Efficacy and Safety of Ginger on Chemotherapy-Induced Nausea and Vomiting: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is a prevalent and distressing side effect. Historically, ginger has been explored as a potential remedy for various ailments, including its potential efficacy against CINV. OBJECTIVE: The aim of this study was to determine whether taking ginger supplements can relieve CINV. METHOD: A comprehensive search was conducted across PubMed, EMBASE, Cochrane Library, and the Wanfang database. Randomized controlled trials meeting our inclusion criteria were analyzed. The primary outcomes were the incidence and severity of CINV. The protocol was registered on PROSPERO, and the number is CRD4202232104. RESULT: Of the 35 randomized controlled trials analyzed, 22 trials employed ginger capsules as the primary intervention, whereas 13 studies evaluated the prophylactic effects of ginger-partitioned moxibustion. The outcomes indicated that combining ginger capsules with standard antiemetic agents can significantly reduce the incidence of grade 3 acute nausea (Risk Ratio [RR], 0.19; P < .001) and the incidence of high-grade overall vomiting (RR, 0.47; P = .01). Moreover, ginger-partitioned moxibustion can significantly alleviate the incidence of both mild (RR, 0.56; P = .001) and severe (RR, 0.39; P < .00001) vomiting. Only 2.8% of patients experienced dizziness after ginger-partitioned moxibustion. CONCLUSIONS: Our findings indicate that ginger capsules, when used alongside antiemetic drugs, enhance the management of severe CINV, particularly in highly emetogenic chemotherapy regimens. IMPLICATIONS FOR PRACTICE: Based on our findings, we recommend initiating ginger supplements before chemotherapy, in conjunction with standard antiemetics, to reduce the severity of CINV. The promising results warrant more rigorous clinical trials to firmly establish the role of ginger in CINV management.

Targeting of Mcl-1 Expression by MiRNA-3614-5p Promotes Cell Apoptosis of Human Prostate Cancer Cells.

MicroRNA (miRNA) acts as a critical regulator of growth in various human malignancies. However, the role of miRNA-3614 in the progression of human prostate cancer remains unknown. In this study, our results demonstrated that miRNA-3614-5p exerts a significant inhibitory effect on cell viability and colony formation and induces sub-G1 cell cycle arrest and apoptosis in human prostate cancer cells. Myeloid cell leukemia-1 (Mcl-1) acts as a master regulator of cell survival. Using the miRNA databases, miRNA-3614-5p was found to regulate Mcl-1 expression by targeting positions of the Mcl-1-3' UTR. The reduction of Mcl-1 expression by miRNA-3614-5p was further confirmed using an immunoblotting assay. Pro-apoptotic caspase-3 and poly (ADP-ribose) polymerase (PARP) were significantly activated by miRNA-3614-5p to generate cleaved caspase-3 (active caspase-3) and cleaved PARP (active PARP), accompanied by the inhibited Mcl-1 expression. These findings were the first to demonstrate the anti-growth effects of miRNA-3614-5p through downregulating Mcl-1 expression in human prostate cancer cells.

Norcantharidin combined with paclitaxel induces endoplasmic reticulum stress mediated apoptotic effect in prostate cancer cells by targeting SIRT7 expression.

Prostate cancer (PCa), an extremely common malignancy in males, is the most prevalent disease in several countries. Norcantharidin (NCTD) has antiproliferation, antimetastasis, apoptosis, and autophagy effects in various tumor cells. Nevertheless, the antitumor effect of NCTD combined with paclitaxel (PTX), a chemotherapeutic drug, in PCa remains unknown. The cell growth, proliferative rate, cell cycle distribution, and cell death were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, colony formation assay, PI staining, and Annexin V/PI staining by flow cytomertry, whereas the mitochondrial membrane potential (MMP) and endoplasmic reticulum (ER) stress was evaluated using the MitoPotential assay and ER-ID red assay. We also evaluated the protein and mRNA expression of SIRTs by Western blotting and qRTPCR assay. Overexpression effectivity was measured by DNA transfection assay. Our study showed that cell viability and proliferative PC3 and DU145 rates were effectively inhibited after NCTD-PTX combination. We also found that NCTD-PTX combination treatment significantly enhance G2/M phase arrest, induction of cell death and ER stress, loss of MMP, and ER- or apoptotic-related protein expression. Furthermore, NCTD-PTX combination treatment was significantly decreasing the protein and mRNA expression of SIRT7 in PCa cells. Combination therapy effectively reduced cell viability, ER stress-mediated apoptosis and p-eIF2α/ATF4/CHOP/cleaved-PARP expression inhibition in SIRT7 overexpression of PCa cells. These results indicate that NCTD combined with PTX induces ER stress-mediated apoptosis of PCa cells by regulating the SIRT7 expression axis. Moreover, combination therapy may become a potential therapeutic strategy against human PCa.

Ionizing Radiation Induces Resistant Glioblastoma Stem-Like Cells by Promoting Autophagy via the Wnt/ß-Catenin Pathway.

Therapeutic resistance in recurrent glioblastoma multiforme (GBM) after concurrent chemoradiotherapy (CCRT) is a challenging issue. Although standard fractionated radiation is essential to treat GBM, it has led to local recurrence along with therapy-resistant cells in the ionizing radiation (IR) field. Lines of evidence showed cancer stem cells (CSCs) play a vital role in therapy resistance in many cancer types, including GBM. However, the molecular mechanism is poorly understood. Here, we proposed that autophagy could be involved in GSC induction for radioresistance. In a clinical setting, patients who received radiation/chemotherapy had higher LC3II expression and showed poor overall survival compared with those with low LC3 II. In a cell model, U87MG and GBM8401 expressed high level of stemness markers CD133, CD44, Nestin, and autophagy marker P62/LC3II after receiving standard fractionated IR. Furthermore, Wnt/ß-catenin proved to be a potential pathway and related to P62 by using proteasome inhibitor (MG132). Moreover, pharmacological inhibition of autophagy with BAF and CQ inhibit GSC cell growth by impairing autophagy flux as demonstrated by decrease Nestin, CD133, and SOX-2 levels. In conclusion, we demonstrated that fractionated IR could induce GSCs with the stemness phenotype by P62-mediated autophagy through the Wnt/ß-catenin for radioresistance. This study offers a new therapeutic strategy for targeting GBM in the future.

Legacy Effect of Antioxidant N-acetylcysteine in Cellular Senescence of Diet-induced Obesity Mice.

BACKGROUND: Cellular senescence is a state of stable growth arrest triggered by mitogenic and metabolic stressors. Ageing and a high-fat diet (HFD) are proven inducers of senescence in various organs, presenting a challenge for ageing populations worldwide. Our previous study demonstrated that ROS scavenger N-acetylcysteine (NAC) can improve insulin resistance (IR) and chronic inflammation in diet-induced obesity mice, an effect better achieved through early intervention. We, herein, investigate whether NAC can improve cellular senescence in a diet-induced obesity mouse model, and whether a legacy effect is presented with early intervention. MATERIALS AND METHODS: For a twelve-month treatment course, all C57B/L6 mice were fed a chow diet (CD), high-fat high-sucrose diet (HFD), CD+NAC1-12 (NAC intervention 1st-12th month), HFD+NAC1-12, and HFD+NAC1-6 (NAC intervention 1st-6th month). Staticalanalysis was used to analyze the different markers of cellular senescence and inflammation. RESULTS: Throughout the study, the HFD group exhibited significantly increased body weight (BW) and body fat, markers of senescence, decreased motor activity (MA) and impaired glucose tolerance. Compared to the HFD group, the HFD+NAC1-12 group exhibited increased MA, decreased BW and body fat, improved glucose tolerance, and decreased senescence markers.The HFD+NAC1-6 group showed similar effects to the HFD+NAC1-12 group, despite discontinuing NAC for 6 months. Our study showed that NAC significantly increased MA in both HFD+NAC1-12 and HFD+NAC1-6 groups, and improved HFD-induced mitochondrial and intracellular ROS expression, DNA and protein oxidative damage, and adipose tissue inflammation. CONCLUSION: Legacy effect was indeed presented in HFD-induced cellular senescence with NAC intervention, with possible mechanisms being persistently increased motor activity and anti-oxidative stress effects.

The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes.

Background: Plenty of evidence suggested that chronic low-grade inflammation triggered by innate immunity activation contributes to the pathogenesis of type 2 diabetes (T2D). Using the trans-mitochondrial cybrid cell model, we have demonstrated that mitochondria independently take part in the pathological process of insulin resistance (IR) and pro-inflammatory phenotype in cybrid cells harboring mitochondrial haplogroup B4, which are more likely to develop T2D. The mitochondrial network is more fragmented, and the expression of fusion-related proteins is low in Cybrid B4. We also discovered the causal role of mitochondrial dynamics (mtDYN) proteins in regulating IR in this cybrid model, and the bidirectional interaction between mtDYN and mitochondrial oxidative stress is considered etiologically important. In this study, we further investigated whether mtDYN bridges the gap between nutrient excess and chronic inflammation in T2D. Methods: Trans-mitochondrial cybrid cells derived from the 143B human osteosarcoma cell line were cultured in a medium containing glucose (25 mM) with or without saturated fatty acid (0.25 mM BSA-conjugated palmitate), and the expression of innate immunity/inflammasome molecules was compared between cybrid B4 (the major T2D-susceptible haplogroup among the Chinese population) and cybrid D4 (the major T2D-resistant haplogroup among the Chinese population). We investigated the causal relationship between mtDYN and nutrient excess-induced inflammation in cybrid B4 by genetic manipulation of mtDYN and by pharmacologically inhibiting mitochondrial fission using the Drp1 inhibitor, mdivi-1, and metformin. Results: Under nutrient excess with high fatty acid, cybrid B4 presented increased mitochondrial pro-fission profiles and enhanced chronic inflammation markers (RIG-I, MDA5, MAVS) and inflammasome (NLRP3, Caspase-1, IL-1ß), whereas the levels in cybrid D4 were not or less significantly altered. In cybrid B4 under nutrient excess, overexpression of fusion proteins (Mfn1 or Mfn2) significantly repressed the expression of innate immunity/inflammasome-related molecules, while knockdown had a less significant effect. On the contrary, knockdown of fission proteins (Drp1 or Fis1) significantly repressed the expression of innate immunity/inflammasome-related molecules, while overexpression had a less significant effect. In addition, Drp1 inhibitor mdivi-1 and metformin inhibited mitochondrial fission and attenuated the pro-inflammation expression as well. Conclusion: Our results discovered the causal relationship between mtDYN and nutrient excess-induced chronic inflammation in a diabetes-susceptible cell model. Targeting mtDYN by direct interfering pro-fission can be a therapeutic intervention for chronic inflammation in T2D.

Synergistic antimetastatic effect of cotreatment with licochalcone A and sorafenib on human hepatocellular carcinoma cells through the inactivation of MKK4/JNK and uPA expression.

To improve the clinical outcome of tumor chemotherapy, more effective combination treatments against tumor metastasis and recurrence are required. Licochalcone A (LicA) is the root of Glycyrrhiza inflata and has been reported to possess anti-inflammatory, antimicrobial, and antitumor effects. Sorafenib (Sor), a multikinase inhibitor, is used to treat patients with solid tumors such as advanced hepatocellular carcinoma (HCC). However, the synergistic effects of LicA and Sor on the metastasis of human HCC cells have not been reported. We found that LicA and Sor did not have cytotoxic effects or arrest growth in human SK-Hep-1 and Huh-7 cells. In addition, treatment with LicA or Sor alone inhibited migration and invasion in human SK-Hep-1 and Huh-7 HCC cells. Furthermore, cotreatment with LicA and Sor synergistically inhibited the migration and invasion of HCC cells and significantly inhibited uPA protein expression. Notably, cotreatment of LicA and Sor synergistically and significantly downregulated MKK4-JNK expression. Through tail vein injection in nude mice, the aforementioned cotreatment synergistically suppressed SK-Hep-1 cell-mediated lung metastasis. These findings first revealed the synergistic effects of LicA and Sor cotreatment against human HCC cells, further suggesting that beneficial effects on tumor regression could be confirmed through prospective clinical trials.

Neuron-Specific HuR-Deficient Mice Spontaneously Develop Motor Neuron Disease.

Human Ag R (HuR) is an RNA binding protein in the ELAVL protein family. To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR-deficient mice of both sexes. After tamoxifen-induced deletion of HuR, these mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength. They performed significantly worse on the rotarod test compared with littermate control mice, indicating coordination deficiency. Using the grip-strength test, it was also determined that the forelimbs of neuron-specific HuR-deficient mice were much weaker than littermate control mice. Immunostaining of the brain and cervical spinal cord showed that HuR-deficient neurons had increased levels of cleaved caspase-3, a hallmark of cell apoptosis. Caspase-3 cleavage was especially strong in pyramidal neurons and α motor neurons of HuR-deficient mice. Genome-wide microarray and real-time PCR analysis further indicated that HuR deficiency in neurons resulted in altered expression of genes in the brain involved in cell growth, including trichoplein keratin filament-binding protein, Cdkn2c, G-protein signaling modulator 2, immediate early response 2, superoxide dismutase 1, and Bcl2. The additional enriched Gene Ontology terms in the brain tissues of neuron-specific HuR-deficient mice were largely related to inflammation, including IFN-induced genes and complement components. Importantly, some of these HuR-regulated genes were also significantly altered in the brain and spinal cord of patients with amyotrophic lateral sclerosis. Additionally, neuronal HuR deficiency resulted in the redistribution of TDP43 to cytosolic granules, which has been linked to motor neuron disease. Taken together, we propose that this neuron-specific HuR-deficient mouse strain can potentially be used as a motor neuron disease model.

Early intervention of N-acetylcysteine better improves insulin resistance in diet-induced obesity mice.

Reactive oxygen species (ROS) plays a crucial role in pathogenesis of insulin resistance (IR) and type 2 diabetes. In the United Kingdom, Prospective Diabetes Study and its 10-year post-trial monitoring, a beneficial effect of early optimisation of blood glucose control is clearly demonstrated. In this study, we investigated whether ROS scavenger N-acetylcysteine (NAC) and the time point of intervention can affect IR in a diet-induced obesity mouse model. Male C57B/L6 mice were fed chow diet (CD), high-fat high-sucrose diet (HFD), CD + NAC1-6 (NAC intervention 1st to 6th month), HFD + NAC1-6, and HFD + NAC3-6 (NAC intervention 3rd to 6th month) for a 6-month treatment course. HFD group showed significantly increased body weight (BW) and body fat, decreased motor activity (MA), impaired intraperitoneal glucose tolerance test (IPGTT), and insulin tolerance test (IPITT) throughout the study. HFD + NAC1-6, as compared with HFD group, had increased MA, improved IPGTT and IPITT since first month, followed by decreased BW and body fat. HFD + NAC3-6 group, although showed improved IPGTT and IPITT than HFD group, still had higher BW, decreased MA, and impaired IPGTT and IPITT as compared with HFD + NAC1-6 at the end of the study. NAC significantly increased MA, and ameliorated the HFD-induced mitochondrial and intracellular ROS expression, DNA and protein oxidative damage, and adipose tissue inflammation. We concluded that ROS scavenger can improve IR and chronic inflammation in diet-induced obesity mice. This action is likely better expressed through early intervention. The mechanism is probably through a virtuous circle of suppressed oxidative stress, and increased motor activity, which helps to reduce body fat.

Induction of endoplasmic reticulum stress and mitochondrial dysfunction dependent apoptosis signaling pathway in human renal cancer cells by norcantharidin.

Previous studies reported that norcantharidin (NCTD) has anti-tumor effects. We investigated the antitumor effects and underlying mechanism of NCTD on human renal cancer in vitro and in vivo. NCTD significantly decreased renal cancer cell viability by induction of apoptosis, as determined by the MTT assay and annexin V/PI staining. NCTD treatment of 786-O and A-498 cells altered the expression of caspase family proteins and PARP. Moreover, NCTD induced mitochondrial depolarization, which was accompanied by an increased level of Bax and decreased levels of Bcl-2 and Mcl-1. NCTD induced endoplasmic reticulum (ER) stress by increasing the expression of Grp78, p-elF2α, ATF4, and CHOP. Pretreatment with an ER stress inhibitor (salubrinal) significantly attenuated the effect of NCTD. NCTD also induced activation of the AKT pathway in 786-O and A-498 cells. Overexpression of AKT partly reversed the effect of NCTD on apoptosis. NCTD treatment led to decreased expression of Bcl-2 and Mcl-1, and increased expression of Bax, cleaved-caspase-9, cleaved-PARP, and p-elF2α. Our in vivo studies demonstrated that NCTD significantly inhibited tumor growth in a nude mouse xenograft model. Taken together, our results suggest that NCTD is a potential anti-tumor agent for treatment of renal carcinoma.

Differential Adaptations of the Musculoskeletal System after Spinal Cord Contusion and Transection in Rats.

Spinal cord injury (SCI) causes impaired neuronal function with associated deficits in the musculoskeletal system, which can lead to permanent disability. Here, the impact of SCI on in vivo musculoskeletal adaptation was determined by studying deficits in locomotor function and analyzing changes that occur in the muscle and bone compartments within the rat hindlimb after contusion or transection SCI. Analyses of locomotor patterns, as assessed via the Basso, Beattie, and Bresnahan (BBB) rating scale, revealed that transection animals showed significant deficits, while the contusion group had moderate deficits, compared with naïve groups. Muscle myofiber cross-sectional areas (CSA) of both the soleus and tibialis anterior muscles were significantly decreased three months after contusion SCI. Such decreases in CSA were even more dramatic in the transection SCI group, suggesting a dependence on muscle activity, which is further validated by the correlation analyses between BBB score and myofiber CSA. Bone compartment analyses, however, revealed that transection animals showed the most significant deficits, while contusion animals showed no significant differences in the trabecular bone content within the proximal tibia compartment. In general, values of bone volume per total bone volume (BV/TV) were similar across the SCI groups. Significant decreases were observed, however, in the transection animals for bone mineral content, bone mineral density, and three-dimensional trabecular structure parameters (trabecular number, thickness, and spacing) compared with the naïve and contusion groups. Together, these findings suggest an altered musculoskeletal system can be correlated directly to motor dysfunctions seen after SCI.

Praeruptorin A Inhibits Human Cervical Cancer Cell Growth and Invasion by Suppressing MMP-2 Expression and ERK1/2 Signaling.

Praeruptorin A (PA) is a pyranocumarin present in the dried root of Peucedanumpraeruptorum Dunn that has anticancer effects against several types of cells. However, the effect of PA on human cervical cancer cells is unknown. Our results indicate that PA significantly inhibited cell proliferation, colony formation, migration, invasion, and wound closure of HeLa and SiHa cells, induced cell cycle arrest at G0/G1 phase, upregulated Rb, p16, p21 and p27 proteins and downregulated cyclin D1 and S-phase kinase-associated protein 2 (Skp2) proteins. PA also significantly reduced expression of matrix metalloproteinase-2 (MMP-2) and increased expression of tissue inhibitor of metalloproteinase-2 (TIMP-2). In addition, PA suppressed ERK1/2 activation and increased the effect of PD98059 (a specific MEK1/2 inhibitor) in downregulation of MMP-2 and upregulation of TIMP-2. PA treatment inhibited the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on upregulation of ERK1/2 activation, MMP-2 expression, cellular migration, and invasion of HeLa cells. Our findings are the first to demonstrate the activity of PA against cervical cancer cells, and suggest this agent has promise as a therapeutic agent in treatment of human cervical cancer.

Combinatory repair strategy to promote axon regeneration and functional recovery after chronic spinal cord injury.

Eight weeks post contusive spinal cord injury, we built a peripheral nerve graft bridge (PNG) through the cystic cavity and treated the graft/host interface with acidic fibroblast growth factor (aFGF) and chondroitinase ABC (ChABC). This combinatorial strategy remarkably enhanced integration between host astrocytes and graft Schwann cells, allowing for robust growth, especially of catecholaminergic axons, through the graft and back into the distal spinal cord. In the absence of aFGF+ChABC fewer catecholaminergic axons entered the graft, no axons exited, and Schwann cells and astrocytes failed to integrate. In sharp contrast with the acutely bridge-repaired cord, in the chronically repaired cord only low levels of serotonergic axons regenerated into the graft, with no evidence of re-entry back into the spinal cord. The failure of axons to regenerate was strongly correlated with a dramatic increase of SOCS3 expression. While regeneration was more limited overall than at acute stages, our combinatorial strategy in the chronically injured animals prevented a decline in locomotor behavior and bladder physiology outcomes associated with an invasive repair strategy. These results indicate that PNG+aFGF+ChABC treatment of the chronically contused spinal cord can provide a permissive substrate for the regeneration of certain neuronal populations that retain a growth potential over time, and lead to functional improvements.

VLDL and LDL, but not HDL, promote breast cancer cell proliferation, metastasis and angiogenesis.

Abnormal lipoprotein profiles are associated with breast cancer progression. However, the mechanisms linking abnormal lipoprotein levels to breast cancer progression, especially metastasis, remain unclear. Herein, we found that L1 and L5 subfractions of LDL and VLDL, but not HDL, enhanced breast cancer cell viability. L1, L5, and VLDL also increased the in vitro tumorigenesis of breast cancer cells in anchorage-independent soft agar assay. In addition, L1, L5, and VLDL, but not HDL, increased the levels of mesenchymal markers Slug, Vimentin, and ß-Catenin, and promoted breast cancer cell migration and invasion. L1, L5, and VLDL increased Akt Ser473 phosphorylation and promoted cell migration, which were reversed by the PI3K/Akt inhibitor wortmannin. Further in vitro angiogenesis assay and cytokine array analysis demonstrated that L1, L5, and VLDL enhanced secretion of angiogenic factors in breast cancer cells and promoted angiogenic activity. However, only VLDL reduced anchorage-dependent cell death and promoted lung metastasis in nude mice. In summary, our data suggest that L1, L5, and especially VLDL promote breast cancer progression and metastasis through Akt-induced EMT and angiogenesis, and provide a novel mechanism of how dyslipoproteinemia promotes breast cancer progression.

Altered mitochondrial dynamics and response to insulin in cybrid cells harboring a diabetes-susceptible mitochondrial DNA haplogroup.

The advantage of using a cytoplasmic hybrid (cybrid) model to study the genetic effects of mitochondria is that the cells have the same nuclear genomic background. We previously demonstrated the independent role of mitochondria in the pathogenesis of insulin resistance (IR) and pro-inflammation in type 2 diabetes. In this study, we compared mitochondrial dynamics and related physiological functions between cybrid cells harboring diabetes-susceptible (B4) and diabetes-protective (D4) mitochondrial haplogroups, especially the responses before and after insulin stimulation. Cybrid B4 showed a more fragmented mitochondrial network, impaired mitochondrial biogenesis and bioenergetics, increased apoptosis and ineffective mitophagy and a low expression of fusion-related molecules. Upon insulin stimulation, increases in network formation, mitochondrial DNA (mtDNA) content, and ATP production were observed only in cybrid D4. Insulin promoted a pro-fusion dynamic status in both cybrids, but the trend was greater in cybrid D4. In cybrid B4, the imbalance of mitochondrial dynamics and impaired biogenesis and bioenergetics, and increased apoptosis were significantly improved in response to antioxidant treatment. We concluded that diabetes-susceptible mtDNA variants are themselves resistant to insulin.

Peripheral Nerve Transplantation Combined with Acidic Fibroblast Growth Factor and Chondroitinase Induces Regeneration and Improves Urinary Function in Complete Spinal Cord Transected Adult Mice.

The loss of lower urinary tract (LUT) control is a ubiquitous consequence of a complete spinal cord injury, attributed to a lack of regeneration of supraspinal pathways controlling the bladder. Previous work in our lab has utilized a combinatorial therapy of peripheral nerve autografts (PNG), acidic fibroblast growth factor (aFGF), and chondroitinase ABC (ChABC) to treat a complete T8 spinal cord transection in the adult rat, resulting in supraspinal control of bladder function. In the present study we extended these findings by examining the use of the combinatorial PNG+aFGF+ChABC treatment in a T8 transected mouse model, which more closely models human urinary deficits following spinal cord injury. Cystometry analysis and external urethral sphincter electromyograms reveal that treatment with PNG+aFGF+ChABC reduced bladder weight, improved bladder and external urethral sphincter histology, and significantly enhanced LUT function, resulting in more efficient voiding. Treated mice's injured spinal cord also showed a reduction in collagen scaring, and regeneration of serotonergic and tyrosine hydroxylase-positive axons across the lesion and into the distal spinal cord. Regeneration of serotonin axons correlated with LUT recovery. These results suggest that our mouse model of LUT dysfunction recapitulates the results found in the rat model and may be used to further investigate genetic contributions to regeneration failure.

Effects of Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression on Dendritic Outgrowth and Demyelination after Spinal Cord Injury.

Suppressors of cytokine signaling-3 (SOCS3) is associated with limitations of nerve growth capacity after injury to the central nervous system. Although genetic manipulations of SOCS3 can enhance axonal regeneration after optic injury, the role of SOCS3 in dendritic outgrowth after spinal cord injury (SCI) is still unclear. The present study investigated the endogenous expression of SOCS3 and its role in regulating neurite outgrowth in vitro. Interleukin-6 (IL-6) induces SOCS3 expression at the mRNA and protein levels in neuroscreen-1 (NS-1) cells. In parallel to SOCS3 expression, IL-6 induced tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3) in NS-1 cells. Lentiviral delivery of short hairpin RNA (shSOCS3) (Lenti-shSOCS3) to decrease SOCS3 expression into NS-1 cells enhanced IL-6-induced tyrosine phosphorylation of STAT3 (P-STAT3 Tyr705) and promoted neurite outgrowth. In addition, we determined if reduction of SOCS3 expression by microinjection of Lenti-shSOCS3 into spinal cord enhances dendrite outgrowth in spinal cord neurons after SCI. Knocking down of SOCS3 in spinal cord neurons with Lenti-shSOCS3 increased complete SCI-induced P-STAT3 Tyr705. Immunohistochemical analysis showed that complete SCI induced a significant reduction of microtubule association protein 2-positive (MAP-2+) dendrites in the gray and white matter at 1 and 4 weeks after injury. The SCI-induced reduction of MAP-2+ dendrites was inhibited by infection with Lenti-shSOCS3 in areas both rostral and caudal to the lesion at 1 and 4 weeks after complete SCI. Furthermore, shSOCS3 treatment enhanced up-regulation of growth associated protein-43 (GAP-43) expression, which co-localized with MAP-2+ dendrites in white matter and with MAP-2+ cell bodies in gray matter, indicating Lenti-shSOCS3 may induce dendritic regeneration after SCI. Moreover, we demonstrated that Lenti-shSOCS3 decreased SCI-induced demyelination in white matter of spinal cord both rostral and caudal to the injury site 1 week post-injury, but not rostral to the injury at 4 weeks post-injury. Importantly, similar effects as Lenti-shSOCS3 on increasing MAP-2+ intensity and dendrite length, and preventing demyelination were observed when a second shSOCS3 (Lenti-shSOCS3 #2) was applied to rule out the possibilities of off target effects of shRNA. Collectively, these results suggest that knocking down of SOCS3 enhances dendritic regeneration and prevents demyelination after SCI.

A new copepod with transformed body plan and unique phylogenetic position parasitic in the acorn worm Ptychodera flava.

Symbiotic copepods compose one-third of the known copepod species and are associated with a wide range of animal groups. Two parasitic copepods endoparasitic in acorn worms (Hemichordata), Ive balanoglossi and Ubius hilli, collected in the Mediterranean Sea and Australian waters, respectively, were described a century ago. Here we report a new parasitic copepod species, Ive ptychoderae sp. nov., found in Ptychodera flava, a widespread acorn worm in the Indo-Pacific Ocean and an emerging organism for developmental and evolutionary studies. The female of I. ptychoderae is characterized by having a reduced maxilliped and five pairs of annular swellings along the body that are morphologically similar but distinguishable from those in the two previously described parasitic copepods in acorn worms. Phylogenetic analysis based on the 18S rDNA sequence shows that I. ptychoderae may belong to Poecilostomatoida but represent a new family, which we name Iveidae fam. nov. Ive ptychoderae is commonly found in the acorn worm population with an average prevalence of 42% during the collecting period. The infection of the parasite induces the formation of cysts and causes localized lesions of the host tissues, suggesting that it may have negative effects on its host. Interestingly, most cysts contain a single female with one or multiple male copepods, suggesting that their sex determination may be controlled by environmental conditions. The relationships between the parasitic copepods and acorn worms thus provide a platform for understanding physiological and ecological influences and coevolution between parasites and hosts.

Perceptions on gender awareness and considerations in career choices of medical students in a medical school in Taiwan.

The trend of medical career choice in the younger generation has resulted in deficiency of manpower in the four major disciplines of internal medicine, surgery, obstetrics/gynecology, and pediatrics, which will threaten people's health care in Taiwan. However, perceptions of gender awareness and factors affecting the career choices of medical students have not been investigated systemically in Taiwan. To explore the perceptions on gender awareness and considerations in career choices, we recruited 280 1(st)- and 7(th)-year male and female medical students at a Medical University for the study. A modified Nijmegen questionnaire using a 5-point Likert scale containing medical curricula (18 items), gender awareness (13 items), and career inclination (9 items) was adopted as the investigation tool in our study. The response rate was 75% (224/280). With regard to gender, the 1(st)-year male students had greater confidence in being a physician than the female students (p < 0.05), and female students subjectively suggested an advantage to communicate with patients or colleagues (p < 0.05). Faculty attitude in treating students differently by gender was more prominent in the 7(th)-year than in the 1(st)-year students (p < 0.001), and they felt male preceptors typically were more enthusiastic to teach and to rank higher grades to female than to male students; however, this was not observed among female preceptors. Both male and female students showed a low level of agreement that clinical skills and performance of a physician were significantly different by gender and "female physicians are more empathetic and provide more communications than male physicians". Factors influencing career choices of medical students, including "personal interests/talents" and "academic achievement of the specialty," were not significantly different by gender. Factors included "training and learning environments of the specialty", "risk of lawsuit", and "economic incentive" were more appreciated by the senior than the junior students (p < 0.05). Effect of "family" or "spouse" did not differ significantly regardless of gender or seniority. The 7(th)-year students had experiences in clinical medicine and had different considerations in career choice in comparison to the 1(st)-year students, and gender played a role in senior students. In addition, the senior rather than the junior students regarded "training and learning environments", "risk of lawsuit", and "economic incentive" as more important factors affecting the career choices, and male students paid more attention to these issues. Other factors such as fixed hours of duty with no emergency, easier lifestyle, and more time to take care his/her families were also important factors affecting career choice in medical students regardless of their gender; however, the junior students disclosed lower concern on the issues. In addition, four major misperceptions of gender and health issues were prevalent in the 7(th)-year students; therefore, we recognized the importance of integrating gender issues into medical curriculum to diminish gender misunderstanding and prejudice, and to provide gender-specific health care is mandatory in Taiwan.