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Exploration of Targeted Anti-tumor... 2024Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this... (Review)
Review
Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this membrane is an essential process in cell biology and metabolism. Monocarboxylate transporters (MCTs) belong to a vast family of solute carriers (SLCs) that facilitate the transport of certain hydrophylic small compounds through the bilipid cell membrane. The existence of 446 genes that code for SLCs is the best evidence of their importance. In-depth research on MCTs is quite recent and probably promoted by their role in cancer development and progression. Importantly, it has recently been realized that these transporters represent an interesting target for cancer treatment. The search for clinically useful monocarboxylate inhibitors is an even more recent field. There is limited pre-clinical and clinical experience with new inhibitors and their precise mechanism of action is still under investigation. What is common to all of them is the inhibition of lactate transport. This review discusses the structure and function of MCTs, their participation in cancer, and old and newly developed inhibitors. Some suggestions on how to improve their anticancer effects are also discussed.
PubMed: 38464385
DOI: 10.37349/etat.2024.00210 -
Biomedicine & Pharmacotherapy =... Nov 2023We examined whether combinig diclofenac and metformin in doses equivalent to human doses would synergize their anticancer activity on fibrosarcoma inoculated to hamsters...
We examined whether combinig diclofenac and metformin in doses equivalent to human doses would synergize their anticancer activity on fibrosarcoma inoculated to hamsters and in vitro. Rescue experiment was performed to examine whether the prosurvival NF-κB stimulation by mebendazole can reverse anticancer effects of the treatment. BHK-21/C13 cell culture was subcutaneously inoculated to Syrian golden hamsters randomly divided into groups (6 animals per group): 1) untreated control; treated daily with 2) diclofenac; 3) metformin; 4) combinations of diclofenac and metformin at various doses; 5) combination of diclofenac, metformin and mebendazole; 6) mebendazole. Dose response curves were made for diclofenac and metformin combination. Tumor growth kinetics, biophysical, pathological, histological and immunohistochemical characteristics of excised tumors and hamster organs as well as biochemical and hematological blood tests were compared among the groups. Single treatments had no anticancer effects. Diclofenac (60 mg/kg/day) exhibited significant (P < 0.05) synergistic inhibitory effect with metformin (500 mg/kg/day) on all tumor growth parameters, without toxicity and influence on biochemical and hematological blood tests. The same results were obtained with double doses of diclofenac and metformin combination. The addition of mebendazole to the diclofenac and metformin combination rescued tumor expansion. Furthermore, diclofenac with metformin demonstrated antiproliferative effects in hamster fibrosarcoma BHK-21/C13, human lung carcinoma A549 (CCL-185), colon carcinoma HT-29 (HTB-38) and cervical carcinoma HeLa (CCL-2) cell cultures, with markedly lower cytotoxicity in the normal fetal lung MRC-5 cells. In conclusion, diclofenac and metformin combination may be recommended for potential use in oncology, due to synergistic anticancer effect in doses achievable in humans.
PubMed: 37738800
DOI: 10.1016/j.biopha.2023.115528 -
Cureus Jul 2023Mandibular third-molar extraction is a frequently executed minor oral surgical procedure, with a subsequent recovery period lasting several days. Typically, preemptive... (Review)
Review
Mandibular third-molar extraction is a frequently executed minor oral surgical procedure, with a subsequent recovery period lasting several days. Typically, preemptive administration of non-steroid anti-inflammatory drugs (NSAIDs) and steroids has been employed, resulting in a notable decrease in postoperative complications like pain, facial swelling, trismus, and alveolar osteitis. This systematic review's primary goal was to investigate the efficacy of preemptive analgesia with dexamethasone and diclofenac in minimizing the post-surgical complications following the surgical extraction of the mandibular third molars. The systematic search was carried out to identify relevant literature in digital databases including PubMed®, Cochrane Library, Web of Science, and Scopus, from January 1990 to January 2022. The search used specific keywords. The randomized clinical trials assessing the efficacy of dexamethasone and diclofenac or dexamethasone alone compared to diclofenac or placebo as preemptive analgesics were considered inclusion criteria for this systematic review. Case reports, literature reviews, letters to the editor, and non-English publications were not included. Two authors screened the titles and abstracts, and articles fulfilling the study criteria were included. After reading the full text and data collection, analysis was performed. The included article's bias was evaluated by the Risk of Bias 2 (RoB 2) tool. A digital database search yielded a total of 207 articles. After excluding duplicates and articles written in languages other than English, 90 were removed. Based on the title and abstract, out of 177, 95 studies were excluded. After full-text reading of 22 articles, 17 were eliminated because they did not meet the inclusion and exclusion criteria. The remaining five studies were found eligible and included in the systematic review. Four studies were of low risk, while one study had some concerns. Two studies evaluated the combination of dexamethasone with diclofenac, while three evaluated dexamethasone alone. Total samples included samples of 436 third-molar surgeries in 420 patients. There was a substantial decrease in the mean pain score and swelling measurement when diclofenac alone was compared with coadministration of diclofenac and dexamethasone. Preemptive administration of dexamethasone and diclofenac has been shown to effectively reduce pain and facial swelling, with the exception of trismus, in third-molar surgeries when compared to diclofenac alone. As a result, it is recommended to administer these drugs prior to the commencement of third-molar extraction. However, further research is mandatory, specifically good quality randomized controlled trials involving large cohorts, in order to assess any significant variations and validate these findings.
PubMed: 37654946
DOI: 10.7759/cureus.42709 -
The Journal of Maternal-fetal &... Dec 2023The aim of this review is to evaluate the relationship between the use of non-steroidal anti-inflammatory drugs (NSAIDs) during last trimesters of the pregnancy and the... (Review)
Review
OBJECTIVE
The aim of this review is to evaluate the relationship between the use of non-steroidal anti-inflammatory drugs (NSAIDs) during last trimesters of the pregnancy and the reduction of amniotic fluid.
METHODS
Electronic databases were searched (PubMed, Medline, and Scopus). Selection criteria included studies reporting the relationship between oligohydramnios and use of NSAID during pregnancy. We analyzed the median age of women, weeks of pregnancy at the beginning of the drug administration, kind of medication, period of exposure and dosage, deepest vertical pocket (DVP), and amniotic fluid index (AFI).
RESULTS
Of the 68 records identified, we analyzed 29 studies investigating the administration of NSAIDs, including 11 studies examined the administration of the Indomethacin, four articles have focused on the use of Nimesulide, and only two manuscripts considered the use of Diclofenac. We found a strict correlation between the development of oligohydramnios and the use of NSAIDs. The oligohydramnios is reversible, and the normal amount of amniotic fluid is restored after the interruption of the treatment.
CONCLUSIONS
The use of NSAIDs should be considered when maternal benefits outweigh the potential fetal risk, at the lowest effective dose for shortest duration. Beyond 48 h of NSAIDs treatment, we consider ultrasound monitoring of amniotic fluid, and we suggest stopping therapy if a decline AFI is present.
Topics: Pregnancy; Female; Humans; Oligohydramnios; Amniotic Fluid; Anti-Inflammatory Agents, Non-Steroidal; Pregnancy Trimester, Third; Ultrasonography; Pregnancy Outcome
PubMed: 38092425
DOI: 10.1080/14767058.2023.2253956 -
Journal of Ayurveda and Integrative... 2023Rheumatoid arthritis (RA) is an inflammation of joints with increased cellularity of synovial tissue. Allopathic drugs possess several adverse effects, which have led to...
BACKGROUND
Rheumatoid arthritis (RA) is an inflammation of joints with increased cellularity of synovial tissue. Allopathic drugs possess several adverse effects, which have led to increase in the utilization of herbal medicines. Polyherbal emulgel resolves the bioavailability issue associated with hydrophobic drugs and can be used effectively in the treatment of RA.
OBJECTIVES
The present study aimed at the formulation of polyherbal emulgel, and evaluation of in vitro anti-inflammatory activity and in vivo antiarthritic activity.
METHODS
Seven emulgels F-1 to F-7 were optimally formulated. In vitro anti-inflammatory activity was determined using protein denaturation method employing Diclofenac sodium as the standard. In antiarthritic study Complete Freund's Adjuvant (CFA) model was used. The various parameters were assessed, like paw volume, body weight, hematological parameters, antioxidant parameters, Rheumatic factor (RF), and histopathological study of ankle joint.
RESULTS
F-4 and F-7 were found to be optimized formulations as compared to other formulations. The in vitro anti-inflammatory activity was found to be highest in F-4 with IC 7.74 and F-7 with IC 8.87 in comparison with Diclofenac sodium having IC 57.0. Both formulations F-7 and F-4 showed a significant reduction in paw volume and normalization of body weights. The formulation F-7 even showed more potent antiarthritic activity than F-4 by decreasing white blood cells (WBC), lymphocytes, increasing packed cell volume (PCV), neutrophils, superoxide dismutase (SOD), catalase and decreasing malondialdehyde (MDA) levels in serum. This was further confirmed by histopathological study.
CONCLUSION
As an anti-inflammatory agent, this newly developed emulgel was found to possess more therapeutic efficacy than commercially available diclofenac sodium.
PubMed: 38016365
DOI: 10.1016/j.jaim.2023.100828 -
Zhongguo Xiu Fu Chong Jian Wai Ke Za... Aug 2023To prepare a novel hyaluronic acid methacrylate (HAMA) hydrogel microspheres loaded polyhedral oligomeric silsesquioxane-diclofenac sodium (POSS-DS) patricles, then...
OBJECTIVE
To prepare a novel hyaluronic acid methacrylate (HAMA) hydrogel microspheres loaded polyhedral oligomeric silsesquioxane-diclofenac sodium (POSS-DS) patricles, then investigate its physicochemical characteristics and and biological properties.
METHODS
Using sulfhydryl POSS (POSS-SH) as a nano-construction platform, polyethylene glycol and DS were chemically linked through the "click chemistry" method to construct functional nanoparticle POSS-DS. The composition was analyzed by nuclear magnetic resonance spectroscopy and the morphology was characterized by transmission electron microscopy. In order to achieve drug sustained release, POSS-DS was encapsulated in HAMA, and hybrid hydrogel microspheres were prepared by microfluidic technology, namely HAMA@POSS-DS. The morphology of the hybrid hydrogel microspheres was characterized by optical microscope and scanning electron microscope. The degradation and drug release efficiency were observed. Cell counting kit 8 (CCK-8) and live/dead staining were used to detect the effect on chondrocyte proliferation. Moreover, a chondrocyte inflammation model was constructed and cultured with HAMA@POSS-DS. The relevant inflammatory indicators, including collagen type Ⅱ, aggrecan (AGG), matrix metalloproteinase 13 (MMP-13), recombinant A disintegrin and metalloproteinase with thrombospondin 5 (Adamts5), and recombinant tachykinin precursor 1 (TAC1) were detected by immunofluorescence staining and real-time fluorescence quantitative PCR, with normal cultured chondrocytes and the chondrocyte inflammation model without treatment as control group and blank group respectively to further evaluate their anti-inflammatory activity. Finally, by constructing a rat model of knee osteoarthritis, the effectiveness of HAMA@POSS-DS on osteoarthritis was evaluated by X-ray film and Micro-CT examination.
RESULTS
The overall particle size of POSS-DS nanoparticles was uniform with a diameter of about 100 nm. HAMA@POSS-DS hydrogel microspheres were opaque spheres with a diameter of about 100 μm and a spherical porous structure. The degradation period was 9 weeks, during which the loaded POSS-DS nanoparticles were slowly released. CCK-8 and live/dead staining showed no obvious cytotoxicity at HAMA@POSS-DS, and POSS-DS released by HAMA@POSS-DS significantly promoted cell proliferation (<0.05). In the chondrocyte anti-inflammatory experiment, the relative expression of collagen type Ⅱ mRNA in HAMA@POSS-DS group was significantly higher than that in control group and blank group (<0.05). The relative expression level of AGG mRNA was significantly higher than that of blank group (<0.05). The relative expressions of MMP-13, Adamts5, and TAC1 mRNA in HAMA@POSS-DS group were significantly lower than those in blank group (<0.05). experiments showed that the joint space width decreased after operation in rats with osteoarthritis, but HAMA@POSS-DS delayed the process of joint space narrowing and significantly improved the periarticular osteophytosis (<0.05).
CONCLUSION
HAMA@POSS-DS can effectively regulate the local inflammatory microenvironment and significantly promote chondrocyte proliferation, which is conducive to promoting cartilage regeneration and repair in osteoarthritis.
Topics: Animals; Rats; Matrix Metalloproteinase 13; Microspheres; Hydrogels; Collagen Type II; Diclofenac; Inflammation; Osteoarthritis, Knee; Hyaluronic Acid; Aggrecans
PubMed: 37586790
DOI: 10.7507/1002-1892.202302105 -
Clinical Ophthalmology (Auckland, N.Z.) 2024To compare the effect of treatment with preservative-free dexamethasone, NSAIDs and trehalose/hyaluronic acid eye drops with the preservative benzalkonium chloride...
PURPOSE
To compare the effect of treatment with preservative-free dexamethasone, NSAIDs and trehalose/hyaluronic acid eye drops with the preservative benzalkonium chloride containing dexamethasone and NSAIDs after cataract surgery in dry versus non-dry eyes.
PATIENTS AND METHODS
In this prospective randomized intervention study, dry eye tests were performed before and 6 weeks after cataract surgery. Patients were considered as having dry eye, SDE (sign of dry eye), if at least one of the following dry eye tests were abnormal; corneal fluorescein staining (CFS), non-invasive keratograph breakup time (NIKBUT) or tear osmolarity. Patients with SDE were randomly assigned to one of two groups. Group 1 patients were treated with dexamethasone and bromfenac eye drops with the preservative benzalkonium chloride (BAC). Group 2 patients were treated with preservative-free dexamethasone and preservative-free diclofenac, as well as a preservative-free lubricant with trehalose and hyaluronic acid both before and after surgery. Patients with normal tear film status acted as the control group (group 3) and received same treatment as group 1.
RESULTS
A total of 215 patients were enrolled six weeks after surgery, the number of patients with SDE decreased significantly in groups 1 and 2 (p <0.001). Subjective symptoms and objective measures including osmolarity, NIKBUT, CFS, and tear film thickness (TFT) improved after surgery, tear production remained unchanged, while corneal sensitivity and meibomian gland dysfunction (MGD) parameters worsened. In the control group with normal tear-film status, SDE increased significantly after the surgery (p <0.001). There were no statistically significant differences in tear film parameters between the three groups after surgery.
CONCLUSION
After cataract surgery, patients with mild to moderate dry eyes may experience improved tear film status and reduced symptoms. However, we found no additional beneficial effect on dry eye parameters with treatment with preservative-free dexamethasone, NSAIDs, and lubricants compared to preservative-containing eye drops.
PubMed: 38435373
DOI: 10.2147/OPTH.S446804 -
Experimental Gerontology Jul 2023Nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, belong to the most prescribed analgesic medication after traumatic injuries. However, there is...
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, belong to the most prescribed analgesic medication after traumatic injuries. However, there is accumulating evidence that NSAIDs impair fracture healing. Because bone regeneration in aged patients is subject to significant changes in cell differentiation and proliferation as well as a markedly altered pharmacological action of drugs, we herein analyzed the effects of diclofenac on bone healing in aged mice using a stable closed femoral facture model. Thirty-three mice (male n = 14, female n = 19) received a daily intraperitoneal injection of diclofenac (5 mg/kg body weight). Vehicle-treated mice (n = 29; male n = 13, female n = 16) served as controls. Fractured mice femora were analyzed by means of X-ray, biomechanics, micro computed tomography (μCT), histology and Western blotting. Biomechanical analyses revealed a significantly reduced bending stiffness in diclofenac-treated animals at 5 weeks after fracture when compared to vehicle-treated controls. Moreover, the callus tissue in diclofenac-treated aged animals exhibited a significantly reduced amount of bone tissue and higher amounts of fibrous tissue. Further histological analyses demonstrated less lamellar bone after diclofenac treatment, indicating a delay in callus remodeling. This was associated with a decreased number of osteoclasts and an increased expression of osteoprotegerin (OPG) during the early phase of fracture healing. These findings indicate that diclofenac delays fracture healing in aged mice by affecting osteogenic growth factor expression and bone formation as well as osteoclast activity and callus remodeling.
Topics: Mice; Male; Female; Animals; Diclofenac; Fracture Healing; Anti-Inflammatory Agents, Non-Steroidal; X-Ray Microtomography; Bony Callus; Femoral Fractures; Biomechanical Phenomena
PubMed: 37169100
DOI: 10.1016/j.exger.2023.112201 -
Molecules (Basel, Switzerland) Aug 2023Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) from the group of phenylacetic acid derivatives, which has analgesic, anti-inflammatory and antipyretic...
Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) from the group of phenylacetic acid derivatives, which has analgesic, anti-inflammatory and antipyretic properties. The interaction of non-steroidal anti-inflammatory drugs with cell membranes can affect their physicochemical properties, which, in turn, can cause a number of side effects in the use of these drugs. Electron paramagnetic resonance (EPR) spectroscopy could be used to study the interaction of diclofenac with a membrane, if its spin-labeled analogs existed. This paper describes the synthesis of spin-labeled diclofenac (diclofenac-SL), which consists of a simple sequence of transformations such as iodination, esterification, Sonogashira cross-coupling, oxidation and saponification. EPR spectra showed that diclofenac-SL binds to a lipid membrane composed of palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). H electron spin echo spectroscopy (ESEEM) was used to determine the position of the diclofenac-SL relative to the membrane surface. It was established that its average depth of immersion corresponds to the 5th position of the carbon atom in the lipid chain.
Topics: Diclofenac; Spin Labels; Anti-Inflammatory Agents, Non-Steroidal; Membranes; Glycerylphosphorylcholine
PubMed: 37630243
DOI: 10.3390/molecules28165991