Effects of the administration of Shinbaro 2 in a rat lumbar disk herniation model.

The current standard for the pharmacological management of lumbar disk herniation (LDH), involving non-steroidal anti-inflammatory drugs, muscle relaxants, and opioid analgesics, often carries a risk of adverse events. The search for alternative therapeutic options remains a vital objective, given the high prevalence of LDH and the critical impact on the quality of life. Shinbaro 2 is a clinically effective herbal acupuncture against inflammation and various musculoskeletal disorders. Therefore, we explored whether Shinbaro 2 exerts protective effects in an LDH rat model. The results showed that Shinbaro 2 suppressed pro-inflammatory cytokines, interleukin-1 beta, tumor necrosis factor-alpha, disk degeneration-related factors, matrix metalloproteinase-1,-3,-9, and ADAMTS-5 in LDH rats. Shinbaro 2 administration reinstated a behavioral activity to a normal level in the windmill test. The results indicated that Shinbaro 2 administration restored spinal cord morphology and functions in the LDH model. Therefore, Shinbaro 2 exerted a protective effect in LDH via actions on inflammatory responses and disk degeneration, indicating that future research is warranted to assess the action mechanisms further and validate its effects.

Association Between Acupuncture and Knee Surgery for Osteoarthritis: A Korean, Nationwide, Matched, Retrospective Cohort Study.

Objectives: The present study was undertaken to investigate the relationship between acupuncture therapy and surgery rate. Design: Matched, retrospective cohort study. Materials and Methods: From nationwide health insurance data (2002-2013 cohort data published by the National Health Insurance Service of Korea), patients with new cases of knee osteoarthritis that occurred between January 1, 2004 and December 31, 2010 were analyzed. Patients were divided into an acupuncture group (AG) and a control group (CG), based on records of acupuncture therapy. Propensity scores were calculated by using gender, age, income level, and Charlson comorbidity index (CCI), with the groups matched at a ratio of 1:3 (AG:CG). The final analysis period was 2 years after the first acupuncture therapy for AG and 2 years after initial diagnosis for CG; surgery rates were compared between the two groups. Stratified analyses were performed based on age, gender, and income level; sensitivity analyses were performed based on the frequency and duration of acupuncture therapy. Results: Propensity score-matched AG and CG included 8,605 and 25,815 subjects, respectively. Post-matching surgery rates were 0.26 and 0.93% in AG and CG, respectively. For all age groups, AG showed a lower surgery rate than CG. In the analysis based on gender, the female group showed a significantly lower hazard ratio of 0.225. In analysis based on income level, the results of the entire group were significant, with the lower income group showing the lowest hazard ratio. In sensitivity analyses, AG tended to show a lower surgery rate than CG. Conclusions: The present study demonstrated that acupuncture therapy is associated with a low rate of surgery for knee osteoarthritis. Additional studies are needed to support this conclusion.

Acromioplasty rates in patients with shoulder disorders with and without acupuncture treatment: a retrospective propensity score-matched cohort study.

OBJECTIVE: This retrospective propensity score-matched cohort study aimed to examine the frequency of acromioplasty among patients with shoulder disorders receiving and not receiving acupuncture, based on Korea National Health Insurance Service-National Sample Cohort (NHIS-NSC) data. METHODS: We included cases of high-frequency shoulder disorders-adhesive capsulitis, rotator cuff syndrome, shoulder impingement syndrome, and sprain and strain of the shoulder joint-stratified from the Korea NHIS-NSC database between 2002 and 2013; cases were classified into two groups based on a history of acupuncture treatment performed at least twice within 6 weeks (acupuncture group: n = 111,561; control group: n = 71,340). We examined propensity scores and hazard ratios (HRs) for the frequency of acromioplasty, within 2 years of the first treatment or first examination in the acupuncture and control groups, respectively; cumulative survival rates were estimated using Kaplan-Meier survival analysis. RESULTS: Following propensity score matching, no differences were observed between the acupuncture and control groups for variables including sex, age, income and the Charlson comorbidity index. In addition, the incidence rates of acromioplasty within 2 years were lower in the acupuncture group than in the control group (HR 0.264; 95% confidence interval 0.224-0.311). Based on differences in sensitivity analyses for the numbers of acupuncture sessions and treatment duration, the frequency of acromioplasty within 2 years was lower in the acupuncture group than in the control group. CONCLUSION: This study found that the frequency of acromioplasty was reduced in patients with shoulder disorders who had been treated with acupuncture. Although the findings need to be verified by prospective randomized clinical trials, these results imply that acupuncture may be effective at reducing the incidence rate of shoulder surgery.

Cervical surgery rate in neck pain patients with and without acupuncture treatment: a retrospective cohort study.

OBJECTIVE: Surgical treatment of neck pain often entails high costs and adverse events. The present cohort study investigated whether utilisation of acupuncture in neck pain patients is associated with a reduced rate of cervical surgery. METHODS: The Korean National Health Insurance Service National Sample Cohort (NHIS-NSC) database was retrospectively analysed to identify the 2 year incidence of cervical surgery in Korean patients suffering neck pain from 2004 to 2010. The incidence was calculated and compared between patients receiving and not receiving acupuncture treatment using Cox proportional hazards models. Cumulative survival rates were compared using Kaplan-Meier survival analysis. RESULTS: The acupuncture and control groups included 50 171 and 128 556 neck pain patients, respectively. A total of 50 161 patients were selected in each group following propensity score matching with regard to sex, age, income and Charlson comorbidity index. The hazard ratio (HR) for surgery within 2 years was significantly lower in the acupuncture group compared with the control group (HR 0.397, 95% CI 0.299 to 0.527). In addition, subgroup analyses according to gender, age and income revealed consistent results for both men (HR 0.337, 95% CI 0.234 to 0.485) and women (HR 0.529, 95% CI 0.334 to 0.836); the results were consistently observed across all age and income strata. Sensitivity analysis with varying numbers of acupuncture treatments and treatment course duration also consistently indicated lower HRs for surgery within 2 years in the acupuncture group compared with the control group. CONCLUSIONS: A significantly lower HR for cervical surgery was observed in neck pain patients following acupuncture treatment. Acupuncture treatment may therefore be an effective method for managing neck pain, and has the potential to mitigate unnecessary surgery. These findings need to be confirmed by prospective studies.

Impact of acupuncture treatment on the lumbar surgery rate for low back pain in Korea: A nationwide matched retrospective cohort study.

INTRODUCTION: Low back pain (LBP) is a globally prevalent disorder with high social significance. Invasive surgical procedures are increasingly being used to treat LBP despite a lack of solid evidence supporting their long-term benefits. This nationwide retrospective cohort study investigated the association between acupuncture treatment and lumbar surgery rate in patients with LBP. METHODS: Using the National Health Insurance Service Sample Cohort Database for 2002-2013, we identified newly diagnosed LBP patients in Korea between 2004 and 2010 and divided them into an acupuncture group and control group according to whether or not they received acupuncture. Propensity scores based on age, sex, income, and Charlson Comorbidity Index were matched between the two study groups. The lumbar surgery rate in the two years following the first visit (control group) or the first acupuncture session (acupuncture group) was calculated. In addition to the overall analysis, stratified analyses were also conducted in different age, sex, and income strata. Sensitivity analyses were further performed using varying definitions of acupuncture treatment. RESULTS: After matching, 130,089 subjects were included in each study group. The lumbar surgery rate was significantly lower in the acupuncture group than in the control group (hazard ratio [HR] 0.633, 95% confidence interval [CI] 0.576-0.696). Decrease in HR was consistently observed in the acupuncture group for all age strata, except for patients in their 20s (HR 1.031, 95% CI 0.804-1.323). HR for lumbar surgery tended to be further reduced in the older age groups upon acupuncture treatment, with no apparent sex-related differences. Lowered HR in the acupuncture group was continuously observed across all income groups; the higher income group showed a tendency of greater decrease. Sensitivity analyses showed that the number of acupuncture sessions had no major impact on the likelihood of lumbar surgery, but also that more intensive acupuncture treatment was associated with further reduction in lumbar surgery rates. CONCLUSION: The present results found that administration of acupuncture treatment is associated with lower lumbar surgery rates for LBP patients in Korea. Prospective studies are warranted in the future to further investigate the effect of acupuncture treatment on lumbar surgery incidence.

The Anti-Inflammatory Effects of Shinbaro3 Is Mediated by Downregulation of the TLR4 Signalling Pathway in LPS-Stimulated RAW 264.7 Macrophages.

Shinbaro3, a formulation derived from the hydrolysed roots of Harpagophytum procumbens var. sublobatum (Engl.) Stapf, has been clinically used in the pharamacopuncture treatment of arthritis in Korea. In the present study, Shinbaro3 inhibited NO generation in LPS-induced RAW 264.7 cells in a dose-dependent manner. Shinbaro3 also downregulated the mRNA and protein expression of inflammatory mediators in a dose-dependent manner. Three mechanisms explaining the effects of Shinbaro3 in RAW 264.7 cells were identified as follows: (1) inhibition of the extracellular signal-regulated kinase 1 and 2 (ERK1/2), stress-activated protein kinase (SAPK)/c-Jun N-terminal protein kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) pathways; (2) suppression of IκB kinase-α/ß (IKK-α/ß) phosphorylation and nuclear factor-kappa B (NF-κB) subunits in the NF-κB pathway, which are involved in MyD88-dependent signalling; and (3) downregulation of IFN-ß mRNA expression via inhibition of interferon regulatory factor 3 (IRF3) and Janus-activated kinase 1 (JAK1)/signal transducer and activator of transcription 1 (STAT1) phosphorylation, which is involved in TRIF-dependent signalling. Shinbaro3 exerted anti-inflammatory effects in LPS-stimulated RAW 264.7 macrophage cells through modulation of the TLR4/MyD88 pathways, suggesting that Shinbaro3 is a novel anti-inflammatory therapeutic candidate in the field of pharmacopuncture.

Analysis of medical service use of knee osteoarthritis and knee meniscal and ligament injuries in Korea: a cross-sectional study of national patient sample data.

BACKGROUND: Osteoarthritis (OA) and meniscal and ligament injuries of the knee are the two most common knee disorders in Korea. The aim of this study was to analyze the demographic characteristics, medical service use and related costs for these disorders, and the results are expected to help inform practitioners, researchers, and policy-makers. METHODS: The present study aimed to evaluate incidence and patient characteristics, and to assess current medical service use, usual care, and medical expenses of knee disorders by analyzing 2014 national patient sample data from the Korean Health Insurance Review and Assessment Service. Data was extracted using 3% stratified sampling from all Korea national health insurance claims submitted in 2014, and analyzed. Usual care for M17 knee osteoarthritis and S83 knee meniscal and ligament injury codes of the International Classification of Diseases, 10th revision (ICD-10) were determined by investigating total number of patients, sociodemographic characteristics, days in care, number of visits, and expenses. RESULTS: Knee OA showed the highest incidence in females aged ≥60 years, whereas meniscal and ligament injuries of the knee were most prevalent among patients aged <20 years and young adults. Total inpatient care expenses exceeded the cost of ambulatory care for both disorders. Ambulatory care was mainly provided at primary care clinics, with 90% of these visits made to orthopedic specialists. Medical expenses for knee OA and meniscal and ligament injuries were largely due to procedures/surgeries and injections, and procedures/surgeries and hospitalizations, respectively. Total replacement arthroplasty was the most commonly performed surgery for knee OA, while meniscectomy and cruciate ligament reconstruction were the most often performed surgeries for meniscal and ligament injuries. Intra-articular injection rates were 55% in knee OA patients and 3% in meniscal and ligament injury patients. Aceclofenac, diclofenac, and tramadol were the most frequently prescribed analgesics. CONCLUSIONS: The current findings may be used as basic data for establishing medical policies and can benefit researchers and clinicians in recognizing trends and patterns of treatment for knee disorders.

Anti-inflammatory effect of Cortex Eucommiae via modulation of the toll-like receptor 4 pathway in lipopolysaccharide-stimulated RAW 264.7 macrophages.

ETHNOPHARMOCOLOGICAL RELEVANCE: Cortex Eucommiae (CE), the bark of Eucommia ulmoides Oliv., has been traditionally used for its kidney-tonifying and bone- and tendon-enhancing properties in Korea, China, and Japan. CE has been historically prescribed for inflammatory conditions such as arthritis of the knee and ankle. AIM OF THE STUDY: Although CE has recently been shown to suppress inflammation in scientific studies, whether this effect involves modulation of the toll-like receptor 4 (TLR-4) pathway is currently unknown. MATERIALS AND METHODS: The modulatory effect of CE on the TLR-4 pathway, both myeloid differentiation primary response gene 88 (Myd88)-dependent and independent, was investigated through real-time reverse transcriptase-polymerase chain reaction (RT-PCR), western blotting, and a reporter gene assay in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. RESULTS: CE dose-dependently inhibited nitric oxide production without significant cytotoxicity with an IC50 of 356.23µg/mL. In addition, CE down-regulated both LPS-induced mRNA and protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) in a dose-dependent manner. CE suppressed LPS-induced activation of nuclear factor-κB (NF-κB) and the mitogen-activated protein kinase (MAPK) pathways, which together comprise the Myd88-dependent TLR-4 pathway. The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was also down-regulated by CE in a dose-dependent manner. CE additionally suppressed LPS-induced activation of interferon-ß (IFN-ß) and signal transducer and activator of transcription (STAT) pathway, which is associated with the Myd88-independent TLR-4 pathway. CONCLUSIONS: CE down-regulated both Myd88-dependent and independent TLR-4 pathways, thus exerting anti-inflammatory effects. These results suggest that CE may be used as a potential therapeutic agent against chronic inflammatory diseases.

Influence of Boiling Duration of GCSB-5 on Index Compound Content and Antioxidative and Anti-inflammatory Activity.

BACKGROUND: GCSB-5, an herbal drug composition with an anti-inflammatory effect, is prepared by boiling, which is the most common herbal extraction method in traditional Korean medicine. Several parameters are involved in the process, i.e., extractant type, herb-to-extractant ratio, extraction temperature and pressure, and total boiling time. OBJECTIVES: The aim of this study was to examine the influence of boiling time on index compound amount and the antioxidative and anti-inflammatory activities of GCSB-5. MATERIALS AND METHODS: Different samples of GCSB-5 were obtained by decocting for 30, 60, 90, 120, 150, and 240 min. Each sample was tested for hydrogen ion concentration (pH), total soluble solid content (TSSC), marker compound profiles, and antioxidative and anti-inflammatory activity. RESULTS: pH was found to decrease while TSSC increased with extended decoction. Marker compound contents for GCSB-5 (acanthoside D for Acanthopanax sessiliflorus Seem, 20-hydroxyecdysone for Achyranthes japonica Nakai, and pinoresinol diglucoside for Eucommia ulmoides Oliver) remained relatively constant regardless of the length of boiling. Total D-glucose amount increased with longer boiling. The antioxidative and anti-inflammatory potentials of GCSB-5 were not substantially affected by decoction duration. CONCLUSION: Biological characteristics and marker compound content of GCSB-5 were not altered significantly in prolonged boiling. SUMMARY: Longer boiling duration of GCSB-5 did not increase yield in a time-dependent manner, but yields of 210 and 240 min samples were significantly higherHydrogen ion concentration of GCSB-5 samples decreased while total soluble solid content and D-glucose concentration levels increased with boiling durationAlthough concentrations of some index compounds increased with extended boiling duration of GCSB-5, increase was small and not in a direct proportional relationshipAntioxidative and anti-inflammatory properties of GCSB-5 were not substantially affected by decoction duration. Abbreviations used: CAM: Complementary and alternative medicine; KIOM: Korea Institute of Oriental Medicine; KMD: Korean medicine doctor; TSSC: Total soluble solid content; pH: Hydrogen ion concentration; HPLC: High-performance liquid chromatography; NO: Nitric oxide; NO2: Nitric dioxide; LPS: Lipopolysaccharide; DMSO: Dimethyl sulfoxide.

Medical service use and usual care of common shoulder disorders in Korea: a cross-sectional study using the Health Insurance Review and Assessment Service National Patient Sample.

OBJECTIVES: This study examined National Health Insurance claims data to investigate the epidemiology of shoulder disorders in Korea. Detailed information on medical services and related costs was assessed by major shoulder disorder category. DESIGN AND SETTING: The 2014 National Patient Sample dataset provided by the Health Insurance Review and Assessment Service was analysed. Among shoulder-related diagnosis codes, adhesive capsulitis of the shoulder (ACS), rotator cuff syndrome (RCS) and shoulder impingement syndrome (SIS) categories were of highest prevalence. Sociodemographic characteristics and medical service use, frequency and medical costs regarding common shoulder disorders were evaluated. RESULTS: The majority of patients with shoulder disorder received ambulatory care (97%). Total and per-patient expenses were highest in patients with RCS. The number of inpatients with RCS was more than twice that of the other two groups, and patients with RCS were more likely to receive surgical management compared with patients with ACS and SIS. Prevalence of shoulder disorders was highest among subjects in their 50s for all three groups. Primary care physicians treated 75.80% of patients with ACS, 56.99% of patients with RCS and 48.06% of patients with SIS, respectively, outlining the difference in medical institution usage patterns. In all three groups, the highest proportion of patients visited orthopaedic surgeons out of medical departments. In the ACS and SIS groups, cost of visits (consultations) took up the largest part of total expenses at 32.30% and 18.88%, respectively, while cost of procedure/surgery constituted the largest portion in patients with RCS (37.77%). The usage proportion of subcutaneous or intramuscular and intra-articular injections ranged between 20% and 30% for outpatients in all three groups. CONCLUSIONS: Medical service use, frequency and cost distributions relating to major shoulder disorders in Korea were assessed using nationwide claims data. These findings are expected to aid policy-makers as well as researchers and practitioners as basic healthcare data.

In Vitro and In Vivo Anti-Allergic and Anti-Inflammatory Effects of eBV, a Newly Developed Derivative of Bee Venom, through Modulation of IRF3 Signaling Pathway in a Carrageenan-Induced Edema Model.

BACKGROUND: Bee venom (BV), a type of toxin extracted from honeybees (Apis mellifera), has been empirically and widely used to treat inflammatory diseases throughout Asia. Essential BV (eBV) was developed by removing phospholipase A2 (PLA2) and histamine to lower occurrence of allergic reaction. This study investigated the anti-allergic and anti-inflammatory activities of eBV in vitro and in vivo and its underlying mechanism of action. METHODS: The anti-inflammatory potential of eBV was assessed in vivo using a carrageenan-induced paw edema model. To further investigate the mechanism by which eBV exerts anti-allergic and anti-inflammatory effects, compound 48/80-stimulated RBL-2H3 cells and lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophage cells were studied in vitro. RESULTS: Release of ß-hexosaminidase and histamine was increased by eBV in a dose-dependent manner, but these levels were lower in eBV compared to original BV at the same concentration. In addition, eBV suppressed compound 48/80-induced expression of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in RBL-2H3 cells. eBV was also shown to suppress nitric oxide (NO) production by down-regulating mRNA expression and subsequent protein expression of inflammatory mediators in LPS-induced RAW 264.7 cells. Phosphorylation of activators and signal transducers of transcription 1/interferon regulatory factor 3 (STAT1/IRF3) was attenuated by eBV treatment. eBV significantly inhibited carrageenan-induced acute edema in vivo. Serum levels of prostaglandin E2 (PGE2), TNF-α, and IL-1ß were also down-regulated by eBV. CONCLUSIONS: These results demonstrate that eBV inhibits allergic and inflammatory response by reducing inflammatory mediator production via regulation of the STAT1/IRF3 signaling pathway, suggesting that eBV is a feasible candidate for regulation of allergic-inflammatory response in complementary and alternative medicine.

Icariside II induces apoptosis in U937 acute myeloid leukemia cells: role of inactivation of STAT3-related signaling.

BACKGROUND: The aim of this study is to determine anti-cancer effect of Icariside II purified from the root of Epimedium koreanum Nakai on human acute myeloid leukemia (AML) cell line U937. METHODOLOGY/PRINCIPAL FINDINGS: Icariside II blocked the growth U937 cells in a dose- and time-dependent manner. In this anti-proliferation process, this herb compound rendered the cells susceptible to apoptosis, manifested by enhanced accumulation of sub-G1 cell population and increased the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. Icariside II was able to activate caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) in a time-dependent manner. Concurrently, the anti-apoptotic proteins, such as bcl-x(L) and survivin in U937 cells, were downregulated by Icariside II. In addition, Icariside II could inhibit STAT3 phosphorylation and function and subsequently suppress the activation of Janus activated kinase 2 (JAK2), the upstream activators of STAT3, in a dose- and time-dependent manner. Icariside II also enhanced the expression of protein tyrosine phosphatase (PTP) SH2 domain-containing phosphatase (SHP)-1, and the addition of sodium pervanadate (a PTP inhibitor) prevented Icariside II-induced apoptosis as well as STAT3 inactivation in STAT3 positive U937 cells. Furthermore, silencing SHP-1 using its specific siRNA significantly blocked STAT3 inactivation and apoptosis induced by Icariside II in U937 cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated that via targeting STAT3-related signaling, Icariside II sensitizes U937 cells to apoptosis and perhaps serves as a potent chemotherapeutic agent for AML.

Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells.

We investigated the molecular mechanisms responsible for fisetin-induced apoptosis in U266 cells. Fisetin elicited the cytotoxicity in U266 cells, manifested as an increased fraction of the cells with sub-G1 content or stained positively with TUNEL labeling. Fisetin enhanced caspase-3 activation, downregulation of Bcl-2 and Mcl-1(L), and upregulation of Bax, Bim and Bad. Fisetin activated AMPK as well as its substrate acetyl-CoA carboxylase (ACC), along with a decreased phosphorylation of AKT and mTOR. Fisetin also stimulated generation of ROS in U266 cells. Conversely, compound C or N-acetyl-L-cystein blocked fisetin-induced apoptosis. Our data suggest that fisetin-induced apoptosis in U266 cells is through ROS and AMPK pathways.

Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells.

BACKGROUND: Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells. RESULTS: Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control. CONCLUSION: These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells.

Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy.

SIGNIFICANCE: Extensive research during the last quarter century has revealed that reactive oxygen species (ROS) produced in the body, primarily by the mitochondria, play a major role in various cell-signaling pathways. Most risk factors associated with chronic diseases (e.g., cancer), such as stress, tobacco, environmental pollutants, radiation, viral infection, diet, and bacterial infection, interact with cells through the generation of ROS. RECENT ADVANCES: ROS, in turn, activate various transcription factors (e.g., nuclear factor kappa-light-chain-enhancer of activated B cells [NF-κB], activator protein-1, hypoxia-inducible factor-1α, and signal transducer and activator of transcription 3), resulting in the expression of proteins that control inflammation, cellular transformation, tumor cell survival, tumor cell proliferation and invasion, angiogenesis, and metastasis. Paradoxically, ROS also control the expression of various tumor suppressor genes (p53, Rb, and PTEN). Similarly, γ-radiation and various chemotherapeutic agents used to treat cancer mediate their effects through the production of ROS. Interestingly, ROS have also been implicated in the chemopreventive and anti-tumor action of nutraceuticals derived from fruits, vegetables, spices, and other natural products used in traditional medicine. CRITICAL ISSUES: These statements suggest both "upside" (cancer-suppressing) and "downside" (cancer-promoting) actions of the ROS. Thus, similar to tumor necrosis factor-α, inflammation, and NF-κB, ROS act as a double-edged sword. This paradox provides a great challenge for researchers whose aim is to exploit ROS stress for the development of cancer therapies. FUTURE DIRECTIONS: the various mechanisms by which ROS mediate paradoxical effects are discussed in this article. The outstanding questions and future directions raised by our current understanding are discussed.

Discovery of curcumin, a component of golden spice, and its miraculous biological activities.

1. Curcumin is the active ingredient of the dietary spice turmeric and has been consumed for medicinal purposes for thousands of years. Modern science has shown that curcumin modulates various signalling molecules, including inflammatory molecules, transcription factors, enzymes, protein kinases, protein reductases, carrier proteins, cell survival proteins, drug resistance proteins, adhesion molecules, growth factors, receptors, cell cycle regulatory proteins, chemokines, DNA, RNA and metal ions. 2. Because of this polyphenol's potential to modulate multiple signalling molecules, it has been reported to possess pleiotropic activities. First demonstrated to have antibacterial activity in 1949, curcumin has since been shown to have anti-inflammatory, anti-oxidant, pro-apoptotic, chemopreventive, chemotherapeutic, antiproliferative, wound healing, antinociceptive, antiparasitic and antimalarial properties as well. Animal studies have suggested that curcumin may be active against a wide range of human diseases, including diabetes, obesity, neurological and psychiatric disorders and cancer, as well as chronic illnesses affecting the eyes, lungs, liver, kidneys and gastrointestinal and cardiovascular systems. 3. Although many clinical trials evaluating the safety and efficacy of curcumin against human ailments have already been completed, others are still ongoing. Moreover, curcumin is used as a supplement in several countries, including India, Japan, the US, Thailand, China, Korea, Turkey, South Africa, Nepal and Pakistan. Although inexpensive, apparently well tolerated and potentially active, curcumin has not been approved for the treatment of any human disease. 4. In the present article, we discuss the discovery and key biological activities of curcumin, with a particular emphasis on its activities at the molecular and cellular levels, as well as in animals and humans.

Analgesic and anti-inflammatory effects of ethyl acetate fraction of Polygonum cuspidatum in experimental animals.

Polygonum cuspidatum (PC) has been used for the treatment of arthritis and urinary diseases in traditional medicine. Despite recent evidence that PC has anti-oxidant, anti-tumoral, and anti-inflammatory effects, analgesic and anti-inflammatory effects of PC have not been elucidated yet in vivo. Thus, in the present study, analgesic and anti-inflammatory effects of ethyl acetate extract of PC (EAPC) were investigated in vivo for the first time. Hot plate test and tail-flick test revealed that EAPC at 200 mg/kg exerts analgesic effect (p < 0.05). In contrast, EAPC did not show significant analgesic effect in acetic acid-induced writhing test. Serotonin-induced paw edema model and Freund's complete adjuvant (FCA)-induced adjuvant arthritis model were used to examine anti-inflammatory effect of EAPC in vivo. In serotonin-induced paw edema model, EAPC suppressed swelling inflammatory response within 12 min after serotonin injection, at both 100- and 200-mg/kg dose (p < 0.05). Consistently, in FCA-induced adjuvant arthritis model, FCA at 200 mg/kg significantly suppressed FCA-induced joint swelling within 3 days (p < 0.05), whereas FCA at 100 mg/kg showed the similar result within 5 days (p < 0.05). Furthermore, EAPC effectively inhibited positive responses of c-reactive protein and rheumatoid factor compared to untreated control. Taken together, our findings suggest that EAPC can be a potent candidate for rheumatoid arthritis treatment.

Herbal cocktail ka-mi-kae-kyuk-tang stimulates mouse bone marrow stem cell hematopoiesis and janus-activated kinase 2/signal transducer and activator of transcription 5 pathway.

Ka-mi-kae-kyuk-tang (KMKKT) is an Oriental herbal medicinal cocktail. Our collaborative team has shown that it has potent anti-angiogenic, anti-cancer and anti-metastatic activities in vivo without observable side effects. We have documented evidence for KMKKT to alleviate drug-induced hematotoxicity in vivo. In the present study, we investigated the mechanistic and signaling events through which KMKKT enhances hematopoiesis, using hematopoietic stem cells (HSCs) isolated from the bone marrow of 8-12 week-old C57BL/6 mice. Our results show that KMKKT significantly increased the expression of the hematopoietic cytokines interleukin (IL)-3, stem cell factor (SCF), granulocyte-macrophage-colony stimulating factor (GM-CSF), thrombopoietin (TPO) and erythropoietin (EPO) at the level of mRNA and secretion in HSCs. KMKKT also increased the expression of c-Kit, a cytokine receptor expressed in HSCs. In addition, KMKKT enhanced phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5), and increased the binding activity of STAT5 to gamma interferon activated sites (GAS) that mediate JAK2 downstream signaling. Furthermore, we found that KMKKT significantly enhanced the growth rate of colony-forming unit granulocyte erythrocyte monocyte macrophages (CFU-GEMM) and burst forming unit erythroid (BFU-E) of mouse HSCs (mHSCs) stimulated by IL-3/EPO. Overall, our results demonstrated that KMKKT alleviated drug-induced side effects through enhanced hematopoiesis, at least in part through cytokine-mediated JAK2/STAT5 signaling.

Are there new therapeutic options for treating lung cancer based on herbal medicines and their metabolites?

ETHONOPHARMACOLOGICAL RELEVANCE: Lung cancer is one of the most lethal cancers in terms of mortality and incidence worldwide. Despite intensive research and investigation, treatment of lung cancer is still unsatisfactory due to adverse effects and multidrug resistance. Recently, herbal drugs have been recognized as one of attractive approaches for lung cancer therapy with little side effects. Furthermore, there are evidences that various herbal medicines have proven to be useful and effective in sensitizing conventional agents, prolonging survival time, preventing side effects of chemotherapy, and improving quality of life (QoL) in lung cancer patients. AIM AND METHODS OF THE STUDY: Nevertheless, the underlying molecular targets and efficacy of herbal medicines in lung cancer treatment still remain unclear. Thus, we reviewed traditionally used herbal medicines and their phytochemicals with antitumor activity against lung cancer from peer-reviewed papers through Scientific Database Medline, Scopus and Google scholar. CONCLUSIONS: We suggest that herbal medicines and phytochemicals can be useful anti-cancer agents for lung cancer treatment by targeting molecular signaling involved in the regulation of angiogenesis, metastasis and severe side effects, only provided quality control and reproducibility issues were solved.

Oral administration of penta-O-galloyl-ß-D-glucose suppresses triple-negative breast cancer xenograft growth and metastasis in strong association with JAK1-STAT3 inhibition.

There is an urgent clinical need for chemotherapeutic and chemopreventive drugs for triple-negative breast cancer (TNBCa). Extending on our recent work, we hypothesize that the herbal compound 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) can inhibit the growth and metastasis of TNBCa xenograft and target Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) 3-signaling axis. Daily oral gavage of 10 mg PGG/kg body wt decreased MDA-MB-231 xenograft weight by 49.3% (P < 0.01) at 40 days postinoculation, whereas weekly intraperitoneal injections of Taxol at the same dosage resulted in a 21.4% reduction (P > 0.1). PGG treatment also decreased the incidence of lung metastasis. Immunohistochemical staining detected decreased Ki-67 (proliferation) index and increased terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (apoptosis) index in PGG-treated and Taxol-treated xenografts. However, the CD34 (angiogenesis) index was decreased only in PGG-treated xenografts along with decreased phospho-STAT3. In cell culture of MDA-MB-231 cells, PGG decreased pSTAT3 and its downstream target proteins, decreased its upstream kinase pJAK1 and induced the expression of SHP1, a JAK1 upstream tyrosine phosphatase, within as early as 1 h of exposure. The phosphatase inhibitor pervanadate reversed the PGG-induced downregulation of pSTAT3 and caspase activation. Orally administered PGG can inhibit TNBCa growth and metastasis, probably through anti-angiogenesis, antiproliferation and apoptosis induction. Mechanistically, PGG-induced inhibition of JAK1-STAT3 axis may contribute to the observed in vivo efficacy and the effects on the cellular processes.