Comprehensive Analysis of the Chemical and Bioactivity Profiles of Endemic Crataegus turcicus Dönmez in Comparison with Other Crataegus Species.

Crataegus turcicus is a plant endemic to Türkiye. For the first time, this study aimed to comparatively assess its flower-bearing branches, leaves, and fruits with other well-known Crataegus species (C. monogyna, C. pentagyna, and C. orientalis) in terms of chemical composition and bioactivity studies to evaluate its potential use as a food supplement. Firstly, the contents of total phenolics (TPC), flavonoids (TFC), proanthocyanidin (TPAC), and anthocyanin (TAC) in different plant parts of Crataegus species were evaluated. The highest TPAC was found in the hydroalcoholic extract of C. turcicus flower-bearing branches. Moreover, all plant parts had comparatively higher amounts of TPC, TFC, and TAC compared to other Crataegus species. The chemical screening by high-performance thin-layer chromatography (HPTLC) resulted that C. turcicus parts were rich with chlorogenic acid, neochlorogenic acid, quercetin and vitexin derivatives, epicatechin, procyanidin, etc., and their quantities were evaluated by high-performance liquid chromatography (HPLC). In terms of several in vitro antioxidant activity outcomes, the flower-bearing branches of C. turcicus showed the highest antioxidant activity by a 2,2-diphenyl-1-picrylhydrazyl (DPPH) test among the assessed antioxidant assays. Additionally, hydroalcoholic extracts of C. turcicus significantly decreased LPS-induced nitric oxide, tumor necrosis factor-alpha, and interleukin-6 production more potently than indomethacin (positive control). In addition to its remarkable anti-inflammatory activity, C. turcicus showed analgesic activity by reducing prostaglandin E2 levels.

Discovery of Novel Thiophene/Hydrazones: In Vitro and In Silico Studies against Pancreatic Cancer.

Cancer is the disease with the highest mortality. Drug studies contribute to promising treatments; however there is an urgent need for selective drug candidates. Pancreatic cancer is difficult to treat and the cancer progresses rapidly. Unfortunately, current treatments are ineffective. In this study, ten new diarylthiophene-2-carbohydrazide derivatives were synthesized and evaluated for their pharmacological activity. The 2D and 3D anticancer activity studies suggested the compounds 7a, 7d, and 7f were promising. Among these, 7f (4.86 µM) showed the best 2D inhibitory activity against PaCa-2 cells. Compounds 7a, 7d and 7f were also tested for their cytotoxic effects on healthy cell line but only compound 7d showed selectivity. Compounds 7a, 7d, and 7f showed the best 3D cell line inhibitory effect according to spheroid diameters. The compounds were screened for their COX-2 and 5-LOX inhibitory activity. For COX-2, the best IC50 value was observed for 7c (10.13 µM) and all compounds showed significantly lower inhibition compared to standard. In the 5-LOX inhibition study, compounds 7a (3.78 µM), 7c (2.60 µM), 7e (3.3 µM), and 7f (2.94 µM) demonstrated influential activity compared to standard. Regarding molecular docking studies, binding mode of compounds 7c, 7e, and 7f to the 5-LOX enzyme were non-redox or redox types, but not the iron-binding type. As dual inhibitors of 5-LOX and pancreatic cancer cell line, 7a and 7f were identified as the most promising compounds.

Chewable tablet with herbal extracts and propolis arrests Wuhan and Omicron variants of SARS-CoV-2 virus.

Prevention of COVID-19 is of paramount importance for public health. Some natural extracts might have the potential to suppress COVID-19 infection. Therefore, this study aimed to design a standardised, efficient, and safe chewable tablet formulation (with propolis and three herbal extracts) for possible prevention against two variants (Wuhan B.1.36 and Omicron BA.1.1) of SARS-CoV-2 virus and other viral infections. Green tea, bilberry, dried pomegranate peel, and propolis extracts were selected for this purpose. Cytotoxicity and antiviral activity of each component, as well as the developed chewable tablet, were examined against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus using Vero E6 cells with the xCELLigence real-time cell analyser-multiple plates system. Anti-inflammatory and analgesic activities, as well as mutagenicity and anti-mutagenicity of the chewable tablet were also analysed. Compared to the control, it was observed that the chewable tablet at concentrations of 110 and 55 µg/mL had antiviral activity rates of 101% and 81%, respectively, for the Wuhan variant and 112% and 35%, respectively, for the Omicron variant. The combination of herbal extracts with propolis extract were synergically more effective (∼7-fold higher) than that of individual extract. The present work suggests that a combination of herbal extracts with propolis at suitable concentrations can effectively be used as a food supplement for the prevention of both variants of the SARS-CoV-2 virus in the oral cavity (the first entry point of the SARS-CoV-2 virus).

Comprehensive estrogenic/anti-estrogenic, anticancer, mutagenic/anti-mutagenic, and genotoxic/anti-genotoxic activity studies on chemically characterized black poplar and Eurasian aspen propolis types.

Propolis is mainly composed of plant resins, and its type is named according to the primary plant origin in its composition. Identification of propolis botanical origin is essential for predicting and repeating its pharmacological activity because of the variations in chemical composition. This study aimed to compare chemical composition of black poplar (Populus nigra L.) type-propolis (PR1 and PR2) and Eurasian aspen (P. tremula L.)-type propolis (PR3) by liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique and to evaluate their biological activity profiles. According to LC-MS/MS results, in addition to marked caffeic acid phenethyl ester content in PR1 and PR2, flavonoid aglycones such as pinocembrin, chrysin, pinobanksin, and galangin were found to be dominant in these samples. On the other hand, PR3 contained relatively high concentrations of phenolic acids such as ferulic acid, p-coumaric acid, and trans-cinnamic acid. The anti-estrogenic activity test showed that PR2 exerted the highest anti-estrogenic activity by inhibiting cell proliferation by 44.6%. All propolis extracts showed anticancer activity, which was justified by decreasing activity on the 3D spheroid size in a concentration-dependent manner. Besides, all extracts showed moderate or potent antimutagenic activity in Salmonella typhimurium TA98 and TA100 strains with and without metabolic activation, respectively. In addition, the Comet assay results revealed that propolis extracts have a geno-protective effect against H2O2-induced DNA damage in CHO-K1 cells at 0.625 and 1.25 µg/mL concentrations. Overall, the result of this study may help in preparing standardized propolis extracts and developing products with defined pharmacological benefits in the food supplements industry.

The Interrelation between Oxidative Stress, Depression and Inflammation through the Kynurenine Pathway.

The prevalence of depression has increased dramatically over the past few decades. Although depression is categorized as a brain disorder, its symptomatology includes some behaviors that also occur during chronic inflammatory stress. According to research, cytokine production and immune system activation may have a role in depression, so this relationship has received much attention. Moreover, there is a bidirectional relationship between oxidative stress and inflammation. Oxidative stress plays a pathogenic role in chronic inflammatory diseases; depressive disorder is being suggested as one of them. Recent research using several oxidative stress indicators demonstrates that antioxidant defenses are diminished and oxidative stress is elevated in depression. Another cytokine- related mechanism widely known for its association with inflammatory illnesses is the kynurenine pathway (KP). KP is responsible for maintaining the balance between neuroprotective and neurogenerative processes in the brain. Therefore, KP plays a role in the pathophysiology of depression. It is thought to impact neurological processes that stem the depression, making it one of the mainstays in explaining oxidative stress-depression-inflammation interrelation. The mechanism is thought to be driven by increasing the expression of proinflammatory cytokines, IDO, and thus the KYN/TRP ratio. This review aims to evaluate the relationship between oxidative stress, depression, and inflammation through the kynurenine pathway through the current studies in the literature.

Development of propolis and essential oils containing oral/throat spray formulation against SARS-CoV-2 infection.

A broad range of evidence has confirmed that natural products and essential oils might have the potential to suppress COVID-19 infection. Therefore, this study aimed to develop an oral/throat spray formulation for prophylactic use in the oral cavity or help treatment modalities. Based on a reference survey, several essential oils, a cold-pressed oil, and propolis were selected, and cytotoxicity and antiviral activity of each component and the developed spray formulation were examined against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection using Vero E6 cells. Anti-inflammatory, antimicrobial, and analgesic activities as well as mutagenicity and anti-mutagenicity of the formulation were analysed. Forty-three phenolics were identified in both propolis extract and oral/throat spray. The spray with 1:640-fold dilution provided the highest efficacy and the cytopathic effect was delayed for 54 h at this dilution, and the antiviral activity rate was 85.3%. A combination of natural products with essential oils at the right concentrations can be used as a supplement for the prevention of SARS-CoV-2 infection.

Novel benzofurane-pyrazole derivatives with anti-inflammatory, cyclooxygenase inhibitory and cytotoxicity evaluation.

Novel benzofurane-pyrazolone hybrids have been synthesized for evaluating their anti-inflammatory and cytotoxic properties. 4-(2-chloroacetyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one were reacted with α-hydroxy aldehyde or α-hydroxy ketone derivatives to obtain nine novel pyrazolone derivatives. Structures were successfully elucidated by 1H NMR, 13C NMR, IR and HRMS. Enzyme inhibitory activity was measured on cyclooxygenases (COXs) as considered to address anti-inflammatory activity. Compound 2 showed the highest activity on both COX-1 and COX-2 subtypes with 12.0 µM and 8.0 µM IC50, respectively. This activity was found close to indomethacin COX-2 inhibition measured as 7.4 µM IC50. Rest of the compounds (1, 3-9) showed 10.4-28.1 µM IC50 on COX-2 and 17.0-35.6 µM IC50 on COX-1 (Compound 1 has no activity on COX-1). Tested compounds (1-9) showed activity on NO production. Only compound was the 4, which showed a low inhibition on IL-6 levels. Cell viability was up to 60% at 100 µM for all compounds (1-9) on RAW 264.7 and NIH3T3 cell lines, thus compounds were reported to be noncytotoxic.

Novel cyanothiouracil and cyanothiocytosine derivatives as concentration-dependent selective inhibitors of U87MG glioblastomas: Adenosine receptor binding and potent PDE4 inhibition.

Thiouracil and thiocytosine are important heterocyclic pharmacophores having pharmacological diversity. Antitumor and antiviral activity is commonly associated with thiouracil and thiocytosine derivatives, which are well known fragments for adenosine receptor affinity with many associated pharmacological properties. In this respect, 33 novel compounds have been synthesized in two groups: 24 thiouracil derivatives (4a-x) and 9 thiocytosine derivatives (5a-i). Antitumor activity of all the compounds was determined in the U87 MG glioblastoma cell line. Compound 5e showed an anti-proliferative IC50 of 1.56 µM, which is slightly higher activity than cisplatin (1.67 µM). The 11 most active compounds showed no signficant binding to adenosine A1, A2A or A2B receptors at 1 µM. Brain tumors express high amounts of phosphodiesterases. Compounds were tested for PDE4 inhibition, and 5e and 5f showed the best potency (5e: 3.42 µM; 5f: 0.97 µM). Remakably, those compounds were also the most active against U87MG. However, the compounds lacked a cytotoxic effect on the HEK293 healthy cell line, which encourages further investigation.

Anti-inflammatory, analgesic and in vivo-in vitro wound healing potential of the Phlomis rigida Labill. extract.

ETHNOPHARMACOLOGICAL RELEVANCE: The preparations of Phlomis aerial parts are used traditionally in Anatolia for wound healing and in inflammatory disorders. METHODS: For the identification of the active fraction, the air dried aerial parts of Phlomis rigida Labill. were extracted by methanol and fractionated successively by n-hexane, dichloromethane and ethyl acetate, respectively. The phenolic constituents were characterized by the Folin-Ciocaltheu method; the antioxidant activity was performed by ABTS and DPPH radical scavenging assays. In vitro anti-inflammatory activity was evaluated by LOX enzyme inhibition, spectrophotometrically as well as cell cultures. The wound healing properties of P. rigida extract gels were studied via in vitro cell culture methods and in vivo by excisional wound model using Balb-c mice. The P. rigida extract was analyzed and characterized by GC-FID, GC-MS, and LC-MS. RESULTS: The P. rigida methanol extract showed moderate LOX inhibitory at IC50 = 19.5 ± 2.8 µg/mL whereas the antioxidant activity was by DPPH• IC50 = 0.89 mg/mL, and by ABTS• IC50 = 0.99 mg/mL, respectively. In addition, a remarkable P. rigida extracts anti-inflammatory activity was observed in the cell culture assay, which was then confirmed by the in vitro wound healing activity applied at 0.125-0.5 mg/mL concentrations, resulting in a dose-dependent increase in wound closure at the final stage. The P. rigida gel formulation was prepared to evaluate the extract in vivo, whereas the experimental results of the new gel formulation supported the findings of the in vitro wound healing activity. CONCLUSION: The findings of this in vitro and in vivo study suggest that the wound healing and anti-inflammatory properties provide a scientific evidence of the ethnopharmacological application of Phlomis species.

In Vivo Wound Healing and In Vitro Anti-Inflammatory Activity Evaluation of Phlomis russeliana Extract Gel Formulations.

The air-dried aerial parts of Phlomis russeliana (Sims) Lag. Ex Benth. was extracted by methanol and fractionated by n-hexane, dichloromethane, and ethyl acetate, respectively. The wound healing properties of P. russeliana extract gel was evaluated using the in vivo excisional wound model using Balb-c mice. Initially, the P. russeliana methanol extract showed LOX inhibitory activity at IC50 = 23.2 µg/mL, whereas the DPPH• assay showed IC50 = 0.89 mg/mL, and the ABTS• assay showed IC50 = 0.99 mg/mL, respectively. In addition, a remarkable anti-inflammatory activity was observed in the cell culture assay. Thereafter, activity-guided fractionation was performed by LOX enzyme inhibition assays, and the structures of the two most active fractions were revealed by both GC-FID and GC/MS analyses, simultaneously. Phytol and 1-heptadecanoic acid were characterized as the active constituents. Moreover, the P. russeliana extract gel formulation was applied for in vivo tests, where the new gel formulation supported the in vitro anti-inflammatory activity findings. As a conclusion, this experimental results support the wound healing evidence based on the ethnobotanical application of Phlomis species with further potential.