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Medicines, Volume 8, Issue 6 (June 2021) – 8 articles

Cover Story (view full-size image): β-Thujaplicin has anticancer effects on various cancer cells via apoptosis. However, the apoptosis regulatory proteins involved in this process have yet to be revealed. We hypothesize that β-thujaplicin could act on XIAP both as a zinc chelator and as a XIAP-BIR3 inhibitor to induce and/or enhance apoptosis. It is revealed that β-thujaplicin enhances TRAIL-induced apoptosis in NCI-H460 NSCLC cells. β-Thujaplicin decreases the amount of XIAP in NCI-H460 cells and binds the XIAP-BIR3 domain at the Smac binding site. Our results validate β-thujaplicin as a potent seed compound that exerts dual effects on XIAP, i.e., XIAP inhibition by binding to the BIR3 domain and XIAP degradation. β-Thujaplicin represents a new scaffold for the development of novel types of XIAP-targeting anticancer drugs. View this paper

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Article
Analgesic Effect of Combined Therapy with the Japanese Herbal Medicine “Yokukansan” and Electroacupuncture in Rats with Acute Inflammatory Pain
Medicines 2021, 8(6), 31; https://doi.org/10.3390/medicines8060031 - 17 Jun 2021
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Abstract
Background: Japanese herbal medicine, called Kampo medicine, and acupuncture are mainly used in Japanese traditional medicine. In this experiment, the analgesic effect of Yokukansan (YKS) alone and a combination of YKS and electroacupuncture (EA) on inflammatory pain induced by formalin injection were examined. [...] Read more.
Background: Japanese herbal medicine, called Kampo medicine, and acupuncture are mainly used in Japanese traditional medicine. In this experiment, the analgesic effect of Yokukansan (YKS) alone and a combination of YKS and electroacupuncture (EA) on inflammatory pain induced by formalin injection were examined. Methods: Animals were divided into four groups: a control group, formalin injection group (formalin), YKS-treated formalin group (YKS), and YKS- and EA-treated formalin group (YKS + EA). The duration of pain-related behaviors and extracellular signal-regulated protein kinase (ERK) activation in the spinal cord after formalin injection in the right hind paw were determined. Results: The duration of pain-related behaviors was dramatically prolonged in the late phase (10–60 min) in the formalin group. The YKS treatment tended to reduce (p = 0.08), whereas YKS + EA significantly suppressed the pain-related behaviors (p < 0.01). Immunohistochemical and Western blot analyses revealed that the number of phosphorylated ERK1/2 (pERK1/2)-positive cells and the pERK expression level, which were increased by formalin injection, were significantly inhibited by YKS (p < 0.05) and YKS + EA (p < 0.01). Conclusions: The YKS + EA combination therapy elicited an analgesic effect on formalin-induced acute inflammatory pain. Full article
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Review
The Etiology and Pathophysiology Genesis of Benign Prostatic Hyperplasia and Prostate Cancer: A New Perspective
Medicines 2021, 8(6), 30; https://doi.org/10.3390/medicines8060030 - 11 Jun 2021
Viewed by 1041
Abstract
Background: The etiology of benign prostatic hyperplasia and prostate cancer are unknown, with ageing being the greatness risk factor. Methods: This new perspective evaluates the available interdisciplinary evidence regarding prostate ageing in terms of the cell biology of regulation and homeostasis, which could [...] Read more.
Background: The etiology of benign prostatic hyperplasia and prostate cancer are unknown, with ageing being the greatness risk factor. Methods: This new perspective evaluates the available interdisciplinary evidence regarding prostate ageing in terms of the cell biology of regulation and homeostasis, which could explain the timeline of evolutionary cancer biology as degenerative, inflammatory and neoplasm progressions in these multifactorial and heterogeneous prostatic diseases. Results: This prostate ageing degeneration hypothesis encompasses the testosterone-vascular-inflamm-ageing triad, along with the cell biology regulation of amyloidosis and autophagy within an evolutionary tumorigenesis microenvironment. Conclusions: An understanding of these biological processes of prostate ageing can provide potential strategies for early prevention and could contribute to maintaining quality of life for the ageing individual along with substantial medical cost savings. Full article
(This article belongs to the Section Cancer Biology and Anticancer Therapeutics)
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Perspective
The Scientific and Cultural Journey to Ovarian Rejuvenation: Background, Barriers, and Beyond the Biological Clock
Medicines 2021, 8(6), 29; https://doi.org/10.3390/medicines8060029 - 08 Jun 2021
Viewed by 847
Abstract
Female age has been known to define reproductive outcome since antiquity; attempts to improve ovarian function may be considered against a sociocultural landscape that foreshadows current practice. Ancient writs heralded the unlikely event of an older woman conceiving as nothing less than miraculous. [...] Read more.
Female age has been known to define reproductive outcome since antiquity; attempts to improve ovarian function may be considered against a sociocultural landscape that foreshadows current practice. Ancient writs heralded the unlikely event of an older woman conceiving as nothing less than miraculous. Always deeply personal and sometimes dynastically pivotal, the goal of achieving pregnancy often engaged elite healers or revered clerics for help. The sorrow of defeat became a potent motif of barrenness or miscarriage lamented in art, music, and literature. Less well known is that rejuvenation practices from the 1900s were not confined to gynecology, as older men also eagerly pursued methods to turn back their biological clock. This interest coalesced within the nascent field of endocrinology, then an emerging specialty. The modern era of molecular science is now offering proof-of-concept evidence to address the once intractable problem of low or absent ovarian reserve. Yet, ovarian rejuvenation by platelet-rich plasma (PRP) originates from a heritage shared with both hormone replacement therapy (HRT) and sex reassignment surgery. These therapeutic ancestors later developed into allied, but now distinct, clinical fields. Here, current iterations of intraovarian PRP are discussed with historical and cultural precursors centering on cell and tissue regenerative effects. Intraovarian PRP thus shows promise for women in menopause as an alternative to conventional HRT, and to those seeking pregnancy—either with advanced reproductive technologies or as unassisted conceptions. Full article
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Article
Anti-Tumor Effects of Ginsenoside 20(S)-Protopanaxadiol and 1,25-Dihydroxyvitamin D3 Combination in Castration Resistant Prostate Cancer
Medicines 2021, 8(6), 28; https://doi.org/10.3390/medicines8060028 - 04 Jun 2021
Viewed by 963
Abstract
In spite of possessing desirable anticancer properties, currently, limited clinical success has been achieved with 20(S)-protopanaxadiol (aPPD) and 1,25-dihydroxyvitamin D3 (calcitriol). This study is designed to evaluate if the combination of aPPD with calcitriol can inhibit human prostate cancer xenograft growth by using [...] Read more.
In spite of possessing desirable anticancer properties, currently, limited clinical success has been achieved with 20(S)-protopanaxadiol (aPPD) and 1,25-dihydroxyvitamin D3 (calcitriol). This study is designed to evaluate if the combination of aPPD with calcitriol can inhibit human prostate cancer xenograft growth by using nuclear receptor signaling. Athymic male nude mice were utilized to establish an androgen-independent human prostate cancer C4-2 cell castration-resistant prostate cancer (CRPC) xenograft model. Mice were treated orally for six weeks with 70 mg/kg aPPD administered once daily or three times per week with 4 µg/kg calcitriol or in combination or only with vehicle control. Contrary to our expectations, calcitriol treatment alone increased C4-2 tumor growth. However, the addition of calcitriol substantially increased aPPD-mediated tumor growth suppression (76% vs. 53%, combination vs. aPPD alone). The combination treatment significantly increased levels of cleaved caspase-3 apoptotic marker compared to vehicle-treated or aPPD-treated C4-2 tumors. The mechanistic elucidations indicate that tumor inhibition by the aPPD and calcitriol combination was accompanied by elevated vitamin D receptor (VDR) protein expression. In silico data suggest that aPPD weakly binds to the native LBD pocket of VDR. Interestingly, the combination of aPPD and calcitriol activated VDR at a significantly higher level than calcitriol alone and this indicates that aPPD may be an allosteric activator of VDR. Overall, aPPD and calcitriol combination significantly inhibited tumor growth in vivo with no acute or chronic toxic effects in the C4-2 xenograft CRPC nude mice. The involvement of VDR and downstream apoptotic pathways are potential mechanistic routes of antitumor effects of this combination. Full article
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Article
Design, Syntheses, and Bioevaluations of Some Novel N2-Acryloylbenzohydrazides as Chemostimulants and Cytotoxic Agents
Medicines 2021, 8(6), 27; https://doi.org/10.3390/medicines8060027 - 03 Jun 2021
Viewed by 882
Abstract
A series of novel N2-acryloylhydrazides 1a–m and a related series of compounds 6a–c were prepared as potential chemostimulants. In general, these compounds are cytotoxic to human HCT 116 colon cancer cells, as well as human MCF-7 and MDA-MB-231 breast cancer cell [...] Read more.
A series of novel N2-acryloylhydrazides 1a–m and a related series of compounds 6a–c were prepared as potential chemostimulants. In general, these compounds are cytotoxic to human HCT 116 colon cancer cells, as well as human MCF-7 and MDA-MB-231 breast cancer cell lines. A representative compound N1-(3,4-dimethoxyphenylcarbonyl)-N2-acryloylhydrazine 1m sensitized HCT 116 cells to the potent antineoplastic agent 3,5-bis(benzylidene)-4-piperidone 2a, and also to 5-fluorouracil. A series of compounds was prepared that incorporated some of the molecular features of 2a and related compounds with various N2-acryloylhydrazides in series 1. These compounds are potent cytotoxins. Two modes of action of representative compounds are the lowering of mitochondrial membrane potential and increasing the concentration of reactive oxygen species. Full article
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Article
β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells
Medicines 2021, 8(6), 26; https://doi.org/10.3390/medicines8060026 - 02 Jun 2021
Viewed by 876
Abstract
Background: β-thujaplicin, a natural tropolone derivative, has anticancer effects on various cancer cells via apoptosis. However, the apoptosis regulatory proteins involved in this process have yet to be revealed. Methods: Trypan blue staining, a WST-8 assay, and a caspase-3/7 activity assay were [...] Read more.
Background: β-thujaplicin, a natural tropolone derivative, has anticancer effects on various cancer cells via apoptosis. However, the apoptosis regulatory proteins involved in this process have yet to be revealed. Methods: Trypan blue staining, a WST-8 assay, and a caspase-3/7 activity assay were used to investigate whether β-thujaplicin sensitizes cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Additionally, western blotting was performed to clarify the effects of β-thujaplicin on X-linked inhibitor of apoptosis protein (XIAP) in NCI-H460 cells and a fluorescence polarization binding assay was used to evaluate the binding-inhibitory activity of β-thujaplicin against XIAP-BIR3. Results: β- and γ-thujaplicins decreased the viability of NCI-H460 cells in a dose-dependent manner; they also sensitized the cells to TRAIL-induced cell growth inhibition and apoptosis. β-thujaplicin significantly potentiated the apoptosis induction effect of TRAIL on NCI-H460 cells, which was accompanied by enhanced caspase-3/7 activity. Interestingly, β-thujaplicin treatment in NCI-H460 cells decreased XIAP levels. Furthermore, β-thujaplicin was able to bind XIAP-BIR3 at the Smac binding site. Conclusions: These findings indicate that β-thujaplicin could enhance TRAIL-induced apoptosis in NCI-H460 cells via XIAP inhibition and degradation. Thus, the tropolone scaffold may be useful for designing novel nonpeptidic small-molecule inhibitors of XIAP and developing new types of anticancer drugs. Full article
(This article belongs to the Special Issue Feature Papers in Cancer Biology and Anticancer Therapeutics)
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Article
The Role of Poly-Herbal Extract in Sodium Chloride-Induced Oxidative Stress and Hyperlipidemia in Male Wistar Rats
Medicines 2021, 8(6), 25; https://doi.org/10.3390/medicines8060025 - 31 May 2021
Viewed by 935
Abstract
Consistent consumption of high salt diet (HSD) has been associated with increased cellular generation of free radicals, which has been implicated in the derangement of some vital organs and etiology of cardiovascular disorders. This study was designed to investigate the combined effect of [...] Read more.
Consistent consumption of high salt diet (HSD) has been associated with increased cellular generation of free radicals, which has been implicated in the derangement of some vital organs and etiology of cardiovascular disorders. This study was designed to investigate the combined effect of some commonly employed medicinal plants on serum lipid profile and antioxidant status of aorta, kidney, and liver of high salt diet-fed animals. Out of the total fifty male Wistar rats obtained, fifteen were used for acute toxicity study, while the remaining thirty-five were divided into 5 groups of 7 animals each. Group 1 and 2 animals were fed normal rat chow (NRC) and 16% high salt diet (HSD) only, respectively. Animals in groups 3, 4 and 5 were fed 16% HSD with 800, 400, and 200 mg/kg bw poly-herbal extract (PHE), respectively, once for 28 consecutive days. Serum low-density lipoprotein (LDL), triacylglycerol (TG), total cholesterol (TC) and high-density lipoprotein (HDL), malondialdehyde, nitric oxide, catalase, superoxide dismutase, glutathione peroxidase, glutathione concentration, and activities were assessed in the aorta, kidney, and liver. Poly-herbal extract (p < 0.05) significantly reduced malondialdehyde and nitric oxide concentrations and also increased antioxidant enzymes and glutathione activity. Elevated serum TG, TC, LDL, and TC content in HSD-fed animals were significantly (p < 0.05) reduced to normal in PHE-treated rats while HDL was significantly elevated (p < 0.05) in a concentration-dependent manner in PHE treated animals. Feeding with PHE attenuated high-salt diet imposed derangement in serum lipid profile and antioxidant status in the organs of the experimental rats. Full article
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Review
Recognition and Management of Antipsychotic-Induced Parkinsonism in Older Adults: A Narrative Review
Medicines 2021, 8(6), 24; https://doi.org/10.3390/medicines8060024 - 26 May 2021
Viewed by 1381
Abstract
Background: Parkinsonism is a common side-effect of antipsychotic drugs especially in older adults, who also present with a higher frequency of neurodegenerative disorders like Idiopathic Parkinson’s disease (IPD). Distinguishing between antipsychotic-induced parkinsonism (AIP) and IPD is challenging due to clinical similarities. Up to [...] Read more.
Background: Parkinsonism is a common side-effect of antipsychotic drugs especially in older adults, who also present with a higher frequency of neurodegenerative disorders like Idiopathic Parkinson’s disease (IPD). Distinguishing between antipsychotic-induced parkinsonism (AIP) and IPD is challenging due to clinical similarities. Up to 20% of older adults may suffer from persisting parkinsonism months after discontinuation of antipsychotics, suggesting underlying neurodegeneration. A review of the literature on AIP in older adults is presented, focusing on epidemiology, clinical aspects, and management. Methods: A literature search was undertaken on EMBASE, MEDLINE and PsycINFO, for articles on parkinsonism induced by antipsychotic drugs or other dopamine 2 receptor antagonists in subjects aged 65 or older. Results: AIP in older adults is the second most common cause of parkinsonism after IPD. Older age, female gender, exposure to high-potency first generation antipsychotics, and antipsychotic dosage are the main risk factors. The clinical presentation of AIP resembles that of IPD, but is more symmetrical, affects upper limbs more, and tends to have associated motor phenomena such as orofacial dyskinesias and akathisia. Presence of olfactory dysfunction in AIP suggests neurodegeneration. Imaging of striatal dopamine transporters is widely used in IPD diagnosis and could help to distinguish it from AIP. There is little evidence base for recommending pharmacological interventions for AIP, the best options being dose-reduction/withdrawal, or switching to a second-generation drug. Conclusions: AIP is a common occurrence in older adults and it is possible to differentiate it from IPD. Further research is needed into its pathophysiology and on its treatment. Full article
(This article belongs to the Special Issue Drug-Induced Diseases in the Elderly)
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