptophan metabolism, steroid hormone biosynthesis, benzo(a)pyrene metabolism, the sulindac metabolic pathway, and the estrogen receptor pathway, which are associated with drug resistance. Both ABCB1 and CYP1B1 correlated with microRNAs in cancer and the Nuclear Receptors Meta-Pathway. STRING analysis predicted protein-protein interactions of ABCB1 and CYP1B1 with Glutathione S-transferase Pi, Catechol O-methyltransferase, UDP-glucuronosyltransferase 1-6, Leucine-rich Transmembrane and O-methyltransferase (LRTOMT), and Epoxide hydrolase 1, with scores of 0.973, 0.971, 0.966, 0.966, and 0.966, respectively. Furthermore, molecular docking analysis of the chemotherapy drug, docetaxel, with CYP1B1 and ABCB1 revealed robust molecular interactions, with binding energies of -20.37 and -15.25 Kcal/mol, respectively. These findings underscore the susceptibility of cancer patients to drug resistance due to increased ABCB1 and CYP1B1 expression in tumor samples from patients in the poor-responders category that affects associated molecular pathways. The potent molecular interactions of ABCB1 and CYP1B1 with docetaxel further emphasize the potential basis for chemotherapy resistance.
PubMed: 38534761
DOI: 10.3390/cimb46030145 -
Frontiers in Neuroscience 2023Chemotherapy-induced peripheral neuropathy (CIPN), a side effect of chemotherapy, is particularly difficult to treat. We explored whether phosphosulindac (PS), a...
BACKGROUND
Chemotherapy-induced peripheral neuropathy (CIPN), a side effect of chemotherapy, is particularly difficult to treat. We explored whether phosphosulindac (PS), a modified NSAID, could treat CIPN.
METHODS
CIPN was induced in male C57BL/6 J mice by paclitaxel, vincristine or oxaliplatin. Mechanical allodynia was measured with the von Frey test and cold allodynia with the acetone test. To determine the preventive effect of PS, it was administered 2 days before the induction of CIPN. Mouse Lewis lung carcinoma xenografts were used to determine if PS altered the chemotherapeutic efficacy of paclitaxel. Cultured cell lines were used to evaluate the effect of PS on neuroinflammation.
RESULTS
Treatment with each of the three chemotherapeutic agents used to induce CIPN lowered the mechanical allodynia scores by 56 to 85% depending on the specific agent. PS gel was applied topically 3x/day for 16-22 days to the hind paws of mice with CIPN. This effect was dose-dependent. Unlike vehicle, PS returned mechanical allodynia scores back to pre-CIPN levels. PS had a similar effect on paclitaxel-induced CIPN cold allodynia. Sulindac, a metabolite of PS, had no effect on CIPN. PS significantly prevented CIPN compared to vehicle. Given concomitantly with paclitaxel to mice with lung cancer xenografts, PS relieved CIPN without affecting the anticancer effect of paclitaxel. The enantiomers of PS were equally efficacious against CIPN, suggesting the therapeutic suitability of the racemate PS. There were no apparent side effects of PS. PS suppressed the levels of IL-6, IL-10, CXCL1, and CXCL2 induced by paclitaxel in a neuroblastoma cell line, and macrophage activation to the M1 proinflammatory phenotype.
CONCLUSION
Topically applied PS demonstrated broad therapeutic and preventive efficacy against CIPN, preserved the anticancer effect of paclitaxel, and was safe. Its anti-CIPN effect appears to be mediated, in part, by suppression of neuroinflammation. These data support further evaluation of topical PS for the control of CIPN.
PubMed: 38347876
DOI: 10.3389/fnins.2023.1240372 -
Cureus Jan 2024Sulindac sulfone, an active metabolite of sulindac, a non-steroidal anti-inflammatory drug, has good anti-inflammatory potential. The antineoplastic effect of sulindac... (Review)
Review
Sulindac sulfone, an active metabolite of sulindac, a non-steroidal anti-inflammatory drug, has good anti-inflammatory potential. The antineoplastic effect of sulindac sulfone is mediated through a cyclooxygenase inhibitory mechanism, followed by apoptosis and inhibition of cell proliferation. Mounting studies have explored the anti-neoplastic effect of sulindac sulfone in various types of cancers in a dose-dependent manner. In this backdrop, we have conducted a systematic review to evaluate the efficacy and dose of sulindac sulfone as an anti-neoplastic agent in human head and neck squamous cell carcinoma cell lines (HNSCCs). In this study, we used a systematic literature review approach, and articles were searched in PubMed, and Medline with the keywords "sulindac sulfone," "anti-neoplastic activity," "chemopreventive," and "head and neck squamous cell carcinoma". A hand-search of journals was also performed. Articles were reviewed and analyzed. The analysis reveals that, based on the in vitro studies on various tumor models, the optimum concentration of sulindac sulfone which elicits anti-neoplastic effects is 200-800 µM. The anti-neoplastic effect is mediated through inhibition of cell proliferation and apoptosis. The results of our systematic review show that the anti-neoplastic activity of pharmacologic Sulindac sulfone is part of its dose-dependent activity, which can be safely employed in the therapy for human HNSCCs and would be responsible for a beneficial outcome of the treatment.
PubMed: 38313951
DOI: 10.7759/cureus.51692 -
Photodiagnosis and Photodynamic Therapy Feb 2024The efficacy of Copal Varnish (CV), dentin bonding agent (DBA), Nd:YAG laser and Er:YAG laser, which occludes dentin tubules by different mechanisms, was investigated in...
Spectrophotometric analysis of the effectiveness of different dentin tubule occlusion techniques in preventing discoloration caused by photosensitizers used in photodynamic therapy.
AIM
The efficacy of Copal Varnish (CV), dentin bonding agent (DBA), Nd:YAG laser and Er:YAG laser, which occludes dentin tubules by different mechanisms, was investigated in order to prevent unwanted coloration caused by methylene blue (MB) and phthalocyanine used in photodynamic therapy (PDT).
MATERIALS AND METHODS
165 upper incisors included in the study. Root canals were prepared up to 30/0.6 size for all teeth using Protaper Next rotary files. Then the teeth were randomly divided into 2 main groups (n = 60); MB and phthalocyanine. Each main group was randomly divided into 5 subgroups (n = 15); Positive control, DBA, CV, Er:YAG and Nd:YAG. Root canals were filled with photosensitizers (PS) and activated after the dentin tubule occlusion method was applied to all teeth. Then, the residual PSs were removed by irrigation. Color measurements of the samples were carried out 5 different time periods.
RESULTS
Clinically detectable color change was observed in all groups except for the negative control (ΔE≥3.3). It was determined that the positive control using MB caused more unwanted coloration in the CV on the 30th and 90th days compared to the phthalocyanine used in the 90th day (p < 0.05). While none of the dentin tubule occlusion methods were superior to each other in preventing undesirable coloration caused by phthalocyanine, Er:YAG caused less unwanetd coloration than CV only on the 90th day in preventing unwanted coloration caused by MB (p < 0.05).
CONCLUSIONS
All dentin tubule occlusion methods used in the present study were effective in preventing some degree of unwanted discoloration. However, it was found that no technique could completely prevent unwanted coloration.
Topics: Photosensitizing Agents; Photochemotherapy; Incisor; Indoles; Methylene Blue; Sulindac; Dentin
PubMed: 38272154
DOI: 10.1016/j.pdpdt.2024.103987 -
Frontiers in Immunology 2023Diabetic retinopathy (DR) is a leading cause of vision loss worldwide. Recent studies highlighted the crucial impact of circadian rhythms (CR) on normal retinopathy in...
BACKGROUND
Diabetic retinopathy (DR) is a leading cause of vision loss worldwide. Recent studies highlighted the crucial impact of circadian rhythms (CR) on normal retinopathy in response to the external light cues. However, the role of circadian rhythms in DR pathogenesis and potential investigational drugs remains unclear.
METHODS
To investigate the weather CR affects DR, differential expression analysis was employed to identify differentially expressed genes (DEGs) from the GEO database (GSE160306). Functional enrichment analysis was conducted to identify relevant signaling pathways. LASSO regression was utilized to screen pivotal genes. Weighted gene co-expression network anlaysis (WGCNA) was applied to identify different modules. Additionally, we use the Comparative Toxicogenomics Database (CTD) database to search key genes related to drugs or molecular compounds. The diabetic mouse model received three consecutive intraperitoneal injections of streptozotocin (STZ) during 3 successive days.
RESULTS
We initially identified six key genes associated with circadian rhythm in DR, including , , , , , and . Compared to normal tissue, the expression levels of COL6A3 and IGFB2 were significantly increased in DR model. Furthermore, we identified several signaling pathways, including death domain binding, insulin-like growth factor I binding, and proteasome binding. We also observed that COL6A3 was positively correlated with macrophages (cor=0.628296895, p=9.96E-08) and Th17 cells (cor=0.665120835, p=9.14E-09), while IGFBP2 showed a negatively correlated with Tgd (cor=-0.459953045, p=0.000247284) and Th2 cells (cor=-0.442269719, p=0.000452875). Finally, we identified four drugs associated with key genes: Resveratrol, Vitamin E, Streptozocin, and Sulindac.
CONCLUSION
Our findings revealed several key genes related to circadian rhythms and several relevant drugs in DR, providing a novel insight into the mechanism of DR and potential implications for future DR treatment. This study contributes to a better understanding of CR in DR and its implications for future therapeutic interventions.
Topics: Mice; Animals; Diabetic Retinopathy; Circadian Rhythm; Gene Regulatory Networks; Disease Models, Animal; Macrophages; Streptozocin; Diabetes Mellitus
PubMed: 38124748
DOI: 10.3389/fimmu.2023.1260350 -
Frontiers in Oncology 2023To evaluate the efficacy of Difluoromethylornithine (DFMO) chemoprevention in the high-risk population for colorectal cancer (CRC).
OBJECTIVES
To evaluate the efficacy of Difluoromethylornithine (DFMO) chemoprevention in the high-risk population for colorectal cancer (CRC).
METHODS
Meta-analysis was conducted to assess the caliber of the included literature by searching five databases for randomized controlled trials of DFMO chemoprevention in the high-risk population of CRC, with RevMan 5.4, Stata 15.0 and TSA 0.9.5.10 employed to statistically analyze the extracted data. Grade profiler 3.6 was employed for grading the evidence for the outcome indicators (disease progression and adenoma incidence).
RESULTS
Six trials were finally included in this research, with the collective data indicating that the DFMO combination therapy was efficacious in lowering the incidence of recurrent adenomas in patients who had experienced advanced CRC [RR 0.34, 95% CI 0.14 - 0.83, P < 0.05]. Meta-analysis showed that DFMO combined therapy had no statistical difference in disease progression in patients with familial adenomatous polyposis[RR 0.52, 95% CI 0.14 - 1.86, P > 0.05]; Trial Sequential Analysis reveals that the combination therapy of DFMO effectively diminishes the occurrence of recurrent adenomas in patients with a history of advanced colorectal tumors, displaying a Risk Ratio (RR) of 0.33 with a 95% Confidence Interval (CI) of 0.12 - 0.90 and a significance level of P < 0.05. This combination exhibits a statistically significant difference. Subgroup analysis demonstrates that, depending on the drug treatment regimen (DFMO+ Aspirin/DFMO+ Sulindac), the combination of DFMO and aspirin exhibits an effect comparable to a placebo in diminishing the occurrence of new adenomas in patients with a history of advanced colorectal tumors. However, the combination of DFMO and sulindac significantly mitigates the incidence of recurrent adenomas in this patient population.
CONCLUSION
This meta-analysis indicates that the existing randomized controlled trials are adequate to ascertain the efficacy of DFMO combination therapy in diminishing the incidence of recurrent adenomas in patients who have previously encountered advanced colorectal tumors. However, further clinical trials need to be conducted to evaluate the optimum dosage and treatment course of prophylactic implementation of DFMO combination therapy in high-risk populations.
PubMed: 38033490
DOI: 10.3389/fonc.2023.1281844 -
Frontiers in Immunology 2023Triple-negative breast cancer (TNBC) comprises a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological...
INTRODUCTION
Triple-negative breast cancer (TNBC) comprises a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy. Despite promising results, the efficacy of immunotherapy and chemo-immunotherapy in TNBC remains limited. There is strong evidence supporting the involvement of Notch signaling in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, including g-secretase inhibitors (GSIs), are quite effective in preclinical models of TNBC. However, the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects, since Notch plays key roles in T-cell activation, including CD8 T-cells in tumors. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and ideally, do not affect tumor immunity. We identified sulindac sulfide (SS), the active metabolite of FDA-approved NSAID sulindac, as a potential candidate to replace GSIs.
METHODS
We investigated the pharmacological and immunotherapeutic properties of SS in TNBC models , and .
RESULTS
We confirmed that SS, a known γ-secretase modulator (GSM), inhibits Notch1 cleavage in TNBC cells. SS significantly inhibited mammosphere growth in all human and murine TNBC models tested. In a transplantable mouse TNBC tumor model (C0321), SS had remarkable single-agent anti-tumor activity and eliminated Notch1 protein expression in tumors. Importantly, SS did not inhibit Notch cleavage in T- cells, and the anti-tumor effects of SS were significantly enhanced when combined with a-PD1 immunotherapy in our TNBC organoids and .
DISCUSSION
Our data support further investigation of SS for the treatment of TNBC, in conjunction with chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option for a patient population in need of more effective therapies.
Topics: Humans; Animals; Mice; Sulindac; Amyloid Precursor Protein Secretases; Triple Negative Breast Neoplasms; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal
PubMed: 37901240
DOI: 10.3389/fimmu.2023.1244159 -
Nature Communications Sep 2023Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in...
Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in the nervous system. Here, we utilized zebrafish larvae to assess the potentially toxic effects of nonsteroidal anti-inflammatory drugs and found that sulindac can selectively induce apoptosis of GABAergic neurons in the brains of zebrafish larvae brains. Zebrafish larvae exhibit hyperactive behaviour after sulindac exposure. We also found that akt1 is selectively expressed in GABAergic neurons and that SC97 (an Akt1 activator) and exogenous akt1 mRNA can reverse the apoptosis caused by sulindac. Further studies showed that sulindac binds to retinoid X receptor alpha (RXRα) and induces autophagy in GABAergic neurons, leading to activation of the mitochondrial apoptotic pathway. Finally, we verified that sulindac can lead to hyperactivity and selectively induce GABAergic neuron apoptosis in mice. These findings suggest that excessive use of sulindac may lead to early neurodevelopmental toxicity and increase the risk of hyperactivity, which could be associated with damage to GABAergic neurons.
Topics: Animals; Mice; Sulindac; Zebrafish; Apoptosis; Anti-Inflammatory Agents, Non-Steroidal; GABAergic Neurons; Larva
PubMed: 37660128
DOI: 10.1038/s41467-023-41114-y