Licochalcone A: A Potential Multitarget Drug for Alzheimer's Disease Treatment.

Licochalcone A (Lico-A) is a flavonoid compound derived from the root of the Glycyrrhiza species, a plant commonly used in traditional Chinese medicine. While the Glycyrrhiza species has shown promise in treating various diseases such as cancer, obesity, and skin diseases due to its active compounds, the investigation of Licochalcone A's effects on the central nervous system and its potential application in Alzheimer's disease (AD) treatment have garnered significant interest. Studies have reported the neuroprotective effects of Lico-A, suggesting its potential as a multitarget compound. Lico-A acts as a PTP1B inhibitor, enhancing cognitive activity through the BDNF-TrkB pathway and exhibiting inhibitory effects on microglia activation, which enables mitigation of neuroinflammation. Moreover, Lico-A inhibits c-Jun N-terminal kinase 1, a key enzyme involved in tau phosphorylation, and modulates the brain insulin receptor, which plays a role in cognitive processes. Lico-A also acts as an acetylcholinesterase inhibitor, leading to increased levels of the neurotransmitter acetylcholine (Ach) in the brain. This mechanism enhances cognitive capacity in individuals with AD. Finally, Lico-A has shown the ability to reduce amyloid plaques, a hallmark of AD, and exhibits antioxidant properties by activating the nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant defense mechanisms. In the present review, we discuss the available findings analyzing the potential of Lico-A as a neuroprotective agent. Continued research on Lico-A holds promise for the development of novel treatments for cognitive disorders and neurodegenerative diseases, including AD. Further investigations into its multitarget action and elucidation of underlying mechanisms will contribute to our understanding of its therapeutic potential.

Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder.

Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.

Antidepressants and Circadian Rhythm: Exploring Their Bidirectional Interaction for the Treatment of Depression.

Scientific evidence that circadian rhythms affect pharmacokinetics and pharmacodynamics has highlighted the importance of drug dosing-time. Circadian oscillations alter drug absorption, distribution, metabolism, and excretion (ADME) as well as intracellular signaling systems, target molecules (e.g., receptors, transporters, and enzymes), and gene transcription. Although several antidepressant drugs are clinically available, less than 50% of depressed patients respond to first-line pharmacological treatments. Chronotherapeutic approaches to enhance the effectiveness of antidepressants are not completely known. Even so, experimental results found until this day suggest a positive influence of drug dosing-time on the efficacy of depression therapy. On the other hand, antidepressants have also demonstrated to modulate circadian rhythmicity and sleep-wake cycles. This review aims to evidence the potential of chronotherapy to improve the efficacy and/or safety of antidepressants. It includes pre-clinical and clinical studies that demonstrate the relevance of determining the most appropriate time of administration for antidepressant drugs. In parallel, their positive influence on the resynchronization of disrupted circadian rhythms is also herein discussed. It is expected that this review will promote the investigation of chronotherapy for the treatment of depression, contribute to a better understanding of the relationship between antidepressants and circadian rhythms, and consequently promote the development of new therapeutics.

Peptide-lipid nanoconstructs act site-specifically towards glioblastoma growth impairment.

Ultra-small nanostructured lipid carriers (usNLCs) have been hypothesized to promote site-specific glioblastoma (GB) drug delivery. Envisioning a multitarget purpose towards tumor cells and microenvironment, a surface-bioconjugated usNLC prototype is herein presented. The comeback of co-delivery by repurposing atorvastatin and curcumin, as complementary therapy, was unveiled and characterized, considering colloidal properties, stability, and drug release behavior. Specifically, the impact of the surface modification of usNLCs with hyaluronic acid (HA) conjugates bearing the cRGDfK and H7k(R2)2 peptides, and folic acid (FA) on GB cells was sequentially evaluated, in terms of cytotoxicity, internalization, uptake mechanism and hemolytic character. As proof-of-principle, the biodistribution, tolerability, and efficacy of the nanocarriers were assessed, the latter in GB-bearing mice through magnetic resonance imaging and spectroscopy. The hierarchical modification of the usNLCs promotes a preferential targeting behavior to the brain, while simultaneously sparing the elimination by clearance organs. Moreover, usNLCs were found to be well tolerated by mice and able to impair tumor growth in an orthotopic xenograft model, whereas for mice administered with the non-encapsulated therapeutic compounds, tumor growth exceeded 181% in the same period. Relevant biomarkers extracted from metabolic spectroscopy were ultimately identified as a potential tumor signature.

Improving the drug-likeness of inspiring natural products - evaluation of the antiparasitic activity against Trypanosoma cruzi through semi-synthetic and simplified analogues of licarin A.

Neolignan licarin A (1) was isolated from leaves of Nectandra oppositifolia (Lauraceae) and displayed activity against trypomastigote forms of the etiologic agent of American trypanosomiasis, Trypanosoma cruzi. Aiming for the establishment of SAR, five different compounds (1a - 1e) were prepared and tested against T. cruzi. The 2-allyl derivative of licarin A (1d) exhibited higher activity against trypomastigotes of T. cruzi (IC50 = 5.0 µM and SI = 9.0), while its heterocyclic derivative 1e displayed IC50 of 10.5 µM and reduced toxicity against NCTC cells (SI > 19.0). However, these compounds presented limited oral bioavailability estimation (<85%, Papp <1.0 × 10-6 cm/s) in parallel artificial membrane permeability assays (PAMPA) due to excessive lipophilicity. Based on these results, different simplified structures of licarin A were designed: vanillin (2), vanillyl alcohol (3), isoeugenol (4), and eugenol (5), as well as its corresponding methyl (a), acetyl (b), O-allyl (c), and C-allyl (d) analogues. Vanillin (2) and its acetyl derivative (2b) displayed expressive activity against intracellular amastigotes of T. cruzi with IC50 values of 5.5 and 5.6 µM, respectively, and reduced toxicity against NCTC cells (CC50 > 200 µM). In addition, these simplified analogues showed a better permeability profile (Papp > 1.0 × 10-6 cm/s) on PAMPA models, resulting in improved drug-likeness. Vanillyl alcohol acetyl derivative (3b) and isoeugenol methyl derivative (4a) displayed activity against the extracellular forms of T. cruzi (trypomastigotes) with IC50 values of 5.1 and 8.8 µM respectively. Based on these results, compounds with higher selectivity index against extracellular forms of the parasite (1d, 1e, 3d, and 4a) were selected for a mechanism of action study. After a short incubation period (1 h) all compounds increased the reactive oxygen species (ROS) levels of trypomastigotes, suggesting cellular oxidative stress. The ATP levels were increased after two hours of incubation, possibly involving a high energy expenditure of the parasite to control the homeostasis. Except for compound 4a, all compounds induced hyperpolarization of mitochondrial membrane potential, demonstrating a mitochondrial imbalance. Considering the unique mitochondria apparatus of T. cruzi and the lethal alterations induced by structurally based on licarin A, these compounds are interesting hits for future drug discovery studies in Chagas disease.

Nose-to-brain Delivery of Natural Compounds for the Treatment of Central Nervous System Disorders.

BACKGROUND: Several natural compounds have demonstrated potential for the treatment of central nervous system disorders such as ischemic cerebrovascular disease, glioblastoma, neuropathic pain, neurodegenerative diseases, multiple sclerosis and migraine. This is due to their well-known antioxidant, anti-inflammatory, neuroprotective, anti-tumor, anti-ischemic and analgesic properties. Nevertheless, many of these molecules have poor aqueous solubility, low bioavailability and extensive gastrointestinal and/or hepatic first-pass metabolism, leading to a quick elimination as well as low serum and tissue concentrations. Thus, the intranasal route emerged as a viable alternative to oral or parenteral administration, by enabling a direct transport into the brain through the olfactory and trigeminal nerves. With this approach, the blood-brain barrier is circumvented and peripheral exposure is reduced, thereby minimizing possible adverse effects. OBJECTIVE: Herein, brain-targeting strategies for nose-to-brain delivery of natural compounds, including flavonoids, cannabinoids, essential oils and terpenes, will be reviewed and discussed. Brain and plasma pharmacokinetics of these molecules will be analyzed and related to their physicochemical characteristics and formulation properties. CONCLUSION: Natural compounds constitute relevant alternatives for the treatment of brain diseases but often require loading into nanocarrier systems to reach the central nervous system in sufficient concentrations. Future challenges lie in a deeper characterization of their therapeutic mechanisms and in the development of effective, safe and brain-targeted delivery systems for their intranasal administration.

Sugar-Lowering Drugs for Type 2 Diabetes Mellitus and Metabolic Syndrome-Review of Classical and New Compounds: Part-I.

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia together with disturbances in the metabolism of carbohydrates, proteins and fat, which in general results from an insulin availability and need imbalance. In a great number of patients, marketed anti-glycemic agents have shown poor effectiveness in maintaining a long-term glycemic control, thus being associated with severe adverse effects and leading to an emerging interest in natural compounds (e.g., essential oils and other secondary plant metabolites, namely, flavonoid-rich compounds) as a novel approach for prevention, management and/or treatment of either non-insulin-dependent diabetes mellitus (T2DM, type 2 DM) and/or Metabolic Syndrome (MS). In this review, some of these promising glucose-lowering agents will be comprehensively discussed.

How shall we treat locally advanced triple negative breast cancer?

Triple negative breast cancer (TNBC) has been shown to respond to neoadjuvant chemotherapy (NACT). It has been established that achieving pathological complete response (pCR) for certain aggressive subtypes of breast cancer, including HER-2 (over-expressed) and TNBC, provides an important surrogate marker for predicting long-term clinical response and survival outcomes. How to increase the number of patients that achieve pCR remains challenging. Platinum-based NACT seems to be part of the solution and capecitabine, an active drug in metastatic breast cancer, but not a standard one in earlier stages may have found its place in the adjuvant setting. In the near future immunotherapy can play a role in early TNBC.

Flavonoid compounds as reversing agents of the P-glycoprotein-mediated multidrug resistance: An in vitro evaluation with focus on antiepileptic drugs.

The pharmacoresistance to antiepileptic drugs (AEDs) remains a major unsolved therapeutic need. The overexpression of multidrug transporters, as the P-glycoprotein (P-gp), at the level of the blood-brain barrier of epileptic patients has been suggested as a key mechanism underlying the refractory epilepsy. Thus, efforts have been made to search for therapeutically useful P-gp inhibitors. Herein, the strategy of flavonoid/AED combined therapy was exploited as a possible approach to overcome the P-gp-mediated pharmacoresistance. For this purpose, several in vitro studies were performed using Madin-Darby canine kidney II (MDCK II) cells and those transfected with the human multidrug resistance-1 (MDR1) gene, overexpressing the P-gp (MDCK-MDR1). Overall, the results showed that baicalein, (-)-epigallocatechin gallate, kaempferol, quercetin and silymarin, at 200µM, produced a marked increase on the intracellular accumulation of rhodamine 123 in MDCK-MDR1 cells, potentially through inhibiting the P-gp activity. In addition, with the exception of lamotrigine, all other AEDs tested (phenytoin, carbamazepine and oxcarbazepine) and their active metabolites (carbamazepine-10,11-epoxide and licarbazepine) demonstrated to be P-gp substrates. Furthermore, the most promising flavonoids as P-gp inhibitors promoted a significant increase on the intracellular accumulation of the AEDs (excluding lamotrigine) and their active metabolites in MDCK-MDR1 cells, evidencing to be important drug candidates to reverse the AED-resistance. Thus, the co-administration of AEDs with baicalein, (-)-epigallocatechin gallate, kaempferol, quercetin and silymarin should continue to be explored as adjuvant therapy for refractory epilepsy. List of chemical compounds studied in this article: Baicalein (PubChem CID: 5,281,605); Carbamazepine (PubChem CID: 2554); Carbamazepine 10,11-epoxide (PubChem CID: 2555); (-)-Epigallocatechin gallate (PubChem CID: 65064); Kaempferol (PubChem CID: 5280863); Lamotrigine (PubChem CID: 3878); Licarbazepine (PubChem CID: 114709); Oxcarbazepine (PubChem CID: 34312); Phenytoin (PubChem CID: 1775); Silymarin (PubChem CID: 7073228); Quercetin (PubChem CID: 5280343); Verapamil (PubChem CID: 2520).

A single- and multiple-dose study to investigate the pharmacokinetics and pharmacodynamics of opicapone, a novel COMT inhibitor, in rat.

Opicapone is a novel catechol-O-methyltransferase (COMT) inhibitor that emerged to fulfil the need of a safer and more efficacious COMT inhibitor. The present study was carried out in order to assess and compare the pharmacokinetics and pharmacodynamics (COMT inhibition) of opicapone after single and multiple oral administrations (30 mg/kg) to Wistar rats. For this purpose, at predefined time points up to 72 h post-dosing, blood, liver and kidneys were collected and, then, the concentrations of opicapone and its active metabolite (BIA 9-1079) were determined in plasma and in liver and kidney tissues, as well as the erythrocyte, liver and kidney COMT activity. No systemic, renal or hepatic accumulation of opicapone was observed following repeated administration. Furthermore, the tissue-systemic exposure relationships to opicapone suggested a low drug exposure in the liver and kidneys. After single-dosing, COMT inhibition profiles were reasonably comparable in all the studied matrices; although similar results were found after multiple-dosing, a higher degree of inhibition was observed, indicating a continuous peripheral COMT inhibition when opicapone is administered once-daily. Despite having a short elimination half-life (≤2.94 h), opicapone showed a strong and long-lasting COMT inhibition in both studies, since more than 50% of the COMT activity was still inhibited at 24 h post-dosing.

P-glycoprotein Mediated Efflux Modulators of Plant Origin: A Short Review.

Drug efflux transporters such as P-glycoprotein (P-gp) help maintain cellular homeostasis but are also major contributors to the development of multidrug resistance (MDR) phenomena. Since P-gp was associated with MDR, several compounds showing potential to inhibit this transporter have been identified. Particular attention has been given to natural products, namely those of plant origin, looking for highly effective and safe P-gp inhibitors with little to no interaction with other cellular or metabolic processes. Here we abridge several examples of plant compounds from distinct classes, polyketides, lignans, anthraquinones, coumarins, alkaloids, mono- and sesqui-terpenes, steroids and limonoids, which have shown the ability to modulate in vitro or in vivo the P-gp activity.

Herb-drug pharmacokinetic interaction between carica papaya extract and amiodarone in rats.

PURPOSE: Carica papaya has been traditionally used worldwide in folk medicine to treat a wide range of ailments in humans, including the management of obesity and digestive disorders. However, scientific information about its potential to interact with conventional drugs is lacking. Thus, this work aimed to investigate the interference of a standardized C. papaya extract (GMP certificate) on the systemic exposure to amiodarone (a narrow therapeutic index drug) in rats. METHODS: In the first pharmacokinetic study, rats were simultaneously co-administered with a single-dose of C. papaya (1230 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.); in the second study, rats were pre-treated for 14 days with C. papaya (1230 mg/kg/day, p.o.) and received amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the herbal extract vehicle. Blood samples were collected before dosing and at 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h following amiodarone administration; in addition, at 24 h post-dose, blood and tissues (heart, liver, kidneys and lungs) were also harvested. Thereafter, the concentrations of amiodarone and its major metabolite (mono-N-desethylamiodarone) were determined in plasma and tissue samples employing a high-performance liquid chromatography-diode array detection method previously developed and validated. RESULTS: In both studies was observed a delay in attaining the maximum plasma concentrations of amiodarone (tmax) in the rats treated with the extract. Nevertheless, it must be highlighted the marked increase (60-70%) of the extent of amiodarone systemic exposure (as assessed by AUC0-t and AUC0-∞) in the rats pre-treated with C. papaya comparatively with the control (vehicle) group. CONCLUSIONS: The results herein found suggest an herb-drug interaction between C. papaya extract and amiodarone, which clearly increase the drug bioavailability. To reliably assess the clinical impact of these findings appropriate human studies should be conducted.

Evaluation of the permeability and P-glycoprotein efflux of carbamazepine and several derivatives across mouse small intestine by the Ussing chamber technique.

PURPOSE: The rational discovery and development of new antiepileptic drugs (AEDs) with safer therapeutic index and better pharmacokinetic properties is still warranted nowadays. Because the long-term management of epilepsy is attained by means of orally administered AEDs, investigation of their potential to be well absorbed at the intestinal level is mandatory. Moreover, involvement of the efflux transport mediated by P-glycoprotein (P-gp) may compromise the systemic and central nervous system disposition of AEDs. Therefore, this study aimed at characterizing mouse jejunal passive transport and the possible active efflux mediated by P-gp of a series of dibenz[b,f]azepine-5-carboxamide derivatives (carbamazepine [CBZ], oxcarbazepine [OXC], S-licarbazepine [S-Lic], R-licarbazepine [R-Lic], carbamazepine-10,11-epoxide [CBZ-E], 10,11-trans-dihydroxy-10,11-dihydro-carbamazepine [trans-diol], and BIA 2-024), which comprise some AEDs and metabolites. METHODS: Permeation studies were performed with freshly excised mouse jejunum segments mounted in Ussing chambers. Absorptive (M-S) and secretive (S-M) transports were analyzed with and without verapamil, which is a P-gp inhibitor widely recognized. Apparent permeability coefficients (P(app) ) in both directions and in absence or presence of verapamil were determined for each test compound. The in vitro method was validated using five controls that included high and low permeable markers with known absorption fraction (Fa) and also well-known P-gp substrates. The integrity of intestinal membrane was guaranteed during the assay by measuring the transepithelial electrical resistance. KEY FINDINGS: The correlation obtained between P(app) (M-S) and Fa of references was high (r(2) = 0.9945), and could be used to classify the derivatives according to Biopharmaceutical Classification System: CBZ and OXC were the only classified as highly permeable. The P(app) (S-M) of OXC, CBZ-E, R-Lic, and BIA 2-024 were significantly higher than their P(app) (M-S). After verapamil addition, their P(app) (S-M) lowered while P(app) (S-M) increased, suggesting the involvement of P-gp on the transport of those compounds across mouse jejunum segments. In opposition, CBZ, S-Lic, and trans-diol presented no statistical differences between the P(app) values reported in both directions, with or without verapamil. The results reported herein suggest that differences in biodisposition of S-Lic and R-Lic might result from their distinct interaction with P-gp. SIGNIFICANCE: The Ussing chamber model used herein showed to be useful for predicting Fa of AEDs and the involvement of efflux transport, namely P-gp, on their absorption. This is an important achievement as compounds that are not transported by P-gp may offer advantages when used in patients with pharmacoresistant epilepsy.

Avaliação de radio e quimioterapia concomitantes pós-operatórias nos pacientes portadores de tumores de cabeça e pescoço localmente avançados / Postoperative concurrent radio-chemotherapy for locally advanced head and neck cancer

OBJETIVO: Avaliar a evolução clínica e as complicações agudas e tardias de pacientes portadores de neoplasia de cabeça e pescoço localmente avançada submetidos a cirurgia com radio e quimioterapiaadjuvantes. MATERIAL E MÉTODO: No período de maio de 2004 a junho de 2007 foram analisados 39 pacientes com neoplasia de cabeça e pescoço localmente avançada submetidos a ressecção cirúrgica, radio e quimioterapia adjuvantes. RESULTADOS: A idade mediana foi de 54 anos. Estádio III foi observado em 30,8% e estádio IVA em 61,5% dos pacientes. Setenta e sete por cento dos pacientes realizaram radioterapia com dose de 66 Gy. Em relação às complicações agudas,a mais prevalente foi dermatite grau III em 46,2%, e 48,7% dos pacientes apresentaram fibrosecomo complicação tardia. O seguimento mediano foi de 30 meses, com estimativa de sobrevidalivre de doença locorregional de 70% e sobrevida global de 76% em cinco anos. CONCLUSÃO: Esteestudo mostra que, em pacientes com neoplasia de cabeça e pescoço localmente avançada, a cirurgia seguida de radio e quimioterapia apresentam resultados de controle locorregional e sobrevida livre de doença satisfatórios. Nossos resultados, bem como porcentagens de complicações agudas e tardias, estão compatíveis com a literatura.

OBJECTIVE: To evaluate the clinical outcome of patients with locallyadvanced head and neck cancer treated with postoperative concurrent radio-chemotherapy. MATERIAL AND METHOD: Thirtynine patients with locally advanced head and neck cancer submittedto resection of all visible and palpable disease, followed byradiotherapy (60–66 Gy in 30 to 33 fractions over a period of 6 to6.6 weeks) and concurrent cisplatin between May 2004 and June2007 were retrospectively analyzed. RESULTS: A predominance of male with a median age of 54 years was observed; 30.8% of patients were in stage III and 61.5% in stage IVA; 77% of patients received a radiation dose of 66 Gy; dermatitis grade III occurred in 46.2% and fibrosis in 48.7% of patients. The 5-year loco-regional failure and overall survival were 30% and 76%, respectively. CONCLUSION: Data show that surgery followed by concurrent radio-chemotherapypresents reasonable rate of loco-regional control and disease-free survival in high-risk patients. Our index of loco-regionaland distant failure and the rate of acute and late complicationare compatible with other series in the literature.