查看更多>>摘要：Paeoniae Radix (PR) has a great therapeutic value in many clinical applications; however， the presence of various bioactive compounds and its complicated effects on human health makes its precise mechanisms of action unclear。 This study investigated the effects of PR at the molecular pathway level by profiling genome-wide gene expression changes following dose-dependent treatment of human lung cancer cells (A549) with PR water extract (WPR)， PR ethanol extracts (EPR)， as well as their individual components。 We found that PR exerts anticancer effects in A549 cells by regulating numerous pathways。 Specifically， EPR and two compounds， namely， heder-agenin (HG) and oleanolic acid (OA)， significantly downregulate the Aurora B pathway。 Furthermore， we generated an integrated PR extracts-compounds-target genes network in the Aurora B pathway to understand their interactions。 Our findings reinforce that inhibiting Aurora kinase activity is a therapeutic target for treating cancers， providing the potential for novel mechanisms of action for PR and its components against lung cancer。
查看更多>>摘要：Intracerebral hemorrhage (ICH) is a severe， life-threatening subtype of stoke that constitutes a crucial health and socioeconomic problem worldwide。 However， the current clinical treatment can only reduce the mortality of patients to a certain extent， but cannot ameliorate neurological dysfunction and has a high recurrence rate。 Increasing evidence has demonstrated that mitochondrial dysfunction occurs in the early stages of brain injury and participates in all stages of secondary brain injury (SBI) after ICH。 As the energy source of cells， various pathobiological processes that lead to SBI closely interact with the mitochondria， such as oxidative stress， calcium overload， and neuronal injury。 In this review， we discussed the structure and function of mitochondria and the abnormal morphological changes after ICH。 In addition， we discussed recent research on the involvement of mitochondrial dynamics in the pathological process of SBI after ICH and introduced the pathological variations and related molecular mechanisms of mitochondrial dysfunction in the occurrence of brain injury。 Finally， we summarized the latest progress in mitochondrion-targeted agents for ICH， which provides a direction for the development of emerging therapeutic strategies targeting the mitochondria after ICH。
查看更多>>摘要：A part of atypical antipsychotics exert mood-stabilising effects via modulation of various monoamine receptors and intracellular signalling。 Recent pharmacodynamic studies suggested that tripartite-synaptic transmission can be involved in pathophysiology of mood-disorders， schizophrenia， their associated cognitive impairments， and several adverse-reactions to atypical antipsychotics。 Therefore， to explore mechanisms underlying antidepressive mood-stabilising and antipsychotic effects of lurasidone， we determined concentration-dependent effects of acute and subchronic lurasidone administrations on astroglial L-glutamate release， and expression of connexin43， ERK， AKT， adenosine monophosphate activated protein kinase (AMPK)， 5-HT1A (5-HT1AR) and 5-HT7 (5-HT7R) receptors in cultured astrocytes using ultra-high-pressure liquid-chromatography with mass-spectrometry and capillary-immunoblotting systems。 Therapeutically-relevant lurasidone concentration suppressed astroglial L-glutamate release through activated connexin43-containing hemichannel by decreasing connexin43 expression in plasma-membrane。 Subchronic lurasidone administration downregulated 5-HT1AR and 5-HT7R in astroglial plasma-membrane concentration-dependently。 Subchronic lurasidone administration attenuated ERK and AMPK signallings concentration-dependently without affecting AKT signalling。 These results suggest that effects of subchronic lurasidone administration on astroglial L-glutamate release， 5-HT receptor， and intracellular signalling are similar to vortioxetine and different from mood-stabilising atypical antipsychotics， clozapine。 Therefore， inhibitory effects of subchronic lurasidone administration on astroglial L-glutamate release through activated connexin43-containing hemichannel probably contribute to pathophysiology of antidepressive mood-stabilising effects of lurasidone。 Furthermore， inhibitory effects of subchronic lurasidone administration on ERK and AMPK activities (without affecting AKT activity) induced by downregulation of 5-HT7R could result in clinical advantages of lurasidone， lower risk of weight gain。
查看更多>>摘要：Infectious diseases and cancer are among the key medical challenges that humankind is facing today。 A growing amount of evidence suggests that ion channels in the endolysosomal system play a crucial role in the pathology of both groups of diseases。 The development of advanced patch-clamp technologies has allowed us to directly characterize ion fluxes through endolysosomal ion channels in their native environments。 Endolysosomes are essential organelles for intracellular transport， digestion and metabolism， and maintenance of homeostasis。 The endolysosomal ion channels regulate the function of the endolysosomal system through four basic mechanisms: calcium release， control of membrane potential， pH change， and osmolarity regulation。 In this review， we put particular emphasis on the endolysosomal cation channels， including TPC2 and TRPML2， which are particularly important in monocyte function。 We discuss existing endogenous and synthetic ligands of these channels and summarize current knowledge of their impact on channel activity and function in different cell types。 Moreover， we summarize recent findings on the importance of TPC2 and TRPML2 channels as potential drug targets for the prevention and treatment of the emerging infectious diseases and cancer。
查看更多>>摘要：Exosomes are nano-sized structures that are found in semen， epididymal -fluid， endometrium， as well as in follicular fluid。 They are responsible for transporting bioactive cargo- proteins， lipids， and nucleic acids。 Exosomes have been proven to influence processes in both female and male reproductive systems， including gametogenesis， acrosomal reaction， sperm capacitation， and embryo implantation in the endometrium。 Exosomes are made of the same particles as the cells they come from and are secreted by normal and pathological cells。 Therefore， exosomes can reflect the physiological state of cells。 Moreover， due to the transportation of bio-molecules， they participate in intercellular communication and can be used as biomarkers of many diseases， including ovarian， endometrial and prostate cancer。 Identification of exosomes as biomarkers could contribute to a better understanding of genital dysfunction and fertility disorders。
Patrícia de Melo OliveiraDaisymara Priscila de Almeida MarquesLinziane Lopes FerreiraFelipe Alves Clarindo...
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查看更多>>摘要：COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2， which continues to be a public health threat。 COVID-19 is principally a respiratory disease and is often associated with sputum retention and cytokine storm， for which there are limited therapeutic options。 In this regard， we evaluated the use of BromAc?， a combination of Bromelain and Acetylcysteine (NAC)。 Both drugs present mucolytic effect and have been studied to treat COVID-19。 Therefore， we sought to examine the mucolytic and anti-inflammatory effect of BromAc? in tracheal aspirate samples from critically ill COVID-19 patients requiring mechanical ventilation。 Method: Tracheal aspirate samples from COVID-19 patients were collected following next of kin consent and mucolysis， rheometry and cytokine analysis using Luminex kit was performed。 Results: BromAc? displayed a robust mucolytic effect in a dose dependent manner on COVID-19 sputum ex vivo。 BromAc? showed anti-inflammatory activity， reducing the action of cytokine storm， chemokines including MIP-1alpha， CXCL8， MIP-1b， MCP-1 and IP-10， and regulatory cytokines IL-5， IL-10， IL-13 IL-1Ra and total reduction for IL-9 compared to NAC alone and control。 BromAc? acted on IL-6， demonstrating a reduction in G-CSF and VEGF-D at concentrations of 125 and 250 μg。 Conclusion: These results indicate robust mucolytic and anti-inflammatory effect of BromAc? ex vivo in tracheal aspirates from critically ill COVID-19 patients， indicating its potential to be further assessed as pharmacological treatment for COVID-19。
查看更多>>摘要：Transforming growth factor-β (TGF-β) is a multifunctional regulatory cytokine that maintains tolerance in the immune system by regulating the proliferation， differentiation and survival of lymphocytes。 TGF-β blockade therapy for cancer has achieved some results but shows limited efficacy and side effects because these drugs are not selective and act on various types of cells throughout the body。 We demonstrate here that dominant negative TGF-β receptor type II specifically targeting T cells decreases tumor load in tumor-bearing mice。 In addition， the dominant negative TGF-β receptor type II promotes the proliferation and differentiation of T cells and increases the expression of T-bet， which in turn promotes the secretion of granzyme A， granzyme B， perforin and IFN-γ secreted by T cells， and enhances the cytotoxicity and anti-tumor effects of T cells。 Moreover， we also found that dominant negative TGF-β receptor type II reduces the proportion of regulatory T cells (Tregs) in tumor tissue and spleen of tumor-bearing mice。 Co-culture experiments with T cells and tumor cells revealed that dominant negative TGF-β receptor type II inhibited tumor cell proliferation and increased apoptosis。 Our results indicate that specifically inhibiting TGF-β receptor type II in T cells increases anti-tumor immunity and has a strong therapeutic potential。
查看更多>>摘要：The 2019 corona virus disease (COVID-19) has caused a global chaos， where a novel Omicron variant has challenged the healthcare system， followed by which it has been referred to as a variant of concern (VOC) by the World Health Organization (WHO)， owing to its alarming transmission and infectivity rate。 The large number of mutations in the receptor binding domain (RBD) of the spike protein is responsible for strengthening of the spike-angiotensin-converting enzyme 2 (ACE2) interaction， thereby explaining the elevated threat。 This is supplemented by enhanced resistance of the variant towards pre-existing antibodies approved for the COVID-19 therapy。 The manuscript brings into light failure of existing therapies to provide the desired effect， however simultaneously discussing the novel possibilities on the verge of establishing suitable treatment portfolio。 The authors entail the risks associated with omicron resistance against antibodies and vaccine ineffectiveness on one side， and novel approaches and targets - kinase inhibitors， viral protease inhibitors， phytoconstituents， entry pathways - on the other。 The manuscript aims to provide a holistic picture about the Omicron variant， by providing comprehensive discussions related to multiple aspects of the mutated spike variant， which might aid the global researchers and healthcare experts in finding an optimised solution to this pandemic。
查看更多>>摘要：Background: Muscle pain and muscle weakness， common symptoms among statin-treated patients， may worsen with COVID-19 infection。 Aims: The aim of the paper was to find out if concomitant COVID-19 infections increase the frequency of specific side effects of statins such as muscle pain and muscle weakness。 Method: A total of 66 patients diagnosed with COVID-19 without comorbidities participated in the study。 The patients were divided into two groups: statin-users who had not experienced adverse effects of statins in the past (statin group (SG)) and patients who had not used any drugs in the past six months (control group (CG))。 The severity of muscle pain and creatinine kinase (CK) activity was evaluated in each patient， and muscle weakness was confirmed by a dynamometer test (grip strength on both hands)。 Results: In SG， muscle pain was more common and it was characterized by a high level of intensity。 Muscle weakness occurred more frequently in the SG and it was more frequent compared to CG。 The CK parameter was observed to be higher in the SG compared to the CG and was often associated with the severity of muscle pain in the range of moderate to severe。 Conclusions: Our study indicates that COVID-19 is associated with the higher risk of occurrence of typical statin-related side effects， especially with more advanced age， which should be considered in future trials and treatments。
查看更多>>摘要：Infectious diseases caused by multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus， pose a significant threat to humanity。 Persistent and repeated invasive infection with MRSA led to higher morbidity and mortality， and required comprehensive measures in treatment and prevention。 Zanthoxylum nitidum (Roxb。) DC。 is used as detoxifying， analgesic， and hemostatic herbal medicine for thousands of years。 Previously pharmacological studies showed that Z。 nitidum had antibacterial bioactivity， but only the MIC of a few compounds， crude extracts， and fractions were reported。 In our ongoing endeavor to explore bioactive compounds， two new coumarins， 6-(3-oxo-butyl)-limettin (1) and toddalin I (2)， and 24 known compounds were isolated from the roots of Z。 nitidum， in which two isoquinoline alkaloids， 6-acetonyl-dihydrofagaridine (16) and 6-acetonyl-dihydrochelerythrine (17) showed anti-MRSA bioactivity in vitro and in vivo。 Both 16 and 17 showed synergistic action with ampicillin， which decreased the MIC significantly， and both compounds had a significant ability to destroy bacterial biofilm combined with ampicillin。 The combined administration showed a strong scavenging effect on the planktonic bacteria in vitro and cleared skin infection effectively in the model of wound infection in vivo。 Furthermore， compound 16 inhibited the efflux of the drug by combining with ampicillin or EtBr， resulting in the MIC decreased obviously。 Our investigation supported the traditional use of Z。 nitidum in treating infections caused by bacteria， and might provide new natural products to reduce the use of antibiotics and the treatment of drug-resistance bacteria。
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