Integrative analysis of WDR12 as a potential prognostic and immunological biomarker in multiple human tumors

Background: Mammalian WD-repeat protein 12 (WDR12), a family member of proteins containing repeats of tryptophan-aspartic acid (WD), is a potential homolog of yeast Ytm1p and consists of seven repeats of WD.Aim of the study: This study aims to investigate the potential oncogenic effects of WDR12 in various human malignancies throughout a pan-cancer analysis that has been carried out to examine the various patterns in which this gene is expressed and behaves in tumor tissues.Methods: Herein, we used The Cancer Genome Atlas (TCGA) and various computational tools to explore expression profiles, prognostic relevance, genetic mutations, immune cell infiltration, as well as the functional characteristics of WDR12 in multiple human cancers.Results: We found that WDR12 was inconsistently expressed in various cancers and that variations in WDR12 expression predicted survival consequences for cancer patients. Furthermore, we observed a significant correlation between WDR12 gene mutation levels and the prognosis of some tumors. Furthermore, significant correlations were found between WDR12 expression patterns and cancer-associated fibroblast (CAF) infiltration, myeloid-derived suppressor cells (MDSCs), tumor mutation burden, microsatellite instability and immunoregulators. Ultimately, pathway enrichment analysis revealed that WDR12-related pathways are involved in carcinogenesis.Conclusions: The findings of our study are stisfactory, demonstrating that WDR12 could serve as a promising reliable prognostic biomarker, as well as a therapeutic target for novel cancer therapeutic approaches

Anti-Cancer Natural Products and Their Bioactive Compounds Inducing ER Stress-Mediated Apoptosis: A Review

Cancer is the second biggest cause of death worldwide. Despite a number of studies being conducted, the effective mechanism for treating cancer has not yet been fully understood. The tumor-microenvironment such as hypoxia, low nutrients could disturb function of endoplasmic reticulum (ER) to maintain cellular homeostasis, ultimately leading to the accumulation of unfolded proteins in ER, so-called ER stress. The ER stress has a close relation with cancer. ER stress initiates unfolded protein response (UPR) to re-establish ER homeostasis as an adaptive pathway in cancer. However, persistent ER stress triggers the apoptotic pathway. Therefore, blocking the adaptive pathway of ER stress or facilitating the apoptotic pathway could be an anti-cancer strategy. Recently, natural products and their derivatives have been reported to have anti-cancer effects via ER stress. Here, we address mechanisms of ER stress-mediated apoptosis and highlight strategies for cancer therapy by utilizing ER stress. Furthermore, we summarize anti-cancer activity of the natural products via ER stress in six major types of cancers globally (lung, breast, colorectal, gastric, prostate and liver cancer). This review deepens the understanding of ER stress mechanisms in major cancers as well as the suppressive impact of natural products against cancers via ER stress

Cisplatin-Induced Nausea and Vomiting: Effect of Herbal Medicines

Cisplatin is a chemotherapeutic agent that is widely used to treat various types of cancers. However, its side effects, most commonly nausea and vomiting, limit its widespread use. Although various drugs, such as ondansetron and aprepitant, are used to alleviate these side effects, their efficacy is still debated. This review aims to summarize the results of 14 studies on the effects of seven single herbal extracts, one multiple herbal extract, and one ginger sub-component (i.e., [6]-gingerol) on cisplatin-induced nausea and vomiting. The results of the included studies were subdivided into four categories: kaolin consumption, retching and vomiting, food intake, and weight loss. Most studies used rodents, whereas four studies used minks or pigeons. The doses of cisplatin used in the studies varied from 3 mg/kg to 7.5 mg/kg, and only a single injection was used. Nine studies analyzed the mechanisms of action of herbal medicines and assessed the involvement of neurotransmitters, cytokines, enzymes, and various hematological parameters. Although further research is needed, this review suggests herbal medicine as a viable treatment option for cisplatin-induced neuropathic pain

The Effect of Ginger and Its Sub-Components on Pain

Zingiber officinale Roscoe (ginger) has long been used as an herbal medicine to treat various diseases, and its main sub-components, [6]-gingerol and [6]-shogaol, were also reported to have anti-inflammatory, anti-oxidant, and anti-tumor effects. However, their effects on various types of pain and their underlying mechanisms of action have not been clearly analyzed and understood yet. Thus, in this review, by analyzing 16 studies that used Z. officinale, [6]-gingerol, and [6]-shogaol on mechanical, spontaneous and thermal pain, their effects and mechanisms of action have been analyzed. Pain was induced by either nerve injury or chemical injections in rodents. Nine studies analyzed the analgesic effect of Z. officinale, and four and three studies focused on [6]-gingerol and [6]-shogaol, respectively. Seven papers have demonstrated the underlying mechanism of action of their analgesic effects. Studies have focused on the spinal cord and one on the dorsal root ganglion (DRG) neurons. Involvement and change in the function of serotonergic receptors (5-HT1A, B, D, and 5A), transient receptor potential vanilloid 1 (TRPV1), N-methyl-D-aspartate (NMDA) receptors, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), histone deacetylase 1 (HDAC1), voltage-gated sodium channel 1.8 (Nav1.8), substance P (SP), and sciatic nerve’s morphology have been observed

Anticancer Activity and Underlying Mechanism of Phytochemicals against Multiple Myeloma

Multiple myeloma (MM)—a common hematologic malignancy of plasma cells—accounts for substantial mortality and morbidity rates. Due to the advent of novel therapies such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs), response rates were increased and free survival and overall survival have been elevated. However, adverse events including toxicity, neuropathy or continuous relapse are still problems. Thus, development of novel drugs which have less side effects and more effective is needed. This review aims to recapitulate the pharmacologic anti-MM mechanisms of various phytochemicals, elucidating their molecular targets. Keywords related to MM and natural products were searched in PUBMED/MEDLINE. Phytochemicals have been reported to display a variety of anti-MM activities, including apoptosis, cell cycle arrest, antiangiogenesis, and miRNA modulation. Some phytochemicals sensitize the conventional therapies such as dexamethasone. Also, there are clinical trials with phytochemicals such as agaricus, curcumin, and Neovastat regarding MM treatment. Taken together, this review elucidated and categorized the evidences that natural products and their bioactive compounds could be potent drugs in treating MM

Red Ginger Extract Prevents the Development of Oxaliplatin-Induced Neuropathic Pain by Inhibiting the Spinal Noradrenergic System in Mice

Oxaliplatin is a well-known chemotherapeutic drug that is widely used to treat colorectal cancer. However, it can induce acute side effects in up to 90% of patients. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are used as first-choice drugs; however, even SNRIs are known to be effective only in treatment and not for prevention. Therefore, finding a drug that can prevent the development of cold and mechanical forms of allodynia induced by oxaliplatin is needed. This study demonstrated that multiple oral administrations of 100 mg/kg and 300 mg/kg of red ginger extract could significantly prevent pain development in mice. The role of the noradrenergic system was investigated as an underlying mechanism of action. Both the spinal α1- and α2-adrenergic receptors were significantly downregulated after treatment. Furthermore, the noradrenaline levels in the serum and spinal cord were upregulated and downregulated after treatment with paclitaxel and red ginger, respectively. As the active sub-component of red ginger, ginsenoside Rg3 (Rg3) was identified and quantified using HPLC. Moreover, multiple intraperitoneal injections of Rg3 prevented the development of pain in paclitaxel-treated mice, suggesting that RG3 may induce the effect of red ginger extract

Red Ginger Extract Prevents the Development of Oxaliplatin-Induced Neuropathic Pain by Inhibiting the Spinal Noradrenergic System in Mice

Oxaliplatin is a well-known chemotherapeutic drug that is widely used to treat colorectal cancer. However, it can induce acute side effects in up to 90% of patients. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are used as first-choice drugs; however, even SNRIs are known to be effective only in treatment and not for prevention. Therefore, finding a drug that can prevent the development of cold and mechanical forms of allodynia induced by oxaliplatin is needed. This study demonstrated that multiple oral administrations of 100 mg/kg and 300 mg/kg of red ginger extract could significantly prevent pain development in mice. The role of the noradrenergic system was investigated as an underlying mechanism of action. Both the spinal α1- and α2-adrenergic receptors were significantly downregulated after treatment. Furthermore, the noradrenaline levels in the serum and spinal cord were upregulated and downregulated after treatment with paclitaxel and red ginger, respectively. As the active sub-component of red ginger, ginsenoside Rg3 (Rg3) was identified and quantified using HPLC. Moreover, multiple intraperitoneal injections of Rg3 prevented the development of pain in paclitaxel-treated mice, suggesting that RG3 may induce the effect of red ginger extract

Activation of ER Stress-Dependent miR-216b Has a Critical Role in Salvia miltiorrhiza Ethanol-Extract-Induced Apoptosis in U266 and U937 Cells

Although Salvia miltiorrhiza has been reported to have anti-cancer mechanisms, such as caspase activation, cell cycle arrest, an anti-angiogenesis effect, and Bcl-2 family regulation, its underlying mechanism of endoplasmic reticulum (ER) stress-mediated apoptosis has never been demonstrated. Thus, in this current study, ER stress-related apoptosis via miR-216b of the ethanol extract of Salvia miltiorrhiza (SM) is elucidated for the first time. SM treatment inhibited the viability of U266 and U937 cells in a concentration-dependent manner. However, SM-exposed Raw264.7 cells were intact compared to U266 or U937 cells. Treatment with SM significantly elevated the generation of reactive oxygen species (ROS). The anti-proliferative effect of SM was reversed by pretreatment with the ROS scavenger, N-acetyl-l-cysteine (NAC), compared to cells treated only with SM. Also, SM treatment increased the ER stress by elevation of phosphorylated activating transcription factor 4 (p-ATF4), phosphorylated eukaryotic Initiation Factor 2 (p-eIF2), and phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK) expression. Caspase-3 and Poly (ADP-ribose) polymerase (PARP) were cleaved and CCAAT-enhancer-binding protein homologous protein (CHOP) was activated by SM treatment. PARP cleavage and CHOP activation were attenuated by NAC pretreatment. Furthermore, SM increased the tumor suppressor, miR-216b, and suppressed its target, c-Jun. miR-216b inhibitor attenuated the apoptotic effect of SM. Taken together, SM treatment induced apoptosis through regulation of miR-216b and ROS/ER stress pathways. SM could be a potential drug for treatment of multiple myeloma and myeloid leukemia

Overview of Salvia miltiorrhiza as a Potential Therapeutic Agent for Various Diseases: An Update on Efficacy and Mechanisms of Action

Salvia miltiorrhiza Bunge (S. miltiorrhiza) is a medicinal herb that has been used for the treatment for various diseases such as cardiovascular and cerebrovascular diseases in East Asia including Korea. Considering its extensive usage as a therapeutic agent for multiple diseases, there is a need to review previous research regarding its therapeutic benefits and their mechanisms. Therefore, we searched PubMed and PubMed Central for articles reporting its therapeutic effects on certain disease groups including cancers, cardiovascular, liver, and nervous system diseases. This review provides an overview of therapeutic benefits and targets of S. miltiorrhiza, including inflammation, fibrosis, oxidative stress, and apoptosis. The findings on multi-functional properties of S. miltiorrhiza discussed in this article support the efficacy of S. miltiorrhiza extract on various diseases, but also call for further research on the multiple mechanisms that mediate its therapeutic effects