Research Progress and New Perspectives of Anticancer Effects of Emodin.

Emodin is a natural compound found in several traditional Chinese medicines, including Rheum palmatum and Polygonum cuspidatum. Recent studies have shown that emodin exhibits potent anticancer effects against a variety of cancer types, including liver, breast, lung, and colon cancer. Emodin's anticancer effects are mediated through several mechanisms, including inhibition of cell proliferation, induction of apoptosis, and suppression of tumor angiogenesis and metastasis. In this review, we provide an overview of recent research progress and new perspectives on emodin's anticancer effect. We summarize the current understanding of the molecular mechanisms underlying emodin's anticancer activity, including its effects on signaling pathways such as the PI3K/Akt, MAPK, and NF-[Formula: see text]B pathways. We also discuss the potential of emodin as a therapeutic agent for cancer treatment, including its use in combination with conventional chemotherapeutic drugs and as a sensitizer for radiotherapy. Furthermore, we highlight recent advances in the development of emodin derivatives and their potential as novel anticancer agents. Finally, we discuss the challenges and opportunities for the translation of emodin's anticancer properties into clinical applications, including the need for further preclinical and clinical studies to evaluate its safety and efficacy. In conclusion, emodin represents a promising natural compound with potent anticancer properties, and its potential as a therapeutic agent for cancer treatment warrants further investigation. This review provides a comprehensive overview of the current research progress and new perspectives on emodin's anticancer effects, which may facilitate the development of novel therapeutic strategies for cancer treatment.

Enhancement of gemcitabine efficacy by K73-03 via epigenetically regulation of miR-421/SPINK1 in gemcitabine resistant pancreatic cancer cells.

BACKGROUND: Gemcitabine (GCB) is a first-line chemotherapeutic drug for pancreatic cancer (PCa). However, the resistance begins developing within weeks of chemotherapy. SPINK1 overexpression enhances resistance to chemotherapy. In a recent study, our laboratory established that the oleanolic acid (OA) derivative, K73-03, had a strong inhibitory effect on a SPINK1 overexpressed PCa cells. PURPOSE: In our current study, we studied the enhancement of GCB inhibitory effect by K73-03, a new novel OA derivative, alone or in combination with GCB on the GCB-resistant PCa cells by mitochondrial damage through regulation of the miR-421/SPINK1. METHODS: We detected the binding between miR-421 and SPINK1-3'-UTR in GCB-resistant PCa cells using Luciferase reporter assays. Cells viability, apoptosis, migration, and mitochondrial damage were investigated. RESULTS: The results demonstrated that the combination of K73-03 and GCB suppressed the growth of AsPC-1 and MIA PaCa-2 cells synergistically, with or without GCB resistance. Mechanistic findings showed that a combination of K73-03 and GCB silences SPINK1 epigenetically by miR-421 up-regulating, which leads to mitochondrial damage and inducing apoptosis in GCB-resistant PCa cells. CONCLUSION: We found an interesting finding that the 73-03 in combination with GCB can improve GCB efficacy and decrease PCa resistance, which induced apoptosis and mitochondrial damage through epigenetic inhibition of SPINK1 transcription by miR-421 up-regulation. This was the first study that used OA derivatives on GCB-resistant PCa cells, so this combined strategy warrants further investigation.

Selaginellin B induces apoptosis and autophagy in pancreatic cancer cells via the JAK2/STAT3 signaling pathway.

Selaginella tamariscina (ST), a well-known traditional medicinal plant, has been used to treat various cancers, including pancreatic cancer. However, the underlying mechanism by which Selaginellin B, a natural pigment isolated and purified from ST, protects against pancreatic cells has yet to be fully elucidated. In the present study, the biological functions of Selaginellin B were investigated using apoptosis, migration and colony formation assays in ASPC-1 and PANC-1 cells. In addition, apoptosis-associated proteins were detected by Western blotting. Our results demonstrated that Selaginellin B induced apoptosis, as evidenced by the increased cleaved caspase-3 level and Bax/Bcl-2 ratio. Moreover, Selaginellin B led to a marked up-regulation of the ratio of LC3-II/LC3-I in ASPC-1 and PANC-1 cells, respectively. Furthermore, reverse pharmacophore screening, molecular docking and molecular dynamics simulation studies revealed that Janus kinase 2 (JAK2) may be a potential target for Selaginellin B. In summary, the results of the present research have demonstrated that Selaginellin B is an effective anticancer agent against PANC-1 and ASPC-1 cells, and the compound holds great promise for the treatment of pancreatic cancer.

Preparation and Optimization Lipid Nanocapsules to Enhance the Antitumor Efficacy of Cisplatin in Hepatocellular Carcinoma HepG2 Cells.

This work aimed to develop and optimize several lipid nanocapsule formulations (LNCs) to encapsulate cisplatin (CDDP) for treatment of hepatocellular carcinoma. By comparing the effect of oil/surfactant ratio, lecithin content, and oil/surfactant type on LNC characteristics, two LNCs were selected as optimal formulations: HS15-LNC (Solutol HS 15/MCT/lecithin, 54.5:42.5:3%, w/w) and EL-LNC (Cremophor EL/MCT/lecithin, 54.5:42.5:3%, w/w). Both LNCs could effectively encapsulate CDDP with the encapsulation efficiency of 73.48 and 78.84%. In vitro release study showed that both LNCs could sustain the release CDDP. Moreover, cellular uptake study showed that C6-labeled LNCs could be effectively internalized by HepG2 cells. Cellular cytotoxicity study revealed that both LNCs showed negligible cellular toxicity when their concentrations were below 313 µg/mL. Importantly, CDDP-loaded LNCs exhibited much stronger cell killing potency than free CDDP, with the IC50 values decreased from 17.93 to 3.53 and 5.16 µM after 72-h incubation. In addition, flow cytometric analysis showed that the percentage of apoptotic cells was significantly increased after treatment with LNCs. Therefore, the prepared LNC formulations exhibited promising anti-hepatocarcinoma effect, which could be beneficial to hepatocellular carcinoma therapy.

6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced damage via inhibition of p38 MAPK to NF-κB signalling.

Intestinal ischemia reperfusion (I/R) injury caused by severe trauma, intestinal obstruction, and operation is one of the tough challenges in clinic. 6-Gingerol (6G), a main active ingredient of ginger, is found to have anti-microbial, anti-inflammatory, anti-oxidative, and anti-cancer activities. The present study was designed to characterize the potential protective effects of 6G on rat intestinal I/R injury and reveal the correlated mechanisms. Rat intestinal I/R model was established with clamping the superior mesenteric artery (SMA) and 6G was intragastrically administered for three consecutive days before I/R injury. Caco-2 and IEC-6 cells were incubated under hypoxia/reoxygenation (H/R) conditions to simulate I/R injury in vitro. The results showed that 6G significantly alleviated intestinal injury in I/R injured rats by reducing the generation of oxidative stress and inhibiting p38 MAPK signaling pathway. 6G significantly reduced MDA level and increased the levels of SOD, GSH, and GSH-Px in I/R injured intestinal tissues. 6G significantly decreased the production of proinflammatory cytokines including TNF-α, IL-1ß, and IL-6, and inhibited the expression of inflammatory mediators iNOS/NO in I/R injured intestinal tissues. The impaired intestinal barrier function was restored by using 6G in I/R injured rats and in both Caco-2 and IEC-6 cells characterized by inhibiting p38 MAPK phosphorylation, nuclear translocation of NF-κB, and expression of myosin light chain kinase (MLCK) protein. 6G also reduced the generation of reactive oxygen species (ROS) in both Caco-2 and IEC-6 cells. In vitro transfection of p38 MAPK siRNA mitigated the impact of 6G on NF-κB and MLCK expression, and the results further corroborated the protective effects of 6G on intestinal I/R injury by repressing p38 MAPK signaling. In conclusion, the present study suggests that 6G exerts protective effects against I/R-induced intestinal mucosa injury by inhibiting the formation of ROS and p38 MAPK activation, providing novel insights into the mechanisms of this therapeutic candidate for the treatment of intestinal injury.

Ameliorative effects of atractylodin on intestinal inflammation and co-occurring dysmotility in both constipation and diarrhea prominent rats.

Intestinal disorders often co-occur with inflammation and dysmotility. However, drugs which simultaneously improve intestinal inflammation and co-occurring dysmotility are rarely reported. Atractylodin, a widely used herbal medicine, is used to treat digestive disorders. The present study was designed to characterize the effects of atractylodin on amelioration of both jejunal inflammation and the co-occurring dysmotility in both constipation-prominent (CP) and diarrhea-prominent (DP) rats. The results indicated that atractylodin reduced proinflammatory cytokines TNF-α, IL-1ß, and IL-6 in the plasma and inhibited the expression of inflammatory mediators iNOS and NF-kappa B in jejunal segments in both CP and DP rats. The results indicated that atractylodin exerted stimulatory effects and inhibitory effects on the contractility of jejunal segments isolated from CP and DP rats respectively, showing a contractile-state-dependent regulation. Atractylodin-induced contractile-state-dependent regulation was also observed by using rat jejunal segments in low and high contractile states respectively (5 pairs of low/high contractile states). Atractylodin up-regulated the decreased phosphorylation of 20 kDa myosin light chain, protein contents of myosin light chain kinase (MLCK), and MLCK mRNA expression in jejunal segments of CP rats and down-regulated those increased parameters in DP rats. Taken together, atractylodin alleviated rat jejunal inflammation and exerted contractile-state-dependent regulation on the contractility of jejunal segments isolated from CP and DP rats respectively, suggesting the potential clinical implication for ameliorating intestinal inflammation and co-occurring dysmotility.

Capsaicin alleviates abnormal intestinal motility through regulation of enteric motor neurons and MLCK activity: Relevance to intestinal motility disorders.

SCOPE: Capsaicin is an active component of chili peppers, having diverse effects. However, the effects of capsaicin on intestinal motility are still controversial. The present study aimed to investigate the effects of capsaicin on intestinal motility disorder and uncover related mechanisms. MATERIALS AND RESULTS: A rat model with intestinal motility disorder was established in vitro through adding different stimuli into tissue bath; in vivo using constipation and diarrhea model, respectively. Capsaicin exerted dual effects on intestinal motility, i.e. the relaxation and contraction of jejunum induced by corresponding stimulus were, respectively, regulated to be normal contraction by capsaicin. The mechanisms underlined capsaicin-induced dual effects were investigated using Western blotting, qRT-PCR, and whole-cell patch clamp, respectively. Results showed that cholinergic excitatory nerves, adrenergic nerves, and neurons containing nitric oxide synthase, which are the main muscle motor neurons in enteric nervous system (ENS), are involved in capsaicin-induced dual effects. The competition for regulation of Ca(2+) influx by capsaicin induced the interaction with components of the ENS. Capsaicin significantly increased myosin light chain kinase (MLCK) expression and myosin phosphorylation extent in jejunal segments of constipation-prominent rats and significantly decreased MLCK expression and myosin phosphorylation extent in jejunal segments of diarrhea-prominent rats. CONCLUSION: In summary, capsaicin alleviates abnormal intestinal motility through regulating enteric motor neurons and MLCK activity, which is beneficial for the treatment of gastrointestinal motility disorders.

Inhibitory effect of potassium alum on smooth muscle contraction of rabbit and its mechanism.

OBJECTIVE: To investigate the effects of potassium alum (Alunite) on smooth muscle contraction and phosphorylation of myosin light chain by myosin light chain kinase (MLCK) and to try to find out the clue of its mechanism. METHODS: An isolated rabbit duodenum smooth muscle strip was selected to study the effects of potassium alum on its contractile activity under the condition of Krebs' solution using HW-400S constant temperature smooth muscle trough. The myosin and MLCK were purified from chicken gizzard smooth muscle. Myosin light chain phosphorylation was determined by glycerol-polyacrylamide gel electrophoresis; myosin Mg2+-ATPase activity was measured by inorganic phosphate liberation method. RESULTS: Potassium alum (2.5-20 mmol/L) inhibited the contraction on duodenum in a dose-related and a time-dependent manner; potassium alum could also inhibit the extent of phosphorylation of myosin light chain in a dose-related and a time-dependent manner; and potassium alum inhibited the extent of Mg2+-ATPase activity in a dose-related manner. CONCLUSIONS: Potassium alum inhibited smooth muscle contraction in a way of inhibiting phosphorylation of myosin light chain and Mg2+-ATPase activity. This has revealed the molecular mechanism of treatment of gastrointestinal spastic disorders by potassium alum.

Effects of ginsenoside Re on rat jejunal contractility.

Ginsenoside Re (GRe) exerts diverse effects. Based on our observations, the present study was designed to investigate GRe-exerted bidirectional regulation (BR) on the contractility of isolated jejunal segment. Six pairs of different low and high contractile states of rat jejunal segment were established and used in the study. Stimulatory effects on the contractility of jejunal segment were exerted by GRe (10.0 µM) in all 6 low contractile states, and inhibitory effects were exerted in all 6 high contractile states, indicating that GRe exerted BR on the contractility of jejunal segment. The effects of GRe on the phosphorylation of 20 kDa myosin light chain, protein contents of myosin light chain kinase (MLCK) and MLCK mRNA expression in jejunal segment in low and high contractile states were also bidirectional. GRe-exerted BR was abolished in the presence of neurotoxin tetrodotoxin or Ca2+ channel blocker verapamil or c-Kit receptor tyrosine kinase inhibitor imatinib. Atropine blocked the stimulatory effects of GRe on jejunal contractility in low-Ca2+-induced low contractile state; phentolamine, propranolol and l-NG-nitro-arginine blocked the inhibitory effects in high-Ca2+-induced high contractile state, respectively. In summary, GRe-exerted BR depends on jejunal contractile state and requires the presence of enteric nervous system, Ca2+, and interstitial cells of Cajal; the stimulatory effects of GRe on jejunal contractility are related to cholinergic stimulation and inhibitory effects are related to adrenergic activation and nitric oxide relaxing mechanisms.

Research progress of ursolic acid's anti-tumor actions.

Ursolic acid (UA) is a sort of pentacyclic triterpenoid carboxylic acid purified from natural plant. UA has a series of biological effects such as sedative, anti-inflammatory, anti-bacterial, anti-diabetic, antiulcer, etc. It is discovered that UA has a broad-spectrum anti-tumor effect in recent years, which has attracted more and more scholars' attention. This review explained anti-tumor actions of UA, including (1) the protection of cells' DNA from different damages; (2) the anti-tumor cell proliferation by the inhibition of epidermal growth factor receptor/mitogen-activated protein kinase signal or of FoxM1 transcription factors, respectively; (3) antiangiogenesis, (4) the immunological surveillance to tumors; (5) the inhibition of tumor cell migration and invasion; (6) the effect of UA on caspase, cytochromes C, nuclear factor kappa B, cyclooxygenase, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or mammalian target of rapamycin signal to induce tumor cell apoptosis respectively, and etc. Moreover, UA has selective toxicity to tumor cells, basically no effect on normal cells. With further studies, UA would be one of the potential anti-tumor agents.

Effects of berberine on rat jejunal motility.

OBJECTIVES: The aim of the study was to evaluate berberine-induced bidirectional regulation on the contractility of jejunum. METHODS: Different low and high contractile states of isolated jejunal segment from rat were established to investigate the effects of berberine. KEY FINDINGS: Stimulatory effects on jejunal segment were exerted by berberine in six low contractile states and inhibitory effects were produced on jejunal segment in six high contractile states. The effects of berberine on myosin light chain kinase (MLCK) mRNA expression, MLCK protein content, and myosin phosphorylation in jejunum were also bidirectional. Bidirectional regulation was not observed in the presence of tetrodotoxin. No regulatory effects of berberine on jejunal contractility were observed in the presence of verapamil. The stimulatory effects of berberine on jejunal contractility were blocked by atropine. The inhibitory effects of berberine on jejunal contractility were abolished by phentolamine, propranolol and L-NG-nitro-arginine, respectively. CONCLUSIONS: Berberine-induced bidirectional regulation needed the presence of the enteric nervous system, and depended on the influx of extracellular Ca(2+) , related to the cholinergic system while jejunum was in low contractile states, and related to the adrenergic system and nitric oxide relaxing mechanism while jejunum was in high contractile states. The results suggested the potential clinical implication of berberine for alternating-type irritable bowel syndrome.

Inhibitory effects of daidzein on intestinal motility in normal and high contractile states.

CONTEXT: Daidzein is a naturally occurring compound and has various health benefits. However, its effects on intestinal smooth muscle contractility remain unknown. AIMS: The present study was to characterize the effects of daidzein on the contractility of isolated jejunal smooth muscle and its underlying mechanisms. METHODS: Ex vivo assay was selected as the major method to determine the effects of daidzein on the contractility of isolated jejunal smooth muscle fragment (JSMF). RESULTS: Daidzein (5-160 µmol/L) inhibited the contractility of JSMF in normal contractile state and in a dose-dependent manner. Daidzein also inhibited the contractility of JSMF induced by ACh, histamine, erythromycin and high Ca²âº, respectively, and decreased charcoal propulsion in the small intestine in vivo. The inhibitory effects of daidzein were partially blocked by phentolamine or propranolol and were abolished in the presence of varapamil or at Ca²âº-free assay condition. However, the inhibitory effects of daidzein on jejunal contraction were not significantly influenced by nitric oxide (NO) synthase inhibitor L-NG-nitro-arginine (L-NNA). Daidzein was also found to directly inhibit the phosphorylation and Mg²âº-ATPase activity of smooth muscle myosin. DISCUSSION AND CONCLUSION: The results implicated that α- and ß-adrenergic receptors were involved in the inhibitory effects produced by daidzein rather than via NO pathway. As a phytoestrogen, daidzein has shown its potential value in relieving the hypercontractility of small intestine.