The effect of reinforcing sutures and trans-anal drainage tube on the outcome of laparoscopic resection for rectal cancer: propensity score­matched analysis.

OBJECTIVES: Laparoscopic resection for rectal cancer is currently the predominant treatment modality for rectal tumors, with an ongoing focus on reducing the incidence of postoperative complications. In an effort to decrease the occurrence of anastomotic leakage, two additional steps worth considering are reinforcing the anastomosis with a barbed suture and retaining an anal drain as part of the procedure. The results of the operation were analyzed by comparing them to cases where the anastomosis was performed with a stapler alone. METHODS: This study retrospectively analyzed patients who underwent laparoscopic radical rectal cancer surgery between July 2020 and March 2023. The patients were categorized into three cohorts based on the postoperative management following instrumented anastomosis: cohort A, the instrumented anastomosis alone group; cohort B, the reinforced suture group; and cohort C, the reinforced suture and indwelling transanal drainage tube group. Propensity score matching was performed twice in a 1:1 ratio, comparing cohort B to cohort A and cohort C to cohort B. The objective was to compare the benefits and drawbacks among the different groups in terms of operative time, postoperative outcomes and operative costs. RESULTS: 529 patients with laparoscopic resection for rectal cancer were eligible for inclusion. the instrumented anastomosis alone group, reinforced suture group and the reinforced suture and indwelling transanal drainage tube group were performed in 205 patients, 198 patients and 126 patients, respectively. Cohort A and Cohort B differed in three variables after PSM: total operative time (p = 0.018), postoperative hospital stay (p < 0.001) and incidence of anastomotic leakage (p = 0.038). Cohort B had a longer total operative time, shorter postoperative hospital stay and a lower incidence of anastomotic leakage. Similarly, cohort C had less postoperative drainage (P = 0.01) and a longer postoperative hospital stay (P = 0.003) when cohort B and cohort C were matched for propensity scores. There was no significant difference in the cost of surgery between the three cohorts. CONCLUSIONS: The incorporation of barbed suture reinforcement significantly reduces the occurrence of postoperative anastomotic leakage in rectal cancer surgeries. On the other hand, although trans-anal drainage was used as an additional measure to the reinforcement suture of the anastomosis, the utilization of trans-anal drainage tubes does not demonstrate a significant improvement in surgical outcomes.

Identification of predictive factors for post-transarterial chemoembolization liver failure in hepatocellular carcinoma patients: A retrospective study.

BACKGROUND: Post-transarterial chemoembolization (TACE) liver failure occurs frequently in hepatocellular carcinoma (HCC) patients. The identification of predictors for post-TACE liver failure is of great importance for clinical decision-making in this population. AIM: To investigate the occurrence rate and predictive factors of post-TACE liver failure in this retrospective study to provide clues for decision-making regarding TACE procedures in HCC patients. METHODS: The clinical records of HCC patients treated with TACE therapy were reviewed. Baseline clinical characteristics and laboratory parameters of these patients were extracted. Logistic models were used to identify candidates to predict post-TACE liver failure. RESULTS: A total of 199 HCC patients were enrolled in this study, and 70 patients (35.2%) developed post-TACE liver failure. Univariate and multivariate logistic models indicated that microspheres plus gelatin embolization and main tumor size > 5 cm were risk predictors for post-TACE liver failure [odds ratio (OR): 4.4, 95% confidence interval (CI): 1.2-16.3, P = 0.027; OR: 2.3, 95%CI: 1.05-5.3, P = 0.039, respectively]. Conversely, HCC patients who underwent tumor resection surgery before the TACE procedure had a lower risk for post-TACE liver failure (OR: 0.4, 95%CI: 0.2-0.95, P = 0.039). CONCLUSION: Microspheres plus gelatin embolization and main tumor size might be risk factors for post-TACE liver failure in HCC patients, while prior tumor resection could be a favorable factor reducing the risk of post-TACE liver failure.

Noradrenergic innervations of the medial prefrontal cortex mediate empathy for pain in rats via the α1 and ß receptors.

Empathy involves integrated affective and cognitive processes to share the emotional state of others. This evolutionarily conserved ability has also been identified in nonhuman primates and rodents. Our previous work demonstrated that social interaction with a cagemate rat in pain induces mechanical pain hypersensitivity in cagemate observer (CO) rats. Moreover, we also demonstrated that the medial prefrontal cortex (mPFC) and the locus coeruleus-norepinephrine (LC-NE) system are involved in this process. The LC sends noradrenergic innervations throughout the brain, and its innervation of the prefrontal cortex plays important roles in working memory and attention. The present study seeks to study the roles of the LC-to-mPFC pathway in pain empathy in rats. Selective ablation of the noradrenergic innervations of the mPFC through bilateral injections of the axonally transported catecholamine immunotoxin, saporin-conjugated antiserum to dopamine-ß-hydroxylase into the mPFC diminished mechanical pain hypersensitivity in CO rats. Bilateral intra-mPFC applications of the adrenergic α1 receptor antagonist prazosin and the ß receptor antagonist propranolol, but not the adrenergic α2 antagonist yohimbine, eliminated mechanical pain hypersensitivity in CO rats. In contrast, intra-mPFC applications of prazosin, yohimbine or propranolol did not affect the mechanical pain sensitivity of rats per se. Our results indicate that noradrenergic innervations in the mPFC mediate empathy for pain in rats via the α1 and ß receptors.

Association between cystatin C and diabetic retinopathy among type 2 diabetic patients in China: a Meta-analysis.

AIM: To explore the correlation between cystatin C (Cys-C) and diabetic retinopathy (DR) in those patients with type 2 diabetes mellitus (DM) in China. METHODS: Articles were collected from China National Knowledge Infrastructure (CNKI), Wanfang, VIP, PubMed, EMBASE, Cochrane Library, Clinical Trials.gov, and Google Scholar. Quality and risk of bias within included studies was assessed using the Newcastle-Ottawa scale (NOS). Heterogeneity was determined by using Cochran's Q-test and Higgins I 2 statistics. Mean differences (MDs) and 95% confidence intervals (CIs) of Cys-C within the diabetes without retinopathy (DWR) and DR, DWR and non-proliferative diabetic retinopathy (NPDR), NPDR and proliferative diabetic retinopathy (PDR) were collected by using random-effects model because of high heterogeneity. Meta-analysis was conducted based on 23 articles of 2331 DR including NPDR and PDR patients and 2023 DWR patients through Review Manager 5.3. Subgroup analyses were also performed according to DM duration, body mass index (BMI), total cholesterol (TC), total triglycerides (TG), low-density lipoprotein C (LDL-C), and high-density lipoprotein C (HDL-C), sample origins and methods. Publication bias was assessed by the funnel plot. RESULTS: Cys-C level in DR patients was increased compared with that of DWR (total MD: 0.69, 95%CI: 0.41 to 0.97, Z=4.79, P<0.01). Besides, the synthesized results of the studies showed the similar findings in the DWR vs NPDR group (total MD: 0.29, 95%CI 0.20 to 0.39, Z=6.02, P<0.01) and the NPDR vs PDR group (total MD: 0.63, 95%CI 0.43 to 0.82, Z=6.33, P<0.01). Heterogeneity of most of the subgroup analyses was still obvious (I 2≥50%, P<0.1). Forest plots of different subgroups indicated that there was a slight increase of Cys-C during the period between DWR and DR, DWR and NPDR, NPDR and PDR. Funnel plot showed that there was no significant publication bias. CONCLUSION: The elevated Cys-C is closely related with DR and probably plays a critical role in its progression.

Ulinastatin Exhibits Antinociception in Rat Models of Acute Somatic and Visceral Pain Through Inhibiting the Local and Central Inflammation.

INTRODUCTION: Ulinastatin, a broad-spectrum serine protease inhibitor, has been widely used to treat various diseases clinically. However, so far, the antinociceptive effect of ulinastatin remains less studied experimentally and the underlying mechanisms of ulinastatin for pain relief remain unclear. This study aimed to find evidence of the analgesic effect of ulinastatin on acute somatic and visceral pain. METHODS: The analgesic effect of ulinastatin on acute somatic and visceral pain was evaluated by using formalin and acetic acid-induced writhing test. The analgesic mechanism of ulinastatin was verified by detecting the peripheral inflammatory cell infiltration and spinal glial activation with hematoxylin-eosin (H&E) and immunohistochemistry staining. RESULTS: We found that both of intraperitoneal (i.p.) pre-administration and post-administration of ulinastatin could reduce the total number of flinching and the licking duration following intraplantar formalin injection in a dose-related manner. However, the inhibitory effect of ulinastatin existed only in the second phase (Phase 2) of formalin-induced spontaneous pain response, with no effect in the first phase (Phase 1). The formalin-induced edema and ulcer were also improved by i.p. administration of ulinastatin. Moreover, i.p. administration of ulinastatin was also able to delay the occurrence of acetic acid-induced writhing and reduced the total number of writhes dose-dependently. We further demonstrated that ulinastatin significantly decreased the local inflammatory cell infiltration in injured paw and peritoneum tissue under formalin and acetic acid test separately. The microglial and astrocytic activation in the spinal dorsal horn induced by intraplantar formalin and i.p. acetic acid injection were also dramatically inhibited by i.p. administration of ulinastatin. CONCLUSION: Our results for the first time provided a new line of evidence showing that ulinastatin could attenuate acute somatic and visceral pain by inhibiting the peripheral and spinal inflammatory reaction.

Early therapeutic interventions of traditional Chinese medicine in COVID-19 patients: A retrospective cohort study.

OBJECTIVE: To observe the early interventions of traditional Chinese Medicine (TCM) on the conversion time of nucleic acid in patients with coronavirus disease 2019 (COVID-19), and find possible underlying mechanisms of action. METHODS: A retrospective cohort study was conducted on 300 confirmed COVID-19 patients who were treated with TCM, at a designated hospital in China. The patients were categorized into three groups: TCM1, TCM2 and TCM3, who respectively received TCM interventions within 7, 8-14, and greater than 15 days of hospitalization. Different indicators such as the conversion time of pharyngeal swab nucleic acid, the conversion time of fecal nucleic acid, length of hospital stay, and inflammatory markers (leukocyte count, and lymphocyte count and percentage) were analyzed to observe the impact of early TCM interventions on these groups. RESULTS: The median conversion times of pharyngeal swab nucleic acid in the three groups were 5.5, 7 and 16 d (P < 0.001), with TCM1 and TCM2 being statistically different from TCM3 (P < 0.01). TCM1 (P < 0.05) and TCM3 (P < 0.01) were statistically different from TCM2. The median conversion times of fecal nucleic acid in the three groups were 7, 9 and 17 d (P < 0.001). Conversion times of fecal nucleic acid in TCM1 were statistically different from TCM3 and TCM2 (P < 0.01). The median lengths of hospital stay in the three groups were 13, 16 and 21 d (P < 0.001). TCM1 and TCM2 were statistically different from TCM3 (P < 0.01); TCM1 and TCM3 were statistically different from TCM2 (P < 0.01). Both leucocyte and lymphocyte counts increased gradually with an increase in the length of hospital stay in TCM1 group patients, with a statistically significant difference observed at each time point in the group (P < 0.001). Statistically significant differences in lymphocyte count and percentage in TCM2 (P < 0.001), and in leucocyte count (P = 0.043) and lymphocyte count (P = 0.038) in TCM3 were observed. The comparison among the three groups showed a statistically significant difference in lymphocyte percentage on the third day of admission (P = 0.044). CONCLUSION: In this study, it was observed that in COVID-19 patients treated with a combination of Chinese and Western medicines, TCM intervention earlier in the hospital stay correlated with faster conversion time of pharyngeal swab and fecal nucleic acid, as well as shorter length of hospital stay, thus helping promote faster recovery of the patient. The underlying mechanism of action may be related to improving inflammation in patients with COVID-19.

Association between miR-27a rs895819 polymorphism and breast cancer susceptibility: Evidence based on 6118 cases and 7042 controls.

BACKGROUND: Polymorphism in miR-27a rs895819 has been associated with breast cancer (BC) risk, but studies have reported inconsistent results. This meta-analysis investigated the possible association between miR-27a rs895819 polymorphism and BC risk. METHODS: PubMed, EMBASE, Google Scholar, and the Chinese National Knowledge Infrastructure (CNKI) databases were systematically searched to identify relevant studies in English and Chinese. Meta-analyses were performed to examine the association between miR-27a rs895819 and BC susceptibility. RESULTS: A total of 16 case-control studies involving 6118 cases and 7042 controls were included. Analysis using five genetic models suggested no significant association between miR-27a rs895819 polymorphism and BC risk in the total population, or specifically in Asian or Chinese subpopulations. In the Caucasian subpopulation, however, the G-allele and AG genotype at rs895819 were significantly associated with decreased BC risk according to the allelic model (OR 0.90, 95% CI 0.84-0.97, P = .004) and heterozygous model (OR 0.89, 95% CI 0.81-089, P = .02), while the wild-type AA genotype was significantly associated with increased BC risk according to the dominant model (OR 1.13, 95% CI 1.03-1.24, P = .007). CONCLUSION: These results indicate that among Caucasians, the wild-type AA genotype at rs895819 may confer increased susceptibility to BC, while the G-allele and AG genotype may be protective factors. These conclusions should be verified in large, well-designed studies.

Effects of Tanreqing Capsule on the negative conversion time of nucleic acid in patients with COVID-19: A retrospective cohort study.

OBJECTIVE: Traditional Chinese medicine plays a significant role in the treatment of the pandemic of coronavirus disease 2019 (COVID-19). Tanreqing Capsule (TRQC) was used in the treatment of COVID-19 patients in the Shanghai Public Health Clinical Center. This study aimed to investigate the clinical efficacy of TRQC in the treatment of COVID-19. METHODS: A retrospective cohort study was conducted on 82 patients who had laboratory-confirmed mild and moderate COVID-19; patients were treated with TRQC in one designated hospital. The treatment and control groups consisted of 25 and 57 cases, respectively. The treatment group was given TRQC orally three times a day, three pills each time, in addition to conventional Western medicine treatments which were also administered to the control group. The clinical efficacy indicators, such as the negative conversion time of pharyngeal swab nucleic acid, the negative conversion time of fecal nucleic acid, the duration of negative conversion of pharyngeal-fecal nucleic acid, and the improvement in the level of immune indicators such as T-cell subsets (CD3, CD4 and CD45) were monitored. RESULTS: COVID-19 patients in the treatment group, compared to the control group, had a shorter negative conversion time of fecal nucleic acid (4 vs. 9 days, P = 0.047) and a shorter interval of negative conversion of pharyngeal-fecal nucleic acid (0 vs. 2 days, P = 0.042). The level of CD3+ T cells increased in the treatment group compared to the control group ([317.09 ± 274.39] vs. [175.02 ± 239.95] counts/µL, P = 0.030). No statistically significant differences were detected in the median improvement in levels of CD4+ T cells (173 vs. 107 counts/µL, P = 0.208) and CD45+ T cells (366 vs. 141 counts/µL, P = 0.117) between the treatment and control groups. CONCLUSION: Significant reductions in the negative conversion time of fecal nucleic acid and the duration of negative conversion of pharyngeal-fecal nucleic acid were identified in the treatment group as compared to the control group, illustrating the potential therapeutic benefits of using TRQC as a complement to conventional medicine in patients with mild and moderate COVID-19. The underlying mechanism may be related to the improved levels of the immune indicator CD3+ T cells.

Ultrasensitive determination of thrombin by using an electrode modified with WSe2 and gold nanoparticles, aptamer-thrombin-aptamer sandwiching, redox cycling, and signal enhancement by alkaline phosphatase.

A sensitive aptamer/protein binding-triggered sandwich assay for thrombin is described. It is based on electrochemical-chemical-chemical redox cycling using a glassy carbon electrode (GCE) that was modified with WSe2 and gold nanoparticles (AuNPs). The AuNPs are linked to thrombin aptamer 1 via Au-S bonds. Thrombin is first captured by aptamer 1 and then sandwiched through the simultaneous interaction with AuNPs modified with thrombin-specific aptamer 2 and signalling probe. Subsequently, the DNA-linked AuNP hybrids result in the capture of streptavidin-conjugated alkaline phosphatase onto the modified GCE through the specific affinity reaction for further signal enhancement. As a result, a linear range of 0-1 ng mL-1 and a detection limit as low as 190 fg mL-1 are accomplished. The specificity for thrombin is excellent. Conceivably, this strategy can be easily expanded to other proteins by using the appropriate aptamer. Graphical abstract Schematic presentation of an electrochemical biosensor for thrombin based on WSe2 and gold nanoparticles, aptamer-thrombin-aptamer sandwiching, redox cycling, and signal enhancement by alkaline phosphatase.

Combined 18F-FDG PET/CT imaging and a gastric orthotopic xenograft model in nude mice are used to evaluate the efficacy of glycolysis-targeted therapy.

As discovered by Warburg 80 years ago most malignant cells rely more on glycolysis than normal cells. The high rate of glycolysis provides faster ATP production and greater lactic acid for tumor proliferation and invasion, thus indicating a potential target in anticancer therapy. Our previous studies demonstrated that 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) inhibited tumor cell proliferation in vitro. However, the underlying mechanisms still warrant further investigation. In the present study, we employed the human SGC-7901 gastric cancer cell line, built an orthotopic xenograft model in nude mice, examined the treatment response by 18F-FDG PET/CT and investigated the mechanisms of 3-BrPA and SCT in vivo. Our results demonstrated that glycolysis and tumor growth were inhibited by intraperitoneal injection of 3-BrPA and SCT, which were imaged using an 18F-FDG PET/CT scanner. In addition, apoptosis induced by 3-BrPA and SCT was initiated by the upregulation of Bax and downregulation of Bcl-2, which promote cytochrome c release and subsequently activate caspase-9 and -3, and ultimately execute mitochondria-mediated apoptosis. Furthermore, apoptosis was also modulated by the generation of ROS and inhibition of survivin. Accordingly, 3-BrPA and SCT can inhibit glycolysis and induce gastric cancer apoptosis through the mitochondrial caspase-dependent pathway.

Social interaction with a cagemate in pain increases allogrooming and induces pain hypersensitivity in the observer rats.

Empathy, which is a highly cognitive and emotional process, is the ability to share the emotional states of others. Empathy has also been observed in rodents. The empathic sharing of the distressful experience of a conspecific can even motivate altruistic behaviors, which are critical for survival. However, previous studies investigating empathy or prosocial behaviors in rodents mainly employed fearful or other stressful stimuli to elicit emotional changes; whether pain empathy can also motivate prosocial behaviors has yet to be investigated. By using the writhing test, the present study found that cagemate observer (CO) rats, compared with non-cagemate observer (NCO) rats, increased partner-directed grooming (allogrooming) toward conspecifics that had received an intraperitoneal injection of acetic acid during a dyadic social interaction. Following a dyadic social interaction with a demonstrator that received an intraperitoneal injection of acetic acid, the CO rats, compared with NCO rats, exhibited bilateral mechanical pain hypersensitivity and an enhanced acetic acid-induced writhing response. Our results here provided further evidence of pain empathy in rats, suggesting that empathy for pain may motivate prosocial behaviors in rats.

The Locus Coeruleus-Norepinephrine System Mediates Empathy for Pain through Selective Up-Regulation of P2X3 Receptor in Dorsal Root Ganglia in Rats.

Empathy for pain (vicariously felt pain), an ability to feel, recognize, understand and share the painful emotions of others, has been gradually accepted to be a common identity in both humans and rodents, however, the underlying neural and molecular mechanisms are largely unknown. Recently, we have developed a rat model of empathy for pain in which pain can be transferred from a cagemate demonstrator (CD) in pain to a naïve cagemate observer (CO) after 30 min dyadic priming social interaction. The naïve CO rats display both mechanical pain hypersensitivity (hyperalgesia) and enhanced spinal nociception. Chemical lesions of bilateral medial prefrontal cortex (mPFC) abolish the empathic pain response completely, suggesting existence of a top-down facilitation system in production of empathy for pain. However, the social transfer of pain was not observed in non-cagemate observer (NCO) after dyadic social interaction with a non-cagemate demonstrator (NCD) in pain. Here we showed that dyadic social interaction with a painful CD resulted in elevation of circulating norepinephrine (NE) and increased neuronal activity in the locus coeruleus (LC) in the CO rats. Meanwhile, CO rats also had over-expression of P2X3, but not TRPV1, in the dorsal root ganglia (DRG). Chemical lesion of the LC-NE neurons by systemic DSP-4 and pharmacological inhibition of central synaptic release of NE by clonidine completely abolished increase in circulating NE and P2X3 receptor expression, as well as the sympathetically-maintained development of empathic mechanical hyperalgesia. However, in the NCO rats, neither the LC-NE neuronal activity nor the P2X3 receptor expression was altered after dyadic social interaction with a painful NCD although the circulating corticosterone and NE were elevated. Finally, in the periphery, both P2X3 receptor and α1 adrenergic receptor were found to be involved in the development of empathic mechanical hyperalgesia. Taken together with our previous results, empathy for pain observed in the CO rats is likely to be mediated by activation of the top-down mPFC-LC/NE-sympathoadrenomedullary (SAM) system that further up-regulates P2X3 receptors in the periphery, however, social stress observed in the NCO rats is mediated by activation of both hypothalamic-pituitary-adrenocortical axis and SAM axis.

Ethanol Increases Mechanical Pain Sensitivity in Rats via Activation of GABAA Receptors in Medial Prefrontal Cortex.

Ethanol is widely known for its ability to cause dramatic changes in emotion, social cognition, and behavior following systemic administration in humans. Human neuroimaging studies suggest that alcohol dependence and chronic pain may share common mechanisms through amygdala-medial prefrontal cortex (mPFC) interactions. However, whether acute administration of ethanol in the mPFC can modulate pain perception is unknown. Here we showed that bilateral microinjections of ethanol into the prelimbic and infralimbic areas of the mPFC lowered the bilateral mechanical pain threshold for 48 h without influencing thermal pain sensitivity in adult rats. However, bilateral microinjections of artificial cerebrospinal fluid into the mPFC or bilateral microinjections of ethanol into the dorsolateral PFC (also termed as motor cortex area 1 in Paxinos and Watson's atlas of The Rat Brain. Elsevier Academic Press, Amsterdam, 2005) failed to do so, suggesting regional selectivity of the effects of ethanol. Moreover, bilateral microinjections of ethanol did not change the expression of either pro-apoptotic (caspase-3 and Bax) or anti-apoptotic (Bcl-2) proteins, suggesting that the dose was safe and validating the method used in the current study. To determine whether γ-aminobutyric acid A (GABAA) receptors are involved in mediating the ethanol effects, muscimol, a selective GABAA receptor agonist, or bicuculline, a selective GABAA receptor antagonist, was administered alone or co-administered with ethanol through the same route into the bilateral mPFC. The results showed that muscimol mimicked the effects of ethanol while bicuculline completely reversed the effects of ethanol and muscimol. In conclusion, ethanol increases mechanical pain sensitivity through activation of GABAA receptors in the mPFC of rats.

Distinct contributions of reactive oxygen species in amygdala to bee venom-induced spontaneous pain-related behaviors.

Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, play essential roles in physiological plasticity and are also involved in the pathogenesis of persistent pain. Roles of peripheral and spinal ROS in pain have been well established, but much less is known about ROS in the amygdala, a brain region that plays an important role in pain modulation. The present study explored the contribution of ROS in the amygdala to bee venom (BV)-induced pain behaviors. Our data show that the amygdala is activated following subcutaneous BV injection into the left hindpaw, which is reflected in the increased number of c-Fos positive cells in the central and basolateral amygdala nuclei in the right hemisphere. Stereotaxic administration of a ROS scavenger (tempol, 10mM), NADPH oxidase inhibitor (baicalein, 5mM) or lipoxygenase inhibitor (apocynin, 10mM) into the right amygdala attenuated the BV-induced spontaneous licking and lifting behaviors, but had no effect on BV-induced paw flinch reflexes. Our study provides further evidence for the involvement of the amygdala in nociceptive processing and pain behaviors, and that ROS in amygdala may be a potential target for treatment strategies to inhibit pain.

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α(2)δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity.

The α2δ-1 subunit of the voltage-gated Ca(2+) channel (VGCC) is a molecular target of gabapentin (GBP), which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the α2δ-1 subunit to the presynaptic membrane, resulting in decreased neurotransmitter release. We previously showed that GBP has an anti-allodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated administration in a rat model of central post-stroke pain (CPSP) hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the α2δ-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the α2δ-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of α2δ-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the α2δ-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor α2δ-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use.

3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis.

[This retracts the article DOI: 10.3892/ol.2014.2779.].

Involvement of Rac1 signalling pathway in the development and maintenance of acute inflammatory pain induced by bee venom injection.

BACKGROUND AND PURPOSE: The Rho GTPase, Rac1, is involved in the pathogenesis of neuropathic pain induced by malformation of dendritic spines in the spinal dorsal horn (sDH) neurons. In the present study, the contribution of spinal Rac1 to peripheral inflammatory pain was studied. EXPERIMENTAL APPROACH: Effects of s.c. bee venom (BV) injection on cellular localization of Rac1 in the rat sDH was determined with double labelling immunofluorescence. Activation of Rac1 and its downstream effector p21-activated kinase (PAK), ERKs and p38 MAPK in inflammatory pain states was evaluated with a pull-down assay and Western blotting. The preventive and therapeutic analgesic effects of intrathecal administration of NSC23766, a selective inhibitor of Rac1, on BV-induced spontaneous nociception and pain hypersensitivity were investigated. KEY RESULTS: Rac1 labelling was mainly localized within neurons in both the superficial and deep layers of the sDH in rats of naïve, vehicle-treated and inflamed (BV injected) groups. GTP-Rac1-PAK and ERKs/p38 were activated following s.c. BV injection. Post-treatment with intrathecal NSC23766 significantly inhibited GTP-Rac1 activity and phosphorylation of Rac1-PAK, ERKs and p38 MAPK in the sDH. Both pre-treatment and post-treatment with intrathecal NSC23766 dose-dependently attenuated the paw flinches, primary thermal and mechanical hyperalgesia and the mirror-image thermal hyperalgesia induced by BV injection, but without affecting the baseline pain sensitivity and motor coordination. CONCLUSIONS AND IMPLICATIONS: The spinal GTP-Rac1-PAK-ERK/p38MAPK signalling pathway is involved in both the development and maintenance of peripheral inflammatory pain and can be used as a potential molecular target for developing a novel therapeutic strategy for clinical pain.

3-bromopyruvate and sodium citrate target glycolysis, suppress survivin, and induce mitochondrial-mediated apoptosis in gastric cancer cells and inhibit gastric orthotopic transplantation tumor growth.

Glycolysis is the primary method utilized by cancer cells to produce the energy (adenosine triphosphate, ATP) required for cell proliferation. Therefore, inhibition of glycolysis may inhibit tumor growth. We previously found that both 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) can inhibit glycolysis in vitro; however, the underlying inhibitory mechanisms remain unclear. In the present study, we used a human gastric cancer cell line (SGC-7901) and an orthotopic transplantation tumor model in nude mice to explore the specific mechanisms of 3-BrPA and SCT. We found that both 3-BrPA and SCT effectively suppressed cancer cell proliferation, arrested the cell cycle, induced apoptosis, and decreased the production of lactate and ATP. 3-BrPA significantly reduced the glycolytic enzyme hexokinase activity, while SCT selectively inhibited phosphofructokinase-1 activity. Furthermore, 3-BrPA and SCT upregulated the expression of pro-apoptotic proteins (Bax, cytochrome c, and cleaved caspase-3) and downregulated the expression of anti-apoptotic proteins (Bcl-2 and survivin). Finally, our animal model of gastric cancer indicated that intraperitoneal injection of 3-BrPA and SCT suppressed orthotopic transplantation tumor growth and induced tumor apoptosis. Taken together, these results suggest that 3-BrPA and SCT selectively suppress glycolytic enzymes, decrease ATP production, induce mitochondrial-mediated apoptosis, downregulate survivin, and inhibit tumor growth. Moreover, an intraperitoneal injection is an effective form of administration of 3-BrPA and SCT.

3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis.

Tumor cells primarily depend upon glycolysis in order to gain energy. Therefore, the inhibition of glycolysis may inhibit tumor growth. Our previous study demonstrated that 3-bromopyruvate (3-BrPA) inhibited gastric cancer cell proliferation in vitro. However, the ability of 3-BrPA to suppress tumor growth in vivo, and its underlying mechanism, have yet to be elucidated. The aim of the present study was to investigate the inhibitory effect of 3-BrPA in an animal model of gastric cancer. It was identified that 3-BrPA exhibited strong inhibitory effects upon xenograft tumor growth in nude mice. In addition, the antitumor function of 3-BrPA exhibited a dose-effect association, which was similar to that of the chemotherapeutic agent, 5-fluorouracil. Furthermore, 3-BrPA exhibited low toxicity in the blood, liver and kidneys of the nude mice. The present study hypothesized that the inhibitory effect of 3-BrPA is achieved through the inhibition of hexokinase activity, which leads to the downregulation of B-cell lymphoma 2 (Bcl-2) expression, the upregulation of Bcl-2-associated X protein expression and the subsequent activation of caspase-3. These data suggest that 3-BrPA may be a novel therapy for the treatment of gastric cancer.

Post-stroke pain hypersensitivity induced by experimental thalamic hemorrhage in rats is region-specific and demonstrates limited efficacy of gabapentin.

Intractable central post-stroke pain (CPSP) is one of the most common sequelae of stroke, but has been inadequately studied to date. In this study, we first determined the relationship between the lesion site and changes in mechanical or thermal pain sensitivity in a rat CPSP model with experimental thalamic hemorrhage produced by unilateral intra-thalamic collagenase IV (ITC) injection. Then, we evaluated the efficacy of gabapentin (GBP), an anticonvulsant that binds the voltage-gated Ca(2+) channel α2δ and a commonly used anti-neuropathic pain medication. Histological case-by-case analysis showed that only lesions confined to the medial lemniscus and the ventroposterior lateral/medial nuclei of the thalamus and/or the posterior thalamic nucleus resulted in bilateral mechanical pain hypersensitivity. All of the animals displaying CPSP also had impaired motor coordination, while control rats with intra-thalamic saline developed no central pain or motor deficits. GBP had a dose-related anti-allodynic effect after a single administration (1, 10, or 100 mg/kg) on day 7 post-ITC, with significant effects lasting at least 5 h for the higher doses. However, repeated treatment, once a day for two weeks, resulted in complete loss of effectiveness (drug tolerance) at 10 mg/kg, while effectiveness remained at 100 mg/kg, although the time period of efficacious analgesia was reduced. In addition, GBP did not change the basal pain sensitivity and the motor impairment caused by the ITC lesion, suggesting selective action of GBP on the somatosensory system.