Transient plasticity response is regulated by histone deacetylase inhibitor in oxygen-glucose deprivation condition.

BACKGROUND: The pathological form of synaptic plasticity, ischemic long-term potentiation (iLTP), induced by oxygen and glucose deprivation (OGD), is implicated in the acute phase of stroke with the potentiation of N-methyl-D-aspartate receptor (NMDAR). While there has been widespread attention on the excitatory system, a recent study reported that γ-aminobutyric acid (GABA)ergic system is also involved in iLTP. Valproic acid (VPA), a histone deacetylase inhibitor, protects against ischemic damage. However, whether VPA regulates early phase plasticity in ischemic stroke remains unknown. The present study aims to investigate the potential role and mechanism of VPA in ischemic stroke. METHODS: A brief exposure of OGD on the hippocampal slices and the induction of photothrombotic ischemia (PTI) were used as ex vivo and in vivo models of ischemic stroke, respectively. RESULTS: Using extracellular recordings, iLTP was induced in the hippocampal Schaffer collateral pathway following OGD exposure. VPA treatment abolished hippocampal iLTP via GABAA receptor enhancement and extracellular signal-regulated kinase (ERK) phosphorylation. Administration of VPA reduced brain infarct volume and motor dysfunction in mice with PTI. Moreover, VPA protected against ischemic injury by upregulating the GABAergic system and ERK phosphorylation, as well as by reducing of matrix metalloproteinase in a PTI-induced ischemic stroke model. CONCLUSIONS: Together, this study revealed the protection of VPA in ex vivo OGD-induced pathological form of neuroplasticity and in vivo PTI-induced brain damage and motor dysfunction through rescuing GABAergic deficiency and the pathological hallmarks of ischemia.

An efficient cellular image-based platform for high-content screening of neuroprotective agents against chemotherapy-induced neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect, with no approved therapy for prevention or treatment. Here, we aimed to establish a high-content image platform based on the neurite outgrowth of dorsal root ganglia (DRG)-derived neuron cells for the discovery of neuroprotective agents against paclitaxel-induced CIPN. ND7/23 cells, an immortalized hybrid DRG cell line, were maturely differentiated by induction with nerve growth factor and upregulation of intracellular cAMP levels. High-content image analyses of the neurofilament-stained neurite network showed that paclitaxel disrupted the neurite outgrowth of well-differentiated ND7/23 DRG neuron cells, recapitulating characteristic effects of paclitaxel on primary cultured DRG neurons. This process coincided with the upregulated activity of store-operated Ca2+ entry, similar to those found in rodent models of paclitaxel-induced CIPN. The previously identified neuroprotective agents, minoxidil and 8-Br-cyclic adenosine monophosphate ribose (8-Br-cADPR), attenuated the reduction in total neurite outgrowth in paclitaxel-damaged ND7/23 cells. Additionally, the total neurite outgrowth of well-differentiated ND7/23 cells was concentration-dependently reduced by the neurotoxic chemotherapeutic agents, oxaliplatin and bortezomib, but not the less neurotoxic 5-fluorouracil. We demonstrated that high-content analyses of neurite morphology in well-differentiated DRG neuron-derived cells provide an effective, reproducible, and high-throughput strategy for developing therapeutics against CIPN.

Different synaptic mechanisms of intermittent and continuous theta-burst stimulations in a severe foot-shock induced and treatment-resistant depression in a rat model.

Treatment-resistant depression (TRD) is a condition wherein patients with depression fail to respond to antidepressant trials. A new form of repetitive transcranial magnetic stimulation (rTMS), called theta-burst stimulation (TBS), which includes intermittent theta-burst stimulation (iTBS) and continuous theta-burst stimulation (cTBS), is non-inferior to rTMS in TRD treatment. However, the mechanism of iTBS and cTBS underlying the treatment of TRD in the prefrontal cortex (PFC) remains unclear. Hence, we applied foot-shock stress as a traumatic event to develop a TRD rat model and investigated the different mechanisms of iTBS and cTBS. The iTBS and cTBS treatment were effective in depressive-like behavior and active coping behavior. The iTBS treatments improved impaired long-term potentiation and long-term depression (LTD), whereas the cTBS treatment only improved aberrant LTD. Moreover, the decrease in mature brain-derived neurotrophic factor (BDNF)-related protein levels were reversed by iTBS treatment. The decrease in proBDNF-related protein expression was improved by iTBS and cTBS treatment. Both iTBS and cTBS improved the decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and downregulation of mammalian target of the rapamycin (mTOR) signaling pathway. The iTBS produces both excitatory and inhibitory synaptic effects, and the cTBS only produces inhibitory synaptic effects in the PFC.

Chemical investigations and cytotoxic effects of metabolites from Antrodia camphorata against human hepatocellular carcinoma cells.

Antrodia camphorata is used as a medicinal fungus in Taiwan to treat fatigue, food intoxication, and enhance liver function. Here we identified fermented metabolic components from the mycelium of A. camphorata KH37 and explored their anti-hepatoma potentials with study models of human hepatoblastoma cell lines. Bioassay-guided fractionation of the solid fermentation powder of A. camphorata KH37 led to the isolation of one new quinonol, antroquinonol Z (1), and nine known compounds (2-10). Treatment with 10 µM antrocamols LT1 (2) or LT3 (3) reduced cell viability of HepG2 and Huh-7 cells to about 60% in 48 hours. Antroquinonol Z (1) exhibited mild cytotoxicity against Huh-7 cells in 48 and 72 hours. Interestingly, two fractions showed cytotoxicity in HepG2 and Huh-7 cells, even better than compounds isolated from these fractions. The significant cytotoxicity of partially purified samples from A. camphorata KH37 exhibited a potential for developing alternative or complementary therapeutics against hepatoma.

2,6-Disubstituted Piperidine Alkaloids with Neuroprotective Activity from Hippobroma longiflora.

Three new alkaloids, hipporidine A (1: ), hipporidine B (2: ), and (-)-lobeline N-oxide (3: ), were discovered from the whole plant of Hippobroma longiflora together with five known compounds (4: -8: ). Their 2,6-disubstituted piperidine structures were established based on the HRESIMS, NMR (COSY, HMBC, HSQC, NOESY), and UV spectroscopic data. Hipporidines A (1: ) and B (2: ) possess a rare 1,3-oxazinane moiety. Compound 3: is the N-oxide derivative of (-)-lobeline (6: ). Moreover, the absolute configuration of norlobeline (5: ) was established by single-crystal X-ray diffraction analysis. Three major secondary metabolites (6: -8: ) were evaluated for their neuroprotective effect against paclitaxel-induced neurotoxicity. Consequently, pretreatment with compound 8: at a concentration of 1.0 µM displayed significant attenuation on paclitaxel-damaged neurite outgrowth of dorsal root ganglion neurons without interfering with the cytotoxicity of paclitaxel on cervical cancer SiHa cells.

Self-Emulsifying Phospholipid Preconcentrates for the Enhanced Photoprotection of Luteolin.

Exposure to ultraviolet B (UVB) leads to the overproduction of reactive oxygen species (ROS), causing higher risks of skin disorders. Luteolin (Lut) is a naturally occurring antioxidant that can absorb a broad range of ultraviolet light, but its water solubility and skin permeability are limited and insufficient. The aim of the current study was to develop a Lut-loaded self-emulsifying phospholipid preconcentrate (LSEPP) for enhancing the solubility, permeability, and photoprotective activity of Lut. The designed formulations were firstly examined for their droplet size, zeta potential, dispersity, and in vitro corneum permeability after dispensing the preconcentrate to form an emulsion; the optimized formulation was further characterized for its emulsified morphology, compatibility with excipients, stability in the preconcentrate form, and photoprotective activity by the HaCaT cell model under the emulsified status. The optimized LSEPP formulation attained a smaller droplet size (140.6 ± 24.2 nm) with the addition of 1,8-cineole and increased the permeability of Lut by 7-fold. As evidenced in the cell model studies, the optimized LSEPP formulation can efficiently deliver Lut into HaCaT cells after emulsification and result in a 115% better cell viability as well as a 203% stronger ROS scavenging capability, compared with those of unformulated Lut after UVB irradiation. To sum up, we have successfully developed an LSEPP formulation, which is a safe and promising topical delivery system for enhancing the photoprotective effects of Lut.

Tyrosinase Inhibitors Derived from Chemical Constituents of Dianella ensifolia.

Dianella ensifolia is a perennial herb with thickened rhizome and is widely distributed in tropical and subtropical regions of Asia, Australia, and the Pacific islands. This plant has the potential to be used as a source of herbal medicine. This study investigated further phytochemistry and tyrosinase inhibitory effect of some constituents isolated from D. ensifolia. Four new flavans, (2S)-4'-hydroxy-6,7-dimethoxyflavan (1), (2S)-3',4'-dihydroxy-7-methoxy-8-methylflavan (2), (2S)-2'-hydroxy-7-methoxyflavan (3), and (2S,1'S)-4-hydroxy-4-(7-methoxy-8-methylchroman-2-yl)-cyclohex-2-enone (4), together with 67 known compounds, including 10 flavans (5−14), 5 flavanones (15−19), 3 flavone (20−22), 5 chalcones (23−27), 3 chromones (28−30), 15 aromatics (31−45), 7 phenylpropanoids (46−52), one lignan (53), 7 steroids (54−60), one monoterpene (61), one diterpene (62), 4 triterpenes (63−66), a carotenoid (67), 2 alkaloids (68 and 69), and 2 fatty acids (70 and 71) were isolated from D. ensifolia. Their structures were elucidated on the basis of physical and spectroscopic data analyses. Moreover, compounds 1−4, 8, 10−15, 20, 21, and 41 were evaluated for their mushroom tyrosinase inhibitory effect. Compounds 11 and 14 strongly inhibited mushroom tyrosinase activity with IC50 values of 8.6 and 14.5 µM, respectively.

NIR-Triggered Generation of Reactive Oxygen Species and Photodynamic Therapy Based on Mesoporous Silica-Coated LiYF4 Upconverting Nanoparticles.

To date, the increase in reactive oxygen species (ROS) production for effectual photodynamic therapy (PDT) treatment still remains challenging. In this study, a facile and effective approach is utilized to coat mesoporous silica (mSiO2) shell on the ligand-free upconversion nanoparticles (UCNPs) based on the LiYF4 host material. Two kinds of mesoporous silica-coated UCNPs (UCNP@mSiO2) that display green emission (doped with Ho3+) and red emission (doped with Er3+), respectively, were successfully synthesized and well characterized. Three photosensitizers (PSs), merocyanine 540 (MC 540), rose bengal (RB), and chlorin e6 (Ce6), with the function of absorption of green or red emission, were selected and loaded into the mSiO2 shell of both UCNP@mSiO2 nanomaterials. A comprehensive study for the three UCNP@mSiO2/PS donor/acceptor pairs was performed to investigate the efficacy of fluorescence resonance energy transfer (FRET), ROS generation, and in vitro PDT using a MCF-7 cell line. ROS generation detection showed that as compared to the oleate-capped and ligand-free UCNP/PS pairs, the UCNP@mSiO2/PS nanocarrier system demonstrated more pronounced ROS generation due to the UCNP@mSiO2 nanoparticles in close vicinity to PS molecules and a higher loading capacity of the photosensitizer. As a result, the three LiYF4 UCNP@mSiO2/PS nanoplatforms displayed more prominent therapeutic efficacies in PDT by using in vitro cytotoxicity tests.

Undescribed alkyne-geranylcyclohexenetriols from the endophyte Diaporthe caulivora 09F0132 and their anti-melanogenic activity.

To explore valuable endophytic fungus from Formosan Lauraceous plants as natural medicinal products, the fungus, Diaporthe caulivora isolated from leaves of Neolitsea daibuensis, was investigated. Through a thorough investigation of the ethanolic extract of the solid fermentation of D. caulivora 09F0132, six undescribed alkyne-geranylcyclohexenetriols, caulivotrioloxins A-F, one undescribed trichopyrone, diapopyrone, two undescribed sesquiterpenes, caulibysins A-B, one compound firstly isolated from the natural source, 3-O-desmethyl phomentrioloxin, and eight known compounds have been successfully identified. The absolute configuration of caulibysin A was confirmed by single-crystal X-ray diffraction, and those of (3R,8S)-5,7-dihydroxy-3-(1-hydroxyethyl)phthalide and (3S,8S)-5,7-dihydroxy-3-(1-hydroxyethyl)phthalide were determined by circular dichroism (CD) spectra. Among the isolated compounds, caulivotrioloxin A concentration-dependently decreased the cellular melanin contents and tyrosinase activities in mouse melanoma B16-F10 cells, suggesting the anti-melanogenic potentials. The anti-melanogenic effects of caulivotrioloxin A involved the decrease in the protein expressions of melanogenic enzymes, including tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2. Taken together, these results suggested that the isolates from D. caulivora could be served as natural melanogenesis inhibitors for cosmeceutical applications.

Super-Resolution Microscopy Reveals That Stromal Interaction Molecule 1 Trafficking Depends on Microtubule Dynamics.

Store-operated Ca2+ entry (SOCE) is an essential pathway for Ca2+ signaling, and regulates various vital cellular functions. It is triggered by the endoplasmic reticulum Ca2+ sensor stromal interaction molecule 1 (STIM1). Illustration of STIM1 spatiotemporal structure at the nanometer scale during SOCE activation provides structural and functional insights into the fundamental Ca2+ homeostasis. In this study, we used direct stochastic optical reconstruction microscopy (dSTORM) to revisit the dynamic process of the interaction between STIM1, end-binding protein (EB), and microtubules to the ER-plasma membrane. Using dSTORM, we found that"powder-like"STIM1 aggregates into "trabecular-like" architectures toward the cell periphery during SOCE, and that an intact microtubule network and EB1 are essential for STIM1 trafficking. After thapsigargin treatment, STIM1 can interact with EB1 regardless of undergoing aggregation. We generated STIM1 variants adapted from a real-world database and introduced them into SiHa cells to clarify the impact of STIM1 mutations on cancer cell behavior. The p.D76G and p.D84Y variants locating on the Ca2+ binding domain of STIM1 result in inhibition of focal adhesion turnover, Ca2+ influx during SOCE and subsequent cell migration. Inversely, the p.R643C variant on the microtubule interacting domain of STIM1 leads to dissimilar consequence and aggravates cell migration. These findings imply that STIM1 mutational patterns have an impact on cancer metastasis, and therefore could be either a prognostic marker or a novel therapeutic target to inhibit the malignant behavior of STIM1-mediated cancer cells. Altogether, we generated novel insight into the role of STIM1 during SOCE activation, and uncovered the impact of real-world STIM1 variants on cancer cells.

Inflammation-related pyroptosis, a novel programmed cell death pathway, and its crosstalk with immune therapy in cancer treatment.

In recent decades, chemotherapies targeting apoptosis have emerged and demonstrated remarkable achievements. However, emerging evidence has shown that chemoresistance is mediated by impairing or bypassing apoptotic cell death. Several novel types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, have recently been reported to play significant roles in the modulation of cancer progression and are considered a promising strategy for cancer treatment. Thus, the switch between apoptosis and pyroptosis is also discussed. Cancer immunotherapy has gained increasing attention due to breakthroughs in immune checkpoint inhibitors; moreover, ferroptosis, necroptosis, and pyroptosis are highly correlated with the modulation of immunity in the tumor microenvironment. Compared with necroptosis and ferroptosis, pyroptosis is the primary mechanism for host defense and is crucial for bridging innate and adaptive immunity. Furthermore, recent evidence has demonstrated that pyroptosis exerts benefits on cancer immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR-T). Hence, in this review, we elucidate the role of pyroptosis in cancer progression and the modulation of immunity. We also summarize the potential small molecules and nanomaterials that target pyroptotic cell death mechanisms and their therapeutic effects on cancer.

Investigations into Chemical Components from Monascus purpureus with Photoprotective and Anti-Melanogenic Activities.

Monascus species are asexually or sexually reproduced homothallic fungi that can produce a red colorant, specifically the so-called red yeast rice or Anka, which is used as a food ingredient in Asia. Traditional experiences of using Monascus for treating indigestion, enhancing blood circulation, and health remedies motivate us to investigate and repurpose Monascus-fermented products. Here, two new 5H-cyclopenta[c]pyridine type azaphilones, 5S,6S-monaspurpyridine A (1) and 5R,6R-monaspurpyridine A (2), two new xanthonoids, monasxanthones A and B (3 and 4), one new naphthalenone, monasnaphthalenone (5), and one new azaphilone, monapurpurin (6), along with two known compounds were isolated from the 70% EtOH extract of a citrinin-free domesticated strain M. purpureus BCRC 38110. The phytochemical properties of the xanthonoid and naphthalenone components were first identified from Monascus sp. differently from the representative ingredients of polyketide-derived azaphilones. UVB-induced cell viability loss and reactive oxygen species (ROS) overproduction in human keratinocytes were attenuated by monascuspirolide B (7) and ergosterol peroxide (8), indicating their photoprotective potentials. Ergosterol peroxide (8) decreased the melanin contents and tyrosinase activities of mouse melanocytes, depending on the concentration, suggesting their anti-melanogenic effects. In conclusion, six new and two known compounds were isolated from M. purpureus BCRC 38110, and two of them exhibited dermal protective activities. The results revealed the novel potential of M. purpureus for developing natural cosmeceutics against skin photoaging.

Different types of components obtained from Monascus purpureus with neuroprotective and anti-inflammatory potentials.

The mold Monascus has been used as a natural food coloring agent and food additive for more than 1000 years in Asian countries. In Chinese herbology, it was also used for easing digestion and antiseptic effects. Through a thorough investigation of a citrinin-free strain: M. purpureus BCRC 38110, four azaphilones, three benzenoids, one benzofuranone, one 5',6'-dihydrospiro[isochromane-1,2'-pyran]-4'(3'H)-one derivative, two steroids, and six tetralones have been successfully identified. Among them, monapyridine A (1), monatetralones A-E (2-6), and monabenzofuranone (7) were first reported. Their structures were characterized by 1D and 2D NMR, UV, IR, and HRESIMS analyses. With a series of bioactivity screening, monascuspirolide B (14) and ergosterol peroxide (16) exhibited concentration-dependent attenuation of the paclitaxel-induced neurite damage of mouse dorsal root ganglion neurons. The interleukin (IL)-1ß-induced release of inflammatory cytokines IL-8 and tumor necrosis factor (TNF)-α in human chondrosarcoma cells was inhibited by monapurpureusone (8) and monascuspirolide B (14). Altogether, M. purpureus BCRC 38110 possessed potentials as natural therapeutics against inflammatory osteoarthritis and paclitaxel-induced neurotoxicity.

The Long-Term DEHP Exposure Confers Multidrug Resistance of Triple-Negative Breast Cancer Cells through ABC Transporters and Intracellular ROS.

The characteristics of phthalates had been thought to be similar to endocrine disruptors, which increases cancer risk. The role of phthalates in acquired drug resistance remains unclear. In this study, we investigated the effect of di-(2-ethylhexyl) phthalate (DEHP) on acquired drug resistance in breast cancer. MCF7 and MDA-MB-231 breast cancer cells were exposed to long-term physiological concentration of DEHP for more than three months. Long-exposure DEHP permanently attenuated the anti-proliferative effect of doxorubicin with estrogen receptor-independent activity even after withdrawal of DEHP. Long term DEHP exposure significantly reduced ROS (O2-) level in MDA-MB-231 cells while increased in MCF7 cells. ATP-binding cassette (ABC) transporters possess a widely recognized mechanism of drug resistance and are considered a target for drug therapy. Upregulation of ABC family proteins, ABCB-1 and ABCC-1 observed in DEHP-exposed clones compared to doxorubicin-resistant (DoxR) and parental MDA-MB-231 cells. A viability assay showed enhanced multidrug resistance in DEHP-exposed clones against Dox, topotecan, and irinotecan. Inhibition of ABC transporters with tariquidar, enhanced drug cytotoxicity through increased drug accumulation reversing acquired multidrug resistance in MDA-MB-231 breast cancer cells. Tariquidar enhanced Dox cytotoxicity by increasing intracellular ROS production leading to caspase-3 mediated apoptosis. Activation of PI3K/Akt signaling enhanced proliferation and growth of DEHP-exposed MDA-MB-231 cells. Overall, long-term DEHP exposure resulted in acquired multidrug resistance by upregulating ABCB-1 and ABCC1; apart from proliferation PI3K/Akt may be responsible for acquired drug resistance through ABC transporter upregulation. Targeting ABCB1 and ABCC1 with tariquidar may be a promising strategy for reversing the acquired multidrug resistance of triple-negative breast cancer cells.

Oenothera laciniata Hill Extracts Exhibits Antioxidant Effects and Attenuates Melanogenesis in B16-F10 Cells via Downregulating CREB/MITF/Tyrosinase and Upregulating p-ERK and p-JNK.

Oenothera laciniata Hill is a perennial herb traditionally used to alleviate inflammatory complications. This study investigated the antioxidant and anti-melanogenic activities of O. laciniata. The methanolic extract (OLM) of O. laciniata and its different fractions, including ethyl acetate (OLEF), n-butanol (OLBF), and water (OLWF) fractions, were prepared. Antioxidant activities were evaluated by total phenolic content, the radical-scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH•), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+•), and superoxide anion (O2-•), reducing capacity, and metal chelating ability. OLM and its fractions exhibited potent antioxidant activity in these in vitro assays, with a correlation between radical-scavenging activity and total phenolic content. OLM and its fractions inhibited the mushroom tyrosinase activity superior to the reference control, ascorbic acid. In B16-F10 melanoma cells, OLM and its fractions significantly decreased melanin production and tyrosinase activity. Mechanistic investigations revealed that OLM and its fractions inhibited tyrosinase and TRP-2 expressions via downregulating MITF and phosphorylated CREB and differentially inducing ERK or JNK phosphorylation. Additionally, OLM and its fractions caused no significant cytotoxicity towards B16-F10 or skin fibroblast cells at concentrations used in these cellular assays. These findings demonstrated the potential of O. laciniata extracts as the ideal skin protective agent with dual antioxidant and anti-melanogenic activities.

Identification of Beilschmiedia tsangii Root Extract as a Liver Cancer Cell-Normal Keratinocyte Dual-Selective NRF2 Regulator.

Transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) plays a crucial role in regulating the expression of genes participating in cellular defense mechanisms against oxidative or xenobiotic insults. However, there is increasing evidence showing that hyperactivation of NRF2 is associated with chemoresistance in several cancers, including hepatocellular carcinoma (HCC), thus making NRF2 an attractive target for cancer therapy. Another important issue in cancer medication is the adverse effects of these substances on normal cells. Here, we attempted to identify a dual-selective NRF2 regulator that exerts opposite effects on NRF2-hyperactivated HCC cells and normal keratinocytes. An antioxidant response element driven luciferase reporter assay was established in Huh7 and HaCaT cells as high-throughput screening platforms. Screening of 3,000 crude extracts from the Taiwanese Indigenous Plant Extract Library resulted in the identification of Beilschmiedia tsangii (BT) root extract as a dual-selective NRF2 regulator. Multiple compounds were found to contribute to the dual-selective effects of BT extract on NRF2 signaling in two cell lines. BT extract reduced NRF2 protein level and target gene expression levels in Huh7 cells but increased them in HaCaT cells. Furthermore, notable combinatory cytotoxic effects of BT extract and sorafenib on Huh7 cells were observed. On the contrary, sorafenib-induced inflammatory reactions in HaCaT cells were reduced by BT extract. In conclusion, our results suggest that the combination of a selective NRF2 activator and inhibitor could be a practical strategy for fine-tuning NRF2 activity for better cancer treatment and that plant extracts or partially purified fractions could be a promising source for the discovery of dual-selective NRF2 regulators.

Additional alkaloids from Zoanthus vietnamensis with neuroprotective and anti-angiogenic effects.

A chemical investigation of the zoantharian Zoanthus vietnamensis, collected off Taiwan, yielded eleven new alkaloids, 7α-hydroxykuroshine J (1), 18ß-hydroxykuroshine J (2), 5α-hydroxyzoanthenamine (3), 5ß-hydroxyzoanthenamine (4), 14α-hydroxyzoanthenamine (5), 30-hydroxyzoanthenamine (6), 11-dehydroxy-18-epi-kuroshine A (7), 5α-hydroxykuroshine A (8), 7ß-hydroxykuroshine A (9), 11-keto-oxyzoanthamine (10), and 30-hydroxyzoanthamine (11), along with eight known compounds (12-19). The structures of these compounds were identified by detailed spectroscopic data, including HRESIMS, IR, NMR, and UV spectra. All secondary metabolites isolated from Z. vietnamensis were investigated for the anti-angiogenic effect in human endothelial progenitor cells (EPCs). Compounds 6, 7, 11, and 13 exhibited mild anti-angiogenic effect by blocking cell growth and tube formation of EPCs. The neuroprotective potential of four major compounds 12, 14, 15, and 19 against paclitaxel-induced neurotoxicity was evaluated. Pretreatment of 14 and 15 protected paclitaxel-damaged neurite outgrowth of dorsal root ganglion (DRG) neurons, without interfering the cytotoxic activity of paclitaxel on cervical cancer SiHa cells.

Polypharmacy and pattern of medication use in community-dwelling older adults: A systematic review.

AIM: To synthesise current study findings on the diseases and the corresponding medications that are potentially associated with polypharmacy in community-dwelling older adults. BACKGROUND: Polypharmacy is receiving increased attention as a potential problem for the older population. Although several scientific investigations have studied polypharmacy, most of them were carried out in long-term care facilities or mixed settings rather than in community settings solely. METHODS: This systematic review followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Relevant studies published in the English language in peer-reviewed journals were identified from searches of seven electronic databases for the period of January 2000 through December 2019. Inclusion criteria were: (1) Participants were older adults aged 65 years and older; (2) Polypharmacy was defined by medication count; (3) Medication classes associated with polypharmacy were revealed; (4) Studies were conducted in outpatient care or community settings. The Joanna Briggs Institute critical appraisal checklists for cross-sectional studies and for cohort studies were used to assess the methodological quality. RESULTS: Ten studies were considered having appropriate and acceptable quality to be reviewed, comprising nine cross-sectional studies and one cohort study. Polypharmacy was most defined as concurrently using five or more medications. Polypharmacy prevalence ranged between 7%-45%. Older age, comorbidity, poor self-perceived health status, limitations in physical activity, history of falls, depression, and pain were positively associated with polypharmacy. The most prevalent medication taken by older adults with polypharmacy was cardiovascular drugs. CONCLUSIONS: The prevalence of polypharmacy in older adults varying widely may be due to geographical locations, clinical practice guidelines, and polypharmacy definition used. RELEVANCE TO CLINICAL PRACTICE: Validated measurements to investigate medications associated with polypharmacy are required. How polypharmacy develops over time needs to be investigated in longitudinal studies in order to formulate strategies for reducing polypharmacy.

The Important Role of Ion Transport System in Cervical Cancer.

Cervical cancer is a significant gynecological cancer and causes cancer-related deaths worldwide. Human papillomavirus (HPV) is implicated in the etiology of cervical malignancy. However, much evidence indicates that HPV infection is a necessary but not sufficient cause in cervical carcinogenesis. Therefore, the cellular pathophysiology of cervical cancer is worthy of study. This review summarizes the recent findings concerning the ion transport processes involved in cell volume regulation and intracellular Ca2+ homeostasis of epithelial cells and how these transport systems are themselves regulated by the tumor microenvironment. For cell volume regulation, we focused on the volume-sensitive Cl- channels and K+-Cl- cotransporter (KCC) family, important regulators for ionic and osmotic homeostasis of epithelial cells. Regarding intracellular Ca2+ homeostasis, the Ca2+ store sensor STIM molecules and plasma membrane Ca2+ channel Orai proteins, the predominant Ca2+ entry mechanism in epithelial cells, are discussed. Furthermore, we evaluate the potential of these membrane ion transport systems as diagnostic biomarkers and pharmacological interventions and highlight the challenges.

The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications.

Over the past decades, promising therapies targeting different signaling pathways have emerged. Among these pathways, apoptosis has been well investigated and targeted to design diverse chemotherapies. However, some patients are chemoresistant to these therapies due to compromised apoptotic cell death. Hence, exploring alternative treatments aimed at different mechanisms of cell death seems to be a potential strategy for bypassing impaired apoptotic cell death. Emerging evidence has shown that necroptosis, a caspase-independent form of cell death with features between apoptosis and necrosis, can overcome the predicament of drug resistance. Furthermore, previous studies have also indicated that there is a close correlation between necroptosis and reactive oxygen species (ROS); both necroptosis and ROS play significant roles both under human physiological conditions such as the regulation of inflammation and in cancer biology. Several small molecules used in experiments and clinical practice eliminate cancer cells via the modulation of ROS and necroptosis. The molecular mechanisms of these promising therapies are discussed in detail in this review.