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.
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.
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 Ca
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 Ca
homeostasis, the Ca
store sensor STIM molecules and plasma membrane Ca
channel Orai proteins, the predominant Ca
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.
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.
Store-operated Ca2+ entry (SOCE) is the principal Ca2+ entry mechanism in nonexcitable cells. Stromal-interaction molecule 1 (STIM1) is an endoplasmic reticulum Ca2+ sensor that triggers SOCE ...activation. However, the role of STIM1 in regulating cancer progression remains controversial and its clinical relevance is unclear. Here we show that STIM1-dependent signaling is important for cervical cancer cell proliferation, migration, and angiogenesis. STIM1 overexpression in tumor tissue is noted in 71% cases of early-stage cervical cancer. In tumor tissues, the level of STIM1 expression is significantly associated with the risk of metastasis and survival. EGF-stimulated cancer cell migration requires STIM1 expression and EGF increases the interaction between STIM1 and Orai1 in juxta-membrane areas, and thus induces Ca2+ influx. STIM1 involves the activation of Ca2+-regulated protease calpain, as well as Ca2+-regulated cytoplasmic kinase Pyk2, which regulate the focal-adhesion dynamics of migratory cervical cancer cells. Because of an increase of p21 protein levels and a decrease of Cdc25C protein levels, STIM1-silencing in cervical cancer cells significantly inhibits cell proliferation by arresting the cell cycle at the S and G2/M phases. STIM1 also regulates the production of VEGF in cervical cancer cells. Interference with STIM1 expression or blockade of SOCE activity inhibits tumor angiogenesis and growth in animal models, confirming the crucial role of STIM1-mediated Ca2+ influx in aggravating tumor development in vivo. These results make STIM1-dependent signaling an attractive target for therapeutic intervention.
Stromal interaction molecules STIM1 and STIM2 are endoplasmic reticulum (ER) Ca2+ sensors that initiate store‐operated Ca
2+ entry (SOCE). The roles of STIM1‐mediated SOCE in cancer biology have been ...highlighted in different types of cancer, but that of STIM2 is unknown. By the model of cervical cancer, here we focus on the cooperative regulation of SOCE by STIM proteins and their distinct roles in cellular function. Immunofluorescent stainings of surgical specimens of cervical cancer show that STIM1 and STIM2 are abundant in tumor tissues, but STIM1 is the major ER Ca
2+ sensor identified in the invasive front of cancer tissues. STIM1 or STIM2 overexpression in cervical cancer SiHa cells induces an upregulated SOCE. Regarding cellular function, STIM1 and STIM2 are necessary for cell proliferation, whereas STIM1 is the dominant ER Ca
2+ sensor involved in cell migration. During SOCE, STIM1 is aggregated and translocated towards the Orai1‐containing plasma membrane in association with the microtubule plus‐end binding protein EB1. In contrast, STIM2 is constitutively aggregated without significant trafficking or association with microtubules. These results show the distinct role of STIM1 and STIM2 in SOCE and cellular function of cervical cancer cells.
Although the roles of STIM1 in cancer cells have been well studied, the role of STIM2 in cellular function remains unclear. By the model of cervical cancer, here we demonstrate the distinct role of STIM1 and STIM2 in the regulation of store‐operated Ca2+ entry (SOCE) and cellular function. The results show that both STIM1 and STIM2 are necessary for cancer cell proliferation, whereas STIM1 is the dominant endoplasmic reticulum (ER) Ca
2+ sensor involved in cancer cell migration. EGF: epidermal growth factor; SOC: store‐operated Ca
2+
Intracellular Ca2+ is one of the crucial signalings that modulate various cellular functions. The dysregulation of Ca2+ homeostasis has been suggested as an important event in driving the expression ...of the malignant phenotypes, such as proliferation, migration, invasion, and metastasis. Cell migration is an early prerequisite for tumor metastasis that has a significant impact on patient prognosis. During cell migration, the exquisite spatial and temporal organization of intracellular Ca2+ provides a rapid and robust way for the selective activation of signaling components that play a central role in cytoskeletal reorganization, traction force generation, and focal adhesion dynamics. A number of known molecular components involved in Ca2+ influx pathways, including stromal interaction molecule (STIM)/Orai-mediated store-operated Ca2+ entry (SOCE) and the Ca2+-permeable transient receptor potential (TRP) channels, have been implicated in cancer cell migration and tumor metastasis. The clinical significance of these molecules, such as STIM proteins and the TRPM7 channel, in tumor progression and their diagnostic and prognostic potentials have also been demonstrated in specific cancer types. In this review, we summarize the recent advances in understanding the important roles and regulatory mechanisms of these Ca2+ influx pathways on malignant behaviors of tumor cells. The clinical implications in facilitating current diagnostic and therapeutic procedures are also discussed.
Chalcones belong to a class of biologically active polyphenolic natural products. As a result of their simple chemical nature, they are easily synthesized and show a variety of promising biological ...activities. 2-Hydroxy-4'-methoxychalcone (AN07) is a synthetic chalcone derivate with potential anti-atherosclerosis effects. In this study, we demonstrated the novel antioxidant, anti-inflammatory, and neuroprotective effects of AN07. In RAW 264.7 macrophages, AN07 attenuated lipopolysaccharide (LPS)-induced elevations in reactive oxygen species (ROS) level and oxidative stress via down-regulating gp91
expression and stimulating the antioxidant system of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) pathways, which were accompanied by increased glutathione (GSH) levels. Additionally, AN07 attenuated LPS-induced inflammatory factors, including NO, inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and phosphorylated inhibitor of nuclear factor kappa B-alpha (p-IκBα) in RAW 264.7 macrophages. However, the effects of AN07 on promoting nuclear Nrf2 levels and decreasing COX-2 expressions were significantly abrogated by the peroxisome proliferator-activated receptor-γ (PPARγ) antagonist GW9662. In human dopaminergic SH-SY5Y cells treated with or without methylglyoxal (MG), a toxic endogenous by-product of glycolysis, AN07 up-regulated neurotrophic signals including insulin-like growth factor 1 receptor (IGF-1R),
-Akt,
-GSK3β, glucagon-like peptide 1 receptor (GLP-1R), and brain-derived neurotrophic factor (BDNF). AN07 attenuated MG-induced apoptosis by up-regulating the B-cell lymphoma 2 (Bcl-2) protein and down-regulating the cytosolic expression of cytochrome c. AN07 also attenuated MG-induced neurite damage via down-regulating the Rho-associated protein kinase 2 (ROCK2)/phosphorylated LIM kinase 1 (p-LIMK1) pathway. Moreover, AN07 ameliorated the MG-induced down-regulation of neuroprotective Parkinsonism-associated proteins
,
, and
. These findings suggest that AN07 possesses the potentials to be an anti-inflammatory, antioxidant, and neuroprotective agent.
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.
The remodeling of Ca2+ homeostasis has been implicated as a critical event in driving malignant phenotypes, such as tumor cell proliferation, motility, and metastasis. Store-operated Ca2+ entry ...(SOCE) that is elicited by the depletion of the endoplasmic reticulum (ER) Ca2+ stores constitutes the major Ca2+ influx pathways in most nonexcitable cells. Functional coupling between the plasma membrane Orai channels and ER Ca2+-sensing STIM proteins regulates SOCE activation. Previous studies in the human breast, cervical, and other cancer types have shown the functional significance of STIM/Orai-dependent Ca2+ signals in cancer development and progression. This article reviews the information on the regulatory mechanisms of STIM- and Orai-dependent SOCE pathways in the malignant characteristics of cancer, such as proliferation, resistance, migration, invasion, and metastasis. The recent investigations focusing on the emerging importance of SOCE in the cells of the tumor microenvironment, such as tumor angiogenesis and antitumor immunity, are also reviewed. The clinical implications as cancer therapeutics are discussed.
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