Current molecular pharmacology最新文献

Background: The treatment of cancer is a current challenge for public health, causing high rates of morbidity and mortality worldwide. Doxorubicin (DOX) and cisplatin (CP) are two well-known chemotherapeutic agents approved by the Food and Drug Administration to treat cancer patients. However, there are two problems associated with DOX and CP: drug resistance and adverse impact. Resveratrol (Res) belongs to the stilbene class and possesses various health-promoting effects, such as antioxidant, anti-inflammatory, anticancer, hepatoprotective, and neuroprotective effects.

Objective: The present review aims to give special attention to the therapeutic impacts of Res in potentiating DOX and CP's antitumor activities and reducing their side effects.

Methods: PubMed, Science Direct, and Google Scholar were used to search articles for the current manuscripts.

Results: Co-administration of Res can prevent chemoresistance and potentiate the induction of apoptosis and cell cycle arrest in cancer cells. Res can enhance the sensitivity of cancer cells to DOX and CP chemotherapy by inhibiting the migration and metastasis of cancer cells. Simultaneously, Res, due to its therapeutic actions ameliorates the adverse impacts of DOX and CP on normal cells and organs, including the liver, kidney, brain, and testes. As Res suffers from poor bioavailability, nanoformulations have been developed with promising results to improve its antitumor activity and protective effects.

Conclusion: Based on preclinical studies, it is obvious that Res is a promising adjsuvant for CP and DOX chemotherapy, and its benefits can be utilized in the clinical course.

In the present study, the health-protective and therapeutic properties of MET have been discussed, focusing on the effect of MET on the Nrf2 expression in patients with different pathological conditions. Metformin (MET) regulates high blood glucose, thus being an integral part of the antidiabetic medications used to treat type 2 diabetes mellitus. It belongs to biguanide class medications that are administered through the oral route. Moreover, the agent is widely known for its anti-cancer, anti-oxidant, anti-inflammatory, and neuroprotective effects. The MET modulates the nuclear factor erythroid-2 related factor-2 (Nrf2) signaling pathway, which in turn yields the above-mentioned medical benefits to patients. The Nrf2 signaling pathways are modulated in multiple ways described subsequently: 1) MET acts on the cancer cells and inactivates Raf-ERK signaling, thus reducing Nrf2 expression, 2) MET obstructs the expression of proteins that are involved in apoptosis of tumor cells and also prevents tumor cells from oxidation through an AMPK-independent pathway; 3) MET carries out Keap1-independent mechanism for reducing the levels of Nrf2 protein in cancer cells; 4) MET upregulates the Nrf2-mediated transcription to stimulate the anti-oxidant process that prevents oxidative stress in cells system and consequently gives neuroprotection from rotenone and 5) MET downregulates p65 and upregulates Nrf2 which helps improve the angiogenesis impairment stimulated by gestational diabetes mellitus. This article presents an analysis of the health-protective properties of MET and also sheds light on the effect of MET on the Nrf2 expression in patients with different pathological conditions.

Background: MicroRNAs (miRs) are small noncoding RNAs that are crucial in the development and progression of tumours. Melanoma is an aggressive form of skin cancer and is resistant to most of the chemotherapeutic agents. However, the role of miRs in melanoma remains poorly studied.

Objective: The work aimed to demonstrate that miR-331-3p is downregulated in melanoma against the benign melanocytic nevi.

Methods: RT-PCR analysis was performed for the expression of proteins; cell proliferation and wound healing assays were carried out. Flow cytometry study was conducted for cell cycle analysis; colony formation assay was performed by soft agar method. For developing a tumour xenograft model, nu/nu mice were selected.

Results: Up-regulation of miR-331-3p in melanoma cells decreased cell proliferation, cell migration, and also drug resistance. Over-expression of miR-331-3p resulted in suppression of NRP2 and up-regulation of E-cadherin levels. Moreover, the levels of MDR1, ABCG-2, and ABCG-5 were decreased. However, the knockdown of NRP2 demonstrated similar effects as that of miR- 331-3p overexpression in tumour cells. Overexpression of miR-331-3p caused significant inhibition of tumour growth and its metastasis in mice model of melanoma, which was associated with depletion of NRP2 protein and increased expression of E-cadherin. However, the effects of miR- 331-3p on the migration, cell proliferation, and self-renewal were overturned by the upregulation of NRP2, which also resulted in the inhibition of E-cadherin and overexpression of MDR-1, ABCG-2, and ABCG-5.

Conclusion: The findings point out the key role of miR-331-3p in the progression and drug resistance of melanoma involving NRP2.

Background: Hepatocellular carcinoma (HCC) is a solid cancer with high predominance in males. Liver tissue of both genders has saturable specific oestrogen receptors. Androgen and its receptor (AR) have been suggested to contribute to the predominance in men. Anti-oestrogens, like tamoxifen may reduce the expression of oestrogen receptors, sustaining cellular in HCC. In vitro and human, studies confirmed that both testosterone and dihydrotestosterone (DHT) enhanced the growth and proliferation of hepatic normal and tumour cells. Although the activity of AR is escalated by the chemical induction of hepatocarcinogenesis; clinical trials with AR-targeted agents alone failed to generate survival benefits.

Purpose: This review will outline the possible pathophysiological mechanisms by which both androgen and AR contribute to hepatocarcinogenesis and to which extent this pathway can be responsible for the male prevalence and if they could be pharmacological targets in HCC management.

Conclusion: Influencing factors that seem to be responsible for male prevalence include testosterone, dihydrotestosterone and androgen receptors, as well as, proteomic deficiency of DNA packaging, nuclear proteins and homeostasis-related functional proteins. Understanding the reasons for males, rather than females the HCC prevalence may help in suggesting new approaches by improving the anti-AR therapies through co-targeting of AR and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway.

Background: The calcium/calmodulin protein kinase II (CaMKII) signaling cascade is crucial for hippocampus-dependent learning and memory. Hypothyroidism impairs hippocampus- dependent learning and memory in adult rats, which can be prevented by simple replacement therapy with L-thyroxine (thyroxine, T4) treatment. In this study, we compared animal models of hypothyroidism induced by thyroidectomy and treatment with propylthiouracil (PTU) in terms of synaptic plasticity and the effect on underlying molecular mechanisms of spatial and non-spatial types of memory.

Methods: Hypothyroidism was induced using thyroidectomy or treatment with propylthiouracil (PTU). L-thyroxin was used as replacement therapy. Synaptic plasticity was evaluated using in vivo electrophysiological recording. Training in the radial arm water maze (RAWM), where rats had to locate a hidden platform, generated spatial and non-spatial learning and memory. Western blotting measured signaling molecules in the hippocampal area CA1 area.

Results: Our findings show that thyroidectomy and PTU models are equally effective, as indicated by the identical plasma levels of thyroid stimulating hormone (TSH) and T4. The two models produced an identical degree of inhibition of synaptic plasticity as indicated by depression of long-term potentiation (LTP). For non-spatial memory, rats were trained to swim to a visible platform in an open swim field. Analysis of hippocampal area CA1 revealed that training, on both mazes, of control and thyroxine-treated hypothyroid rats, produced significant increases in the P-calcium calmodulin kinase II (P-CaMKII), protein kinase-C (PKCγ), calcineurin and calmodulin protein levels, but the training failed to induce such increases in untreated thyroidectomized rats.

Conclusion: Thyroxine therapy prevented the deleterious effects of hypothyroidism at the molecular level.

Background: Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease. In previous studies, we found extracts from the roots of Rosa odorata Sweet var. gigantea (Coll.et Hemsl.) Rehd. et Wils have a therapeutic effect on UC. Furthermore, sericic acid (SA) is a pentacyclic triterpenoid isolated from this plant that is being used for the first time. The purpose of this study was to investigate whether SA has anti-inflammatory and therapeutic effects on UC and its underlying mechanisms.

Methods: In this study, we used a dextran sulfate-induced UC mouse model and lipopolysaccharide (LPS)-induced inflammatory cell model along with an enzyme-linked immunosorbent assay (ELISA) to quantify the abundance of inflammatory factors and oxidative stress factors in tissues and cells. HE staining was used to analyze the therapeutic effect of the drugs on the UC mouse model. The expression levels of oxidative stress-related proteins were detected using immunoblotting and immunohistochemistry. The anti-inflammatory targets of SA were screened using protein chip arrays and verified by immunoblotting.

Results: We found that SA had anti-inflammatory and antioxidant effects in animal and cellular inflammation models. SA inhibited the levels of NO, TNF-α, IL-6, IL-1β, and MDA in tissues and cells and upregulated the expression level of SOD. Animal experiments showed that SA alleviated the shortening of colon length and colon pathological damage caused by DSS. The antiinflammatory targets of SA were screened using protein chip arrays, and SA was found to inhibit proteins related to the NF-κB signaling pathway. Finally, immunoblotting and immunohistochemistry showed that SA downregulated the expression of p-IKKα/β and its downstream protein p-NF-κB, while promoting the expression of Nrf2 and its downstream protein HO-1.

Conclusion: The above results indicated that SA alleviated DSS-induced colitis by inhibiting NF-κB signaling pathway and activating Nrf2 pathway.

Background: Despite the implementation of various cancer therapies, adequate therapeutic efficacy has not been achieved. A growing number of studies have been dedicated to the discovery of new molecules to combat refractory cancer cells efficiently. Recently, the use of a rare type of sugar, D-allose, has attracted the attention of research communities. In combination with the first-line treatment of cancers, including different types of radiotherapies and chemotherapies, D-allose has been detected with favorable complementary effects. Understanding the mechanism of therapeutic target molecules will enable us to develop new strategies for cancer patients that do not currently respond to the present therapies.

Objective: We aimed to provide a review of the effects of D-allose in cancer treatment, its mechanisms of action, and gaps in this field that require more investigations.

Discussion: With rare exceptions, in many cancer types, including head and neck, lung, liver, bladder, blood, and breast, D-allose consistently has exhibited anticancer activity in vitro and/or in vivo. Most of the D-allose functions are mediated through thioredoxin-interacting protein molecules. D-allose exerts its effects via reactive oxygen species regulation, cell cycle arrest, metabolic reprogramming, autophagy, apoptosis induction, and sensitizing tumors to radiotherapy and chemotherapy.

Conclusion: D-allose has shown great promise for combating tumor cells with no side effects, especially in combination with first-line drugs; however, its potential for cancer therapy has not been comprehensively investigated in vitro or in vivo.

Background and objective: Hydroxychloroquine (HCQ) is a molecule derived from quinacrine; it displays a wide range of pharmacological properties, including anti-inflammatory, immunomodulatory, and antineoplastic. However, little is known about this molecule's role in lung injury. This study aimed to identify HCQ's regulatory role of HCQ in sepsis-induced lung injury and its molecular mechanism.

Methods: To test the protective properties of HCQ, we established an in vivo model of lipopolysaccharide (LPS)-induced lung injury in mice. The extent of the injury was determined by evaluating histopathology, inflammatory response, oxidative stress, and apoptosis. Mechanistically, conventional nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 (NLRP3) knockout mice were employed to investigate whether HCQ exerted pulmonary protection by inhibiting NLRP3-mediated pyroptosis.

Results: Our findings revealed that HCQ pretreatment significantly mitigated LPS-induced lung injury in mice in terms of histopathology, inflammatory response, oxidative stress, and apoptosis, while inhibiting LPS-induced NLRP3 inflammasome activation and pyroptosis. Additionally, the indicators of lung injury, including histopathology, inflammatory response, oxidative stress, and apoptosis, were still reduced drastically in LPS-treated NLRP3 (-/-) mice after HCQ pretreatment. Notably, HCQ pretreatment further decreased the levels of pyroptosis indicators, including IL-1β, IL-18 and Cle-GSDMD, in LPS-treated NLRP3 (-/-) mice.

Conclusion: Taken together, HCQ protects against lung injury by inhibiting pyroptosis, maybe not only through the NLRP3 pathway but also through non-NLRP3 pathway; therefore, it may be a new therapeutic strategy in the treatment of lung injury.

Clozapine, a superior treatment for treatment-resistant schizophrenia can cause potentially life-threatening myocarditis and dilated cardiomyopathy. While the occurrence of this condition is well known, its molecular mechanisms are unclear and may be multifactorial. Putative mechanisms warrant an in-depth review not only from the perspective of toxicity but also for understanding the molecular mechanisms of the adverse cardiac effects of clozapine and the development of novel therapeutic approaches. Clozapine-induced cardiac toxicity encompasses a diverse set of pathways, including (i) immune modulation and proinflammatory processes encompassing an IgEmediated (type I hypersensitivity) response and perhaps a cytokine release syndrome (ii) catecholaminergic activation (iii) induction of free radicals and oxidative stress (iv) activation of cardiomyocyte cell death pathways, including apoptosis, ischemia through impairment in coronary blood flow via changes in endothelial production of NO and vasoconstriction induced by norepinephrine as well as other factors released from cardiac mast cells. (v) In addition, an extensive examination of the effects of clozapine on non-cardiac cellular proteins demonstrates that clozapine can impair enzymes involved in cellular metabolism, such as pyruvate kinase, mitochondrial malate dehydrogenase, and other proteins, including α-enolase, triosephosphate isomerase and cofilin, which might explain clozapine-induced reductions in myocardial energy generation for cell viability as well as contractile function. Pharmacologic antagonism of these cellular protein effects may lead to the development of strategies to antagonize the cardiac damage induced by clozapine.

Background: Mexico has the largest number of the genus salvia plant species, whose main chemical compounds of this genus are diterpenes, these chemical compounds have shown important biological activities such as: antimicrobial, anti-inflammatory and immunomodulatory.

Objective: This study aimed to evaluate the immunomodulatory activity of three diterpenes: 1) icetexone, 2) anastomosine and 3) 7,20-dihydroanastomosine, isolated from Salvia ballotiflora, over innate immunity and cytokine production in a human alveolar epithelial cell line infected with Mycobacterium tuberculosis.

Methods: The immunomodulatory activity of diterpenes over innate immunity included reactive oxygen and nitrogen species (ROS and RNS) induction in response to infection; cytokine production included TNF-α and TGF-β induction in response to infection.

Results: The diterpenes anastomosine and 7,20-dihydroanastomosine showed a statically significant (p < 0.01) increase of RNS after 36 h of infection and treatment of 2.0 μg/mL. Then, the ROS induction in response to infection showed a consistent statically significant (p < 0.01) increase after 12 h of diterpenes treatments. The cell cultures showed an anti-inflammatory effect, in the case of TGF-β induction, in response to infection when treated with the diterpenes. On the other hand, there was not any significant effect on TNF-α release.

Conclusion: The diterpenes anastomosine and 7,20-dihydroanastomosine increased the production of RNS after 36 h of infection and treatment. Besides, the three diterpenes increased the production of ROS after 12 h. This RNS and ROS modulation can be considered as an in vitro correlation of innate immunity in response to Mycobacterium tuberculosis infection; and an indicator of the damage of epithelial lung tissue. This study also showed an anti-inflammatory immune response by means of TGF-β modulation when compared with control group.