Overcoming the limited bioavailability and extensive metabolism of effective in vitro drugs remains a challenge that limits the translation of promising drugs into clinical trials. Resveratrol, despite its well-reported therapeutic benefits, is not metabolically stable and thus has not been utilized as an effective clinical drug. This is because it needs to be consumed in large amounts to overcome the burdens of bioavailability and conversion into less effective metabolites. Herein, we summarize the more relevant approaches to modify resveratrol, aiming to increase its biological and therapeutic efficacy. We discuss combination therapies, derivatization, and the use of resveratrol nanoparticles. Interestingly, the combination of resveratrol with established chemotherapeutic drugs has shown promising therapeutic effects on colon cancer (with oxaliplatin), liver cancer (with cisplatin, 5-FU), and gastric cancer (with doxorubicin). On the other hand, derivatizing resveratrol, including hydroxylation, amination, amidation, imidation, methoxylation, prenylation, halogenation, glycosylation, and oligomerization, differentially modifies its bioavailability and could be used for preferential therapeutic outcomes. Moreover, the encapsulation of resveratrol allows its trapping within different forms of shells for targeted therapy. Depending on the nanoparticle used, it can enhance its solubility and absorption, increasing its bioavailability and efficacy. These include polymers, metals, solid lipids, and other nanoparticles that have shown promising preclinical results, adding more “hype” to the research on resveratrol. This review provides a platform to compare the different approaches to allow directed research into better treatment options with resveratrol.

Benzofuran and 2,3-dihydrobenzofuran scaffolds are heterocycles of high value in medicinal chemistry and drug synthesis. Targeting inflammation in cancer associated with chronic inflammation is a promising therapy. In the present study, we investigated the anti-inflammatory effects of fluorinated benzofuran and dihydrobenzofuran derivatives in macrophages and in the air pouch model of inflammation, as well as their anticancer effects in the human colorectal adenocarcinoma cell line HCT116. Six of the nine compounds suppressed lipopolysaccharide-stimulated inflammation by inhibiting the expression of cyclooxygenase-2 and nitric oxide synthase 2 and decreased the secretion of the tested inflammatory mediators. Their IC₅₀ values ranged from 1.2 to 9.04 µM for interleukin-6; from 1.5 to 19.3 µM for Chemokine (C-C) Ligand 2; from 2.4 to 5.2 µM for nitric oxide; and from 1.1 to 20.5 µM for prostaglandin E₂. Three novel synthesized benzofuran compounds significantly inhibited cyclooxygenase activity. Most of these compounds showed anti-inflammatory effects in the zymosan-induced air pouch model. Because inflammation may lead to tumorigenesis, we tested the effects of these compounds on the proliferation and apoptosis of HCT116. Two compounds with difluorine, bromine, and ester or carboxylic acid groups inhibited the proliferation by approximately 70%. Inhibition of the expression of the antiapoptotic protein Bcl-2 and concentration-dependent cleavage of PARP-1, as well as DNA fragmentation by approximately 80%, were described. Analysis of the structure–activity relationship suggested that the biological effects of benzofuran derivatives are enhanced in the presence of fluorine, bromine, hydroxyl, and/or carboxyl groups. In conclusion, the designed fluorinated benzofuran and dihydrobenzofuran derivatives are efficient anti-inflammatory agents, with a promising anticancer effect and a combinatory treatment in inflammation and tumorigenesis in cancer microenvironments.

Low-dose aspirin irreversibly acetylates cyclooxygenase (COX)-1 in anucleate platelets and progenitor megakaryocytes, permanently suppressing thromboxane (TX)A₂-dependent platelet activation. Although aspirin pharmacodynamics is well characterized in platelets, the kinetics of COX inhibition and recovery in human megakaryocytes remains poorly defined, due to ethical issues associated with invasive, bone-marrow trephine sampling, and low megakaryocyte yield. We studied aspirin pharmacodynamics in human megakaryocytic cell lines as a reliable and feasible surrogate model. We characterized COX-1 and COX-2 expression and activity in MEG-01 and CHRF-288-11 megakaryocytic cell lines, treated with a range of aspirin concentrations and exposure duration. COX activity was quantified by the production of TXB₂ from exogenous arachidonic acid. A single 10-μM aspirin exposure suppressed TXB₂ by 90 ± 2% (MEG-01) and 85 ± 4% (CHRF-288-11), with full recovery within 48-72 hours. Both COX-isozymes were detected by western blot and immunohistochemistry; however, selective COX-1 inhibition by SC-560 reduced TXB₂ by >75%, whereas COX-2 inhibition by NS-398 had minimal effect. Repeated aspirin exposure every 24 hours produced concentration- and time-dependent TXB₂ suppression, achieving 89 ± 2% inhibition by day 2 at 1 μM and 73 ± 3% by day 4 at 0.1 μM. TXB₂ biosynthesis recovered by 86 ± 2% and 99 ± 10% at days 2 and 3, respectively. These findings identify COX-1 as the principal source of TXA₂ in megakaryocytes and demonstrate that aspirin inhibits megakaryocyte COX-1 time- and dose-dependently, with delayed recovery likely reflecting de novo synthesis of COX-1 protein, thereby providing mechanistic insight into the sustained antiplatelet effect of low-dose aspirin in humans. SIGNIFICANCE STATEMENT: In human megakaryocyte cell lines, once-daily aspirin treatment at low-concentration range time-dependently inhibits COX-1 with delayed recovery after aspirin withdrawal. This closely mimics the kinetics of platelets, supporting the translational utility of the megakaryocyte-based surrogate model.

This study investigated the anti-inflammatory effects of Micromeria Barbata (MB) and 3-O-acetyl-11-keto-β-boswellic acid (AKBA) in human PBMCs and THP-1 cells following stimulation with advanced glycation end products (AGEs). Cytotoxicity of MB, AKBA, and AGE-BSA was evaluated using MTT assays. Subsequently, RT-PCR was employed to quantify cytokine responses and assess how MB and AKBA modulated IL-6, TNF-α, and IL-1β expression in PBMCs and THP-1 cells. MTT assays confirmed that MB (5–40 µg/mL), AKBA (0.01–0.5 µg/mL), and AGE-BSA (10–100 µg/mL) were non-toxic under 24–48 hours exposure. AGE-BSA (10 µg/mL) significantly increased cytokine expression in PBMCs (IL-6, IL-1β, TNF-α: 115-, 11.7-, 0.7-fold) and THP-1 cells (325-, 11-, 7.3-fold). Pretreatment with MB or AKBA mitigated this inflammatory response in a dose-dependent manner. MB (40 µg/mL) reduced IL-6, IL-1β, and TNF-α to 0.2, 0.19, and 0.3-fold, whereas AKBA (0.3 µg/mL) resulted in 0.7, 0.6, and 0.46-fold. The study revealed that both MB and AKBA pretreatment reduced inflammatory responses in a dose-response manner to AGE-BSA in PBMC and THP-1 cells. This study offers new insights into treating AGE-induced complications and highlights potential in treating diabetes.