Autophagy in Multidrug-Resistant Cancers

Multidrug resistance (MDR) in cancers is the major challenge in cancer therapy, thus the development of sensitizing agents or small molecules with new mechanisms of action to kill the resistant cancers is highly desired. Autophagy is a cellular process responsible for the turnover of misfolded proteins or damaged organelles and recycling of nutrients to maintain cellular homeostasis. Recently, autophagy has been shown to regulate MDR in cancers. In this chapter, both intrinsic and acquired drug resistance affecting the efficiency of chemotherapy, and the MDR mechanisms including nonclassical MDR phenotype and classical transport-based MDR phenotype were discussed. In addition, the development of apoptosis-resistant cancer by the deregulation of apoptotic gene machinery, such as BCL-2, BAX, BAK, and TRAILR, was also covered. We then further discussed the controversial role of autophagy by illustrating how induction of autophagy could work as a tumor suppressor or promote tumor survival. The modulation of MDR in cancer by either induction or inhibition of autophagy was also discussed. We have further summarized the current compounds or drugs for modulating MDR cancers and how autophagy modulators could circumvent the MDR phenotypes in cancers. Finally, the new mechanisms participating in MDR phenotypes were proposed for future MDR drugs discovery

Immunotherapeutic Approaches of Rheumatoid Arthritis and the Implication on Novel Interventions for Refractoriness

Rheumatoid arthritis is an autoimmune disorder involving the chronic inflammation of affected joints which lead to the distortion and eventually destruction of the articular tissues. Clinically, many therapeutic methods are being used for RA treatment. Non-steroidal anti-inflammatory drugs (NSAIDs), steroid, and disease-modifying anti-rheumatic drugs (DMARDs) are the three main categories of intervention approaches. Among which DMARDs, targeting mainly the release of pro-inflammatory cytokines, demonstrated high efficacy because of its direct drug action that alter the underlying disease mechanisms rather than simply to mediate symptoms relieve. However, the use of DMARDs also accompanying some unwanted adverse side effects, in particular, the development of refractoriness, which hampers the successful rate of treatment. In this chapter, the conventional RA drugs will be reviewed, focusing on the currently used and latest development of DMARDs. Novel methods that could improve RA pathogenesis will also be introduced. Because of the critical role of refractory RA, the progress of the disease to develop resistance to standard drug treatment will also be described. Finally, innovative RA therapeutic methods inspired by researches concerning the pathogenesis and contemporary treatments of RA will be discussed

ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation

Selective treatments for myocardial infarction (MI) induced cardiac fibrosis are lacking. In this study, we focus on the therapeutic potential of a synthetic cardio-protective agent named ZYZ-168 towards MI-induced cardiac fibrosis and try to reveal the underlying mechanism. ZYZ-168 was administered to rats with coronary artery ligation over a period of six weeks. Ecocardiography and Masson staining showed that ZYZ-168 substantially improved cardiac function and reduced interstitial fibrosis. The expression of α–smooth muscle actin (α-SMA) and Collagen I were reduced as was the activity of matrix metalloproteinase 9 (MMP-9). These were related with decreased phosphorylation of ERK1/2 and expression of Rho-associated coiled-coil containing protein kinase 1 (ROCK1). In cardiac fibroblasts stimulated with TGF-β1, phenotypic switches of cardiac fibroblasts to myofibroblasts were observed. Inhibition of ERK1/2 phosphorylation or knockdown of ROCK1 expectedly reduced TGF-β1 induced fibrotic responses. ZYZ-168 appeared to inhibit the fibrotic responses in a concentration dependent manner, in part via a decrease in ROCK 1 expression through inhibition of the phosphorylation status of ERK1/2. For inhibition of ERK1/2 phosphorylation with a specific inhibitor reduced the activation of ROCK1. Considering its anti-apoptosis activity in MI, ZYZ-168 may be a potential drug candidate for treatment of MI-induced cardiac fibrosis

The current status, trends, and challenges of Alzheimer’s disease and other dementias in Asia (1990–2036)

BackgroundWith global aging, Alzheimer’s disease (AD) and other dementias have emerged as significant health threats to the older adults, garnering considerable attention due to their impact on public health. Despite the substantial burden of dementia in Asia, targeted research remains limited. This study aims to assess the current burden, future trends, risk factors, and inequalities in Asia.MethodThe GBD 2021 study was utilized to evaluate the numbers and age-standardized rates (ASRs) of prevalence, mortality, and disability-adjusted life-years (DALYs) of AD and other dementias from 1990 to 2021. Joinpoint regression analysis was performed to assess the trends during this period, while the Autoregressive Integrated Moving Average (ARIMA) model was employed to predict future trends. Additionally, the relationship between disease burden and sociodemographic index (SDI) was also analyzed.ResultsIn 2021, Asia experienced a 250.44% increase in prevalent cases, a 297.34% rise in mortality, and a 249.54% surge in DALYs for AD and other dementias compared to 1990. Meanwhile, the age-standardized prevalence rate, age-standardized mortality rate, and age-standardized DALY rate also exhibited varying degrees of rise from 1990 to 2021. Demographically, the disease burden was higher in women and those aged 65 and above. Regionally, the burden was highest in East Asia and relatively low in South and Central Asia. Nationally, China, India, Japan, and Indonesia reported the most cases. Over the next 15 years, the age-standardized prevalence rate in Asia is expected to peak in 2028 before declining, while the age-standardized mortality rate is anticipated to keep rising. An overall “V” shaped association was found between sociodemographic index (SDI) and the age-standardized DALY rate in Asia. Only smoking, high fasting plasma glucose (FPG), and high BMI were identified as causal risk factors within the GBD framework.ConclusionThe burden of AD and other dementias in Asia has significantly increased over the past three decades and is expected to persistently impact Asian populations, particularly in developing countries experiencing rapid demographic shifts. Women and the older adult should be a focus of attention. It is imperative to implement targeted prevention and intervention strategies, enhance chronic disease management, and control risk factors

The New Application of UHPLC-DAD-TOF/MS in Identification of Inhibitors on β-Amyloid Fibrillation From Scutellaria baicalensis

Literary evidence depicts that aggregated β-amyloid (Aβ) leads to the pathogenesis of Alzheimer’s disease (AD). Although many traditional Chinese medicines (TCMs) are effective in treating neurodegenerative diseases, there is no effective way for identifying active compounds from their complicated chemical compositions. Instead of using a traditional herbal separation method with low efficiency, we herein apply UHPLC-DAD-TOF/MS for the accurate identification of the active compounds that inhibit the fibrillation of Aβ (1-42), via an evaluation of the peak area of individual chemical components in chromatogram, after incubation with an Aβ peptide. Using the neuroprotective herbal plant Scutellaria baicalensis (SB) as a study model, the inhibitory effect on Aβ by its individual compounds, were validated using the thioflavin-T (ThT) fluorescence assay, biolayer interferometry analysis, dot immunoblotting and native gel electrophoresis after UHPLC-DAD-TOF/MS analysis. The viability of cells after Aβ (1-42) incubation was further evaluated using both the tetrazolium dye (MTT) assay and flow cytometry analysis. Thirteen major chemical components in SB were identified by UHPLC-DAD-TOF/MS after incubation with Aβ (1–42). The peak areas of two components from SB, baicalein and baicalin, were significantly reduced after incubation with Aβ (1–42), compared to compounds alone, without incubation with Aβ (1–42). Consistently, both compounds inhibited the formation of Aβ (1–42) fibrils and increased the viability of cells after Aβ (1–42) incubation. Based on the hypothesis that active chemical components have to possess binding affinity to Aβ (1–42) to inhibit its fibrillation, a new application using UHPLC-DAD-TOF/MS for accurate identification of inhibitors from herbal plants on Aβ (1–42) fibrillation was developed

Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca 2+ -dependent mechanism

Resistance of cancer cells to chemotherapy is a significant clinical concern and mechanisms regulating cell death in cancer therapy, including apoptosis, autophagy or necrosis, have been extensively investigated over the last decade. Accordingly, the identification of medicinal compounds against chemoresistant cancer cells via new mechanism of action is highly desired. Autophagy is important in inducing cell death or survival in cancer therapy. Recently, novel autophagy activators isolated from natural products were shown to induce autophagic cell death in apoptosis-resistant cancer cells in a calcium-dependent manner. Therefore, enhancement of autophagy may serve as additional therapeutic strategy against these resistant cancers. By computational docking analysis, biochemical assays, and advanced live-cell imaging, we identified that neferine, a natural alkaloid from Nelumbo nucifera, induces autophagy by activating the ryanodine receptor and calcium release. With well-known apoptotic agents, such as staurosporine, taxol, doxorubicin, cisplatin and etoposide, utilized as controls, neferine was shown to induce autophagic cell death in a panel of cancer cells, including apoptosis-defective and -resistant cancer cells or isogenic cancer cells, via calcium mobilization through the activation of ryanodine receptor and Ulk-1-PERK and AMPK-mTOR signaling cascades. Taken together, this study provides insights into the cytotoxic mechanism of neferine-induced autophagy through ryanodine receptor activation in resistant cancers