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The FEBS Journal May 2024Cancer cells exhibit a unique metabolic preference for the glycolytic pathway over oxidative phosphorylation for maintaining the tumor microenvironment. Lactate...
Cancer cells exhibit a unique metabolic preference for the glycolytic pathway over oxidative phosphorylation for maintaining the tumor microenvironment. Lactate dehydrogenase A (LDHA) is a key enzyme that facilitates glycolysis by converting pyruvate to lactate and has been shown to be upregulated in multiple cancers due to the hypoxic tumor microenvironment. Diclofenac (DCF), a nonsteroidal anti-inflammatory drug, has been shown to exhibit anticancer effects by interfering with the glucose metabolism pathway. However, the specific targets of this drug remain unknown. Using in silico, biochemical, and biophysical studies, we show that DCF binds to LDHA adjacent to the substrate binding site and inhibits its activity in a dose-dependent and allosteric manner in HeLa cells. Thus, DCF inhibits the hypoxic microenvironment and induces apoptosis-mediated cell death. DCF failed to induce cytotoxicity in HeLa cells when LDHA was knocked down, confirming that DCF exerts its antimitotic effects via LDHA inhibition. DCF-induced LDHA inhibition alters pyruvate, lactate, NAD, and ATP production in cells, and this could be a possible mechanism through which DCF inhibits glucose uptake in cancer cells. DCF-induced ATP deprivation leads to mitochondria-mediated oxidative stress, which results in DNA damage, lipid peroxidation, and apoptosis-mediated cell death. Reduction in intracellular ATP levels additionally activates the sensor kinase, adenosine monophosphate-activated protein kinase (AMPK), which further downregulates phosphorylated ribosomal S6 kinase (p-S6K), leading to apoptosis-mediated cell death. We find that in LDHA knocked down cells, intracellular ATP levels were depleted, resulting in the inhibition of p-S6K, suggesting the involvement of DCF-induced LDHA inhibition in the activation of the AMPK/S6K signaling pathway.
PubMed: 38767406
DOI: 10.1111/febs.17158 -
Nanoscale Jun 2024A BiO/COF composite was successfully synthesized by simple mechanical ball milling. Compared to pure BiO and COFs, the BiO/COF composite (1 : 9) showed superior...
A BiO/COF composite was successfully synthesized by simple mechanical ball milling. Compared to pure BiO and COFs, the BiO/COF composite (1 : 9) showed superior photocatalytic capability. Under visible light irradiation for 90 min, the photocatalytic degradation rate of DCF reached 97%. In addition, the characterization results showed that the formation of heterojunctions and the increase in oxygen vacancy concentration were the reasons for the enhancement of the photocatalytic activity. It is confirmed by free radical capture experiments that ˙O and h are the main reactive substances in the photocatalytic process. The photocatalytic degradation mechanism of the composite and the photocatalytic degradation pathway of diclofenac were deduced.
PubMed: 38766844
DOI: 10.1039/d4nr00608a -
Inflammopharmacology May 2024Small intestine damage caused by diclofenac is called diclofenac enteropathy. Berberine (BBR), a class of isoquinoline alkaloids derived from Berberis vulgaris and...
Small intestine damage caused by diclofenac is called diclofenac enteropathy. Berberine (BBR), a class of isoquinoline alkaloids derived from Berberis vulgaris and Phellodendron amurense, is widely used in intestinal diseases. The present study evaluated the protective effect of BBR on the intestinal mucosal mechanical barrier in diclofenac enteropathy and its possible action mechanism. The in vitro animal experiment revealed that BBR downregulated the expression of long non-coding RNA H19 (lncRNA H19) in the small intestine and exosomes. In the co-culture experiment involving exosomes and intestinal epithelial cell-6 (IEC-6) cells, the results of qRT-PCR, western blotting, and immunofluorescence assays demonstrated that the elevated expression of lncRNA H19 in the small intestine, conveyed via exosomes derived from the diclofenac group, suppressed the expression levels of autophagy-associated protein 5 (Atg 5) and light chain 3 (LC 3), as well as and the tight junction (TJ) proteins zonula occludens-1 (ZO-1), claudin-1, and occluding, relative to the control group. BBR treatment attenuated exosomal lncRNA H19 levels, upregulated the expression of Atg5 and LC3 expression, enhanced TJ protein expression, and increased the light chain 3 (LC3)-II/LC3-I ratio. These findings significantly elucidated that BBR promoted the restoration of autophagy in IECs by inhibiting exosomal lncRNA H19, thereby mitigating the impairment of the intestinal mucosal mechanical barrier function in diclofenac enteropathy. The process involving exosomal lncRNA H19 regulating autophagy, thereby affecting the intestinal mucosal mechanical barrier, offers a novel perspective for the application of BBR in the treatment of diclofenac enteropathy.
PubMed: 38758516
DOI: 10.1007/s10787-024-01487-y -
RSC Advances May 2024Numerous pollutants endanger the safety and purity of water, making water pollution a major worldwide concern. The health of people and aquatic ecosystems are at risk...
Numerous pollutants endanger the safety and purity of water, making water pollution a major worldwide concern. The health of people and aquatic ecosystems are at risk from these contaminants, which include hazardous microbes, industrial waste, and agricultural runoff. Fortunately, there appears to be a viable option to address this problem with adsorptive water treatment techniques. The present study presents a magnetic adsorbent (MMIP) based on molecularly imprinted polyaniline and magnetite nanoparticles for the solid-phase extraction of diclofenac, an anti-inflammatory medication, from industrial wastewater. The adsorbent nanomaterial was characterized using dynamic light scattering, zeta potential measurement, vibrating sample magnetometry, X-ray diffraction, and scanning electron microscopy. The MMIP demonstrated a particle size of 86.3 nm and an adsorption capacity of 139.7 mg g at 600 mg L of diclofenac and after a 200 min incubation period. The highest %removal was attained at pH range of 3-7. The adsorption process follows the pseudo-second order kinetic model. In addition, it was found that the adsorption process is enthalpy-driven and may occur hydrogen bonding and/or van der Waals interactions.
PubMed: 38756847
DOI: 10.1039/d4ra02529f -
Chemical Science May 2024Developing tunable materials which exhibit sustained drug release is a considerable challenge. Herein, we report the concept of Therapeutic Coordination Polymers (TCPs);...
Developing tunable materials which exhibit sustained drug release is a considerable challenge. Herein, we report the concept of Therapeutic Coordination Polymers (TCPs); non-porous coordination polymers constructed from biocompatible components which demonstrate tunable zero-order drug release kinetics upon degradation of metal-ligand bonds. TCPs were constructed from three principal components: (i) a cationic metal center (M = Mg, Mn, Zn, or Cu); (ii) an anionic drug (Diclofenac); and (iii) an alkyl bis-imidazole organic ligand which behaves as a "linker" between metal centers. Most drug-release materials, such as amorphous polymer dispersions, or metal-organic frameworks rely on a diffusion-based mechanism for drug release, but the degradation-controlled release of drugs from non-porous one-periodic coordination polymers has been largely unexplored. TCPs described herein exhibit a high wt% of pharmaceutical (>62%), tailorable zero-order drug release rate kinetics which span over three orders of magnitude, and stimuli-responsive drug release behavior making them well suited for extended drug-release applications.
PubMed: 38756811
DOI: 10.1039/d4sc00732h -
Environmental Science and Pollution... May 2024Contaminations by pharmaceuticals, personal care products, and other emerging pollutants in water resources have become a seriously burgeoning issue of global concern in...
Contaminations by pharmaceuticals, personal care products, and other emerging pollutants in water resources have become a seriously burgeoning issue of global concern in the first third of the twenty-first century. As societal reliance on pharmaceuticals continues to escalate, the inadvertent introduction of these substances into water reservoirs poses a consequential environmental threat. Therefore, the aim of this study was to investigate reductive degradation, particularly, catalytic hydrogenation regarding model pollutants such as diclofenac (DCF), ibuprofen (IBP), 17α-ethinylestradiol (EE2), or bisphenol-A (BPA), respectively, in aqueous solutions at lab scale. Iron bimetals (zero valent iron, ZVI, and copper, Cu, or nickel, Ni) as well as zero valent magnesium (Mg, ZVM) in combination with rhodium, Rh, or palladium, Pd, as hydrogenation catalysts (HK), were investigated. Studies were executed through various short-term batch experiments, with multiple sample collections, over a total range of 120 min. The results indicated that DCF was attenuated at over 90 % when exposed to Fe-Cu or a Fe-Ni bimetal (applied as a single model pollutant). However, when DCF was part of a mixture alongside with IBP, EE2, and BPA, the attenuation efficacy decreased to 79 % with Fe-Cu and 23 % with Fe-Ni. Conversely, both IBP and BPA exhibit notably low attenuation levels with both bimetals, less than 50 %, both deployed as single substances or in mixtures. No reaction (degradation) products could be identified employing LC-MS, but sometimes a release of the parent pollutant when applying an acetic acid buffer could be noted to a certain extent, suggesting adsorption processes on corrosion products such as iron hydroxide and/or oxides. Surprisingly, Mg in combination with Rh (Rh-HK) or Pd (Pd-HK) showed a significantly rapid decrease in the concentrations of DCF, EE2, and BPA, in part up to approximately 100 %, that is, within a few minutes only in part due to hydrogenation degradation reactions (related reaction products could actually be identified by LC-MS; adsorption processes were not observed here). Moreover, kinetic modeling of the DCF degradation with Mg-Rh-HK was conducted at different temperatures (15 °C, 20 °C, 25 °C, 35 °C) and varied initial concentrations (2.5 mg/L, 5.0 mg/L, 7.5 mg/L, 10.0 mg/L). The outcomes prove that the degradation of DCF at the Rh-HK's surface followed a modified first-order kinetics, most probably by catalytic hydrodehalogenation and subsequent hydrogenation of the aromatic moieties (molecular hydrogen was provided by the corrosion of Mg). From the determined reaction rate constants at four different temperatures, the activation energy was estimated to be 59.6 kJ/mol by means of the Arrhenius equation what is in good agreement with similar results reported in the literature. This coupled hydrodehalogenation and hydrogenation approach may be upscaled into a new promising technical process for comprehensively removing such pharmaceuticals and similar pollutants in sewage plants in a single step, furthermore, even in combination with adsorption by activated carbon and/or ozonation which have already been established at some sewage plants in Switzerland and Germany recently.
Topics: Water Pollutants, Chemical; Catalysis; Pharmaceutical Preparations; Magnesium; Hydrogen; Benzhydryl Compounds; Metals; Phenols
PubMed: 38744765
DOI: 10.1007/s11356-024-32777-1 -
Turkish Journal of Pharmaceutical... May 2024The iatrogenic triad is a significant global health problem in the elderly population. This study aimed to evaluate the iatrogenic triad in the elderly and identify...
OBJECTIVES
The iatrogenic triad is a significant global health problem in the elderly population. This study aimed to evaluate the iatrogenic triad in the elderly and identify potential preventive measures to mitigate its occurrence.
MATERIALS AND METHODS
A preliminary observational study was conducted on 150 ambulatory elderly patients to assess potentially inappropriate medications (PIMs), polypharmacy, and drug interactions. The AGS Beers Criteria 2019, Polypharmacy, Medication Complexity Regimen Index (MRCI), and Micromedex (a drug information software) were used to assess the harmful triad. Before and after data collection, we observed, identified, and unfolded potential strategies to avoid the harmful triad in the elderly population.
RESULTS
MRCI is 30.49 ± 13.77, suggesting a moderate level of complexity in the drug regimens of elderly patients. Among the PIMs identified by the AGS Beer criteria for 2019, glimepiride (45) and diclofenac (23) were found to be the most frequently prescribed. Moderate-level drug-drug interactions were identified between aspirin and metoprolol (20), metoprolol and metformin (13), and aspirin and enalapril (11). All drug-ethanol and drug-food interactions were rapid and often unknown to patients. Furthermore, the study found that MRCI and polypharmacy were significantly associated with the number of PIMs and drug interactions ( < 0.01). Based on data collection, this study identified three possible ways to prevent the iatrogenic triad in elderly patients: interaction, collaboration, and continuing education.
CONCLUSION
In conclusion, this study sheds light on medication regimen complexity, PIMs, and drug interactions in elderly patients. The study also highlights three possible ways to prevent the iatrogenic triad: interaction, collaboration, and continuing education. By implementing these strategies, healthcare providers can help prevent harm and improve the quality of care for elderly patients.
PubMed: 38742853
DOI: 10.4274/tjps.galenos.2023.89457 -
Analytical Methods : Advancing Methods... May 2024The non-steroidal anti-inflammatory drug (NSAID) diclofenac (DCF) is an important environmental contaminant occurring in surface waters all over the world, because,...
The non-steroidal anti-inflammatory drug (NSAID) diclofenac (DCF) is an important environmental contaminant occurring in surface waters all over the world, because, after excretion, it is not adequately removed from wastewater in sewage treatment plants. To be able to monitor this pollutant, highly efficient analytical methods are needed, including immunoassays. In a medical research project, monoclonal antibodies against diclofenac and its metabolites had been produced. Based on this monoclonal anti-DCF antibody, a new indirect competitive enzyme-linked immunosorbent assay (ELISA) was developed and applied for environmental samples. The introduction of a spacer between diclofenac and the carrier protein in the coating conjugate led to higher sensitivity. With a test midpoint of 3 μg L and a measurement range of 1-30 μg L, the system is not sensitive enough for direct analysis of surface water. However, this assay is quite robust against matrix influences and can be used for wastewater. Without adjustment of the calibration, organic solvents up to 5%, natural organic matter (NOM) up to 10 mg L, humic acids up to 2.5 mg L, and salt concentrations up to 6 g L NaCl and 75 mg L CaCl are tolerated. The antibody is also stable in a pH range from 3 to 12. Cross-reactivity (CR) of 1% or less was determined for the metabolites 4'-hydroxydiclofenac (4'-OH-DCF), 5-hydroxydiclofenac (5-OH-DCF), DCF lactam, and other NSAIDs. Relevant cross-reactivity occurred only with an amide derivative of DCF, 6-aminohexanoic acid (DCF-Ahx), aceclofenac (ACF) and DCF methyl ester (DCF-Me) with 150%, 61% and 44%, respectively. These substances, however, have not been found in samples. Only DCF-acyl glucuronide with a cross-reactivity of 57% is of some relevance. For the first time, photodegradation products were tested for cross-reactivity. With the ELISA based on this antibody, water samples were analysed. In sewage treatment plant effluents, concentrations in the range of 1.9-5.2 μg L were determined directly, with recoveries compared to HPLC-MS/MS averaging 136%. Concentrations in lakes ranged from 3 to 4.4 ng L and were, after pre-concentration, determined with an average recovery of 100%.
Topics: Diclofenac; Antibodies, Monoclonal; Water Pollutants, Chemical; Enzyme-Linked Immunosorbent Assay; Anti-Inflammatory Agents, Non-Steroidal; Environmental Monitoring; Wastewater
PubMed: 38742423
DOI: 10.1039/d3ay01333b -
BMC Public Health May 2024Unused pharmaceuticals are currently a public health problem. This study aimed to identify unused pharmaceuticals, research practices about the disposal methods,...
BACKGROUND
Unused pharmaceuticals are currently a public health problem. This study aimed to identify unused pharmaceuticals, research practices about the disposal methods, classify the medicines according to Anatomical Therapeutic Chemical codes (ATC) and, to determine the number of unused medicines.
METHODS
The study was designed as a cross-sectional study. Data were collected between April and August 2023 in Burdur-Türkiye by non-probability sampling technique (convenience method). Pharmaceuticals were classified according to ATC. Statistical Package for Social Science SPSS (V.24) package program was used for data analysis.
RESULTS
A total of 1120 people, 1005 in the first sample group and 115 in the second sample group, participated in the study. Findings of first sample group: A total of 4097 boxes of unused pharmaceuticals (4.7 ± 4.3 boxes/per capita) were detected. It was found that pharmaceuticals were stored in areas such as kitchens (59.1%) and refrigerators (38.6%), the reason for keeping them was reuse (41%), and the disposal practice was household garbage (81%). Paracetamol (648 boxes), Other cold preparation (303 boxes), Dexketoprofen (239 boxes), Diclofenac (218 boxes), Amoxicillin and beta-lactamase inhibitor (190 boxes) were found to be the most frequently unused pharmaceuticals. Using the unused medicines at home without consulting a physician was 94.1% (self-medication). Findings of second sample group: Of the 6189 dosage forms in 265 boxes pharmaceutical, 3132(50.6%) dosage forms were used and 3057(49.4%) were found to be unused.
CONCLUSION
There is a significant amount and number of unused medicines in households, and self-medication is common. Medicines are not properly disposed of and some of them expire. Public information is needed. A "drug take-back system" for unused medicines can be useful in solving this problem.
Topics: Cross-Sectional Studies; Humans; Adult; Pharmaceutical Preparations; Female; Male; Middle Aged; Turkey; Young Adult; Refuse Disposal; Adolescent; Drug Storage
PubMed: 38741105
DOI: 10.1186/s12889-024-18788-0 -
Journal of Hazardous Materials Jul 2024The capacity for organic micropollutant removal in granular activated carbon (GAC) filters for wastewater treatment changes over time. These changes are in general...
The capacity for organic micropollutant removal in granular activated carbon (GAC) filters for wastewater treatment changes over time. These changes are in general attributed to changes in adsorption, but may in some cases also be affected by biological degradation. Knowledge on the degradation of organic micropollutants, however, is scarce. In this work, the degradation of micropollutants in several full-scale GAC and sand filters was investigated through incubation experiments over a period of three years, using C-labeled organic micropollutants with different susceptibilities to biological degradation (ibuprofen, diclofenac, and carbamazepine), with parallel 16S rRNA gene sequencing. The results showed that the degradation of diclofenac and ibuprofen in GAC filters increased with increasing numbers of bed volumes when free oxygen was available in the filter, while variations over filter depth were limited. Despite relatively large differences in bacterial composition between filters, a degradation of diclofenac was consistently observed for the GAC filters that had been operated with high influent oxygen concentration (DO >8 mg/L). The results of this comprehensive experimental work provide an increased understanding of the interactions between microbial composition, filter material, and oxygen availability in the biological degradation of organic micropollutants in GAC filters.
Topics: Diclofenac; Water Pollutants, Chemical; Ibuprofen; Filtration; Biodegradation, Environmental; Carbamazepine; Charcoal; Bacteria; RNA, Ribosomal, 16S; Oxygen; Waste Disposal, Fluid; Water Purification
PubMed: 38733780
DOI: 10.1016/j.jhazmat.2024.134449