Advances in Pharmacological Sciences最新文献

Depression is currently recognized as a crucial problem in everyday clinical practice, in light of ever-increasing rates of prevalence, as well as disability, morbidity, and mortality related to this disorder. Currently available antidepressant drugs are notoriously problematic, with suboptimal remission rates and troubling side-effect profiles. Their mechanisms of action focus on the monoamine hypothesis for depression, which centers on the disruption of serotonergic, noradrenergic, and dopaminergic neurotransmission in the brain. Nevertheless, views on the pathophysiology of depression have evolved notably, and the comprehension of depression as a complex neuroendocrine disorder with important systemic implications has sparked interest in a myriad of novel neuropsychopharmacological approaches. Innovative pharmacological targets beyond monoamines include glutamatergic and GABAergic neurotransmission, brain-derived neurotrophic factor, various endocrine axes, as well as several neurosteroids, neuropeptides, opioids, endocannabinoids and endovanilloids. This review summarizes current knowledge on these pharmacological targets and their potential utility in the clinical management of depression.

Different solvent extracts of Pereskia bleo leaves were evaluated for total phenolic content (TPC) and antioxidant activities based on the Folin-Ciocalteu test and DPPH scavenging activities. The antibacterial activities against four bacteria, namely, Gram-positive bacteria: Streptococcus pyogenes ATCC 19615 (SP) and Staphylococcus aureus ATCC 29737 (SA) and Gram-negative bacteria: Escherichia coli ATCC 10536 (EC) and Pseudomonas aeruginosa ATCC 9027 (PA), were also performed based on the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays. The findings demonstrated that both the methanolic and chloroform extracts displayed strong activities against SA, SP, EC, and PA while the hexane extract demonstrated the weakest activities towards all the four bacteria. The methanolic extract also exhibited higher TPC and possessed higher antioxidant activity with the IC₅₀ value 33.83 µg/mL compared to the chloroform and hexane extracts. As such, the methanolic extract has a higher ability to scavenge free radical compared to other extracts. Due to the interesting result, activities are shown by the methanolic and chloroform crude extracts of P. bleo; hence, the study has been extended to the isolation of bioactive compounds to uncover its great potential as a natural source for antibacterial and antioxidant agents.

Background: Higher levels of parathyroid hormone have been associated with the use of tenofovir disoproxil fumarate (TDF) in people with and without HIV infection. Yet, alterations in calcium levels have never been elucidated in detail.

Objective: To compare the association of parathyroid hormone with serum calcium levels and other markers of calcium and bone metabolism in people living with HIV on TDF- and non-TDF-containing antiretroviral therapy.

Patients and methods: A retrospective single center cohort study in Munich, Germany. Median and interquartile ranges and absolute and relative frequencies were used to describe continuous and categorical variables, respectively. The Mann-Whitney U test and chi²-test were used for comparisons. Multivariate median regression was performed in a stepwise backward approach.

Results: 1,002 patients were included (786 (78.4%) male; median age 48 (40-55) years). 564 patients (56.3%) had a TDF-containing ART regimen. PTH concentrations were 46.9 (33.0-64.7) pg/mL and 35.2 (26.4-55.4) pg/mL (P=0.001), 43.3 (30.8-59.8) pg/mL and 31.8 (22.3-49.6) pg/mL (P < 0.001), 46.1 (29.5-65.4) pg/mL and 33.4 (22.6-50.1) pg/mL (P < 0.001), and 37.8 (25.3-57.9) pg/mL and 33.8 (20.1-45.3) pg/mL (P=0.012) within the first, second, third, and fourth quartile of corrected calcium levels for patients with and without TDF-containing ART, respectively. In multivariate median regression, PTH concentration was significantly associated with Ca_corr. (-32.2 (-49.8 to -14.8); P < 0.001), female sex (5.2 (1.2-9.2); P=0.010), 25(OH)D (-0.4 (-0.5 to -0.3); P < 0.001), and TDF-use (9.2 (6.0-12.5); P < 0.001).

Discussion: Higher levels of PTH seem to be needed to maintain normal calcium levels in PLWH on TDF-containing ART compared to non-TDF-containing ART. Optimal concentrations for 25-hydroxy vitamin D and calcium might therefore be different in people using TDF than expected from general populations but also people living with HIV with non-TDF-containing antiretroviral therapy. This might require different supplementation strategies but warrants further investigation.

Alteration of epigenetic enzymes is associated with the pathophysiology of colon cancer with an overexpression of histone deacetylase 8 (HDAC8) enzyme in this tissue. Numerous reports suggest that targeting HDAC8 is a viable strategy for developing new anticancer drugs. Flavonols provide a rich source of molecules that are effective against cancer; however, their clinical use is limited. The present study investigated the potential of quercetin and synthetic 3-hydroxyflavone analogues to inhibit HDAC8 enzyme and evaluated their anticancer property. Synthesis of the analogues was carried out, and cytotoxicity was determined using MTT assay. Nonspecific and specific HDAC enzyme inhibition assays were performed followed by the expression studies of target proteins. Induction of apoptosis was studied through annexin V and caspase 3/7 activation assay. Furthermore, the analogues were assessed against in vivo colorectal cancer. Among the synthesized analogues, QMJ-2 and QMJ-5 were cytotoxic against HCT116 cells with an IC₅₀ value of 68 ± 2.3 and 27.4 ± 1.8 µM, respectively. They inhibited HDAC enzyme in HCT116 cells at an IC₅₀ value of 181.7 ± 22.04 and 70.2 ± 4.3 µM, respectively, and inhibited human HDAC8 and 1 enzyme at an IC₅₀ value of <50 µM with QMJ-5 having greater specificity towards HDAC8. A reduction in the expression of HDAC8 and an increase in acetyl H3K9 expression were observed with the synthesized analogues. Both QMJ-2 and QMJ-5 treatment induced apoptosis through the activation of caspase 3/7 evident from 55.70% and 83.55% apoptotic cells, respectively. In vivo studies revealed a significant decrease in colon weight to length ratio in QMJ-2 and QMJ-5 treatment groups compared to DMH control. Furthermore, a reduction in aberrant crypt foci formation was observed in the treatment groups. The present study demonstrated the potential of novel 3-hydroxyflavone analogues as HDAC8 inhibitors with anticancer property against colorectal cancer.

Both honeybees (Apis spp.) and stingless bees (Trigona spp.) produce honeys with high nutritional and therapeutics value. Until recently, the information regarding potential health benefits of stingless bee honey (SBH) in medical databases is still scarce as compared to the common European bee honey (EBH) which is well known for their properties as therapeutic agents. Although there have been very few reports on SBH, empirically these products would have similar therapeutic quality as the EBH. In addition, due to the structure of the nest, few studies reported that the antimicrobial activity of SBH is a little bit stronger than EBH. Therefore, the composition of both the types of honey as well as the traditional uses and clinical applications were compared. The results of various studies on EBH and SBH from tissue culture research to randomised control clinical trials were collated in this review. Interestingly, there are many therapeutic properties that are unique to SBH. Therefore, SBH has a great potential to be developed for modern medicinal uses.

Ganoderma lucidum (G. lucidum) fungus (Family Ganodermataceae) is widely used as a traditional medicine in China, Japan, and many Asian countries on account of its numerous medicinal properties such as antioxidant, anticancer, antimicrobial, energy enhancing, and immunostimulatory. This broad spectrum of therapeutic effects exhibited by G. lucidum is ascribed to its abundance in several classes of chemical constituents, namely, carbohydrates, flavonoids, minerals, phenolics, proteins, and steroids which possess substantial bioactivities. The aim of the current study was to prepare phenolic rich fractions (PRFs) from aqueous extract of the Indian variety of G. lucidum mycelium and fruiting body. These fractions were assessed for their antioxidant capacity by TPC (total phenolic content), TFC (total flavonoid content), FRAP (ferric reducing antioxidant power), and ABTS [2,2-azino-bis(3-ethylbenzothiazoline)-6-sulfonic acid] assays. Quantification of flavonoids and nucleobases present in the fractions was carried out by high-performance thin layer chromatography (HPTLC). The antibacterial activity of the fractions was evaluated against Escherichia coli, Salmonella typhi, and Staphylococcus aureus. The antibacterial mechanism of action of the PRFs was established to be generation of reactive oxygen species and leakage of proteins within bacterial cells. Additionally, the protective effect of the PRFs in counteracting hypoxia was observed in HEK 293 cell lines.

Niosomes (the nonionic surfactant vesicles), considered as novel drug delivery systems, can improve the solubility and stability of natural pharmaceutical molecules. They are established to provide targeting and controlled release of natural pharmaceutical compounds. Many factors can influence on niosome construction such as the preparation method, type and amount of surfactant, drug entrapment, temperature of lipids hydration, and the packing factor. The present review discusses about the most important features of niosomes such as their diverse structures, the different preparation approaches, characterization techniques, factors that affect their stability, their use by various routes of administration, their therapeutic applications in comparison with natural drugs, and specially the brain targeting with niosomes-ligand conjugation. It also provides recent data about the various types of ligand agents which make available active targeting drug delivery to the central neuron system. This system has an optimistic upcoming in pharmaceutical uses, mostly with the improving availability of innovative schemes to overcome blood-brain barrier and targeting the niosomes to the brain.

Many pathological problems are initiated by ultraviolet radiation (UVR), such as skin cancer, the most commonly diagnosed cancer worldwide. The UVA (320-400 nm) and UVB (290-320 nm) wavelengths may cause effects such as photoaging, DNA damage, and a series of cellular alterations. The UVA radiation can damage the DNA, oxidize the lipids, and produce dangerous free radicals, which can cause inflammation, modify the gene expression in response to stress, and weaken the skin immune response. With a minor penetration, the UVB radiation is more harmful, being responsible for immediate damage. Ultraviolet radiation light emitted by the sun is considered necessary for the existence of life but cause radiation problems, especially in the skin. The photoprotective activities of plant extracts and isolated composts were evaluated by many reports, as well as the correlation of these compounds with the antioxidant activity. This review presents plant compounds with interest to the cosmetic industry to be used in sunscreens such as flavonoids and cinnamates.

Neuronal developmental disorder is a class of diseases in which there is impairment of the central nervous system and brain function. The brain in its developmental phase undergoes tremendous changes depending upon the stage and environmental factors. Neurodevelopmental disorders include abnormalities associated with cognitive, speech, reading, writing, linguistic, communication, and growth disorders with lifetime effects. Computational methods provide great potential for betterment of research and insight into the molecular mechanism of diseases. In this study, we have used four samples of microarray neuronal developmental data: control, RV (resveratrol), NGF (nerve growth factor), and RV + NGF. By using computational methods, we have identified genes that are expressed in the early stage of neuronal development and also involved in neuronal diseases. We have used MeV application to cluster the raw data using distance metric Pearson correlation coefficient. Finally, 60 genes were selected on the basis of coexpression analysis. Further pathway analysis was done using the Metascape tool, and the biological process was studied using gene ontology database. A total of 13 genes AKT1, BAD, BAX, BCL2, BDNF, CASP3, CASP8, CASP9, MYC, PIK3CD, MAPK1, MAPK10, and CYCS were identified that are common in all clusters. These genes are involved in neuronal developmental disorders and cancers like colorectal cancer, apoptosis, tuberculosis, amyotrophic lateral sclerosis (ALS), neuron death, and prostate cancer pathway. A protein-protein interaction study was done to identify proteins that belong to the same pathway. These genes can be used to design potential inhibitors against neurological disorders at the early stage of neuronal development. The microarray samples discussed in this publication are part of the data deposited in NCBI's Gene Expression Omnibus (Yadav et al., 2018) and are accessible through GEO Series (accession number GSE121261).