Salivary orosomucoid 1 as a biomarker of hepatitis B associated hepatocellular carcinoma.

Saliva is rich in proteins, DNA, RNA and microorganisms, and can be regarded as a biomarker library. In order to explore a noninvasive and simple means of early screening for liver cancer, proteomics was used to screen salivary markers of hepatitis B associated liver cancer. We used mass spectrometry coupled isobaric tags for relative and absolute quantitation (iTRAQ)-technology to identify differentially expressed proteins (DEPs). Western blot, immunohistochemistry and enzyme linked immunosorbent assay were used to detect marker expression of in tissues and saliva. Statistical analysis was used to analyze the diagnostic efficacy of the markers was analyzed through statistical analyses. By comparing the hepatocellular carcinoma (HCC) group with non-HCC groups, we screened out 152 salivary DEPs. We found orosomucoid 1(ORM1) had significantly higher expression in saliva of HCC patients compared with non-HCC groups (p < 0.001) and the expression of ORM1 in liver cancer tissues was significantly higher than that in adjacent normal tissues (p < 0.001). The combination of salivary ORM1 and alpha-fetoprotein (AFP) showed reasonable specificities and sensitivities for detecting HCC. In a word, salivary ORM1 as a new biomarker of hepatitis B associated hepatocellular carcinoma, combination of salivary ORM1 and AFP as an improved diagnostic tool for hepatocellular carcinoma.

Efficacy of aerobic and resistance exercises in improving visceral adipose in patients with non-alcoholic fatty liver: a meta-analysis of randomized controlled trials.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common chronic disease that can cause liver deterioration if insufficiently diagnosed and untreated. The verification of whether exercise interventions improve liver enzymes and lipid and glucose parameters is scant. AIM: We conducted this systematic review and meta-analysis to examine the efficacy of aerobic and resistance exercise interventions in patients with NAFLD. METHODS: We searched the related studies in the PubMed, Embase, Cochrane Library, and Web of Science databases. We screened 1129 articles published before September 1, 2021, based on the inclusion and exclusion standards, after which 17 articles with a total of 1168 participants were finally included. The indices of liver enzymes and lipid and glucose metabolism were gathered and examined by Stata SE. RESULTS: The outcomes suggested that aerobic and resistance exercise can markedly improve the parameters of liver enzymes, blood lipids, and glucose, and especially visceral adipose tissue (weighted mean different [WMD] = -8.3 at 95% CI [-11.59 to -5.00], p < 0.0001), in patients with NAFLD. CONCLUSION: This study demonstrated that aerobic and resistance exercises positively affect NAFLD treatment. To further quantify the effects on patients with NAFLD, a more specific and uniform exercise program should be proposed.

Vagally mediated, nonparacrine effects of cholecystokinin-8s on rat pancreatic exocrine secretion.

Cholecystokinin (CCK) has been proposed to act in a vagally dependent manner to increase pancreatic exocrine secretion via actions exclusively at peripheral vagal afferent fibers. Recent evidence, however, suggests the CCK-8s may also affect brain stem structures directly. We used an in vivo preparation with the aims of 1) investigating whether the actions of intraduodenal casein perfusion to increase pancreatic protein secretion also involved direct actions of CCK at the level of the brain stem and, if so, 2) determining whether, in the absence of vagal afferent inputs, CCK-8s applied to the dorsal vagal complex (DVC) can also modulate pancreatic exocrine secretion (PES). Sprague-Dawley rats (250-400 g) were anesthetized and the common bile-pancreatic duct was cannulated to collect PES. Both vagal deafferentation and pretreatment with the CCK-A antagonist lorglumide on the floor of the fourth ventricle decreased the casein-induced increase in PES output. CCK-8s microinjection (450 pmol) in the DVC significantly increased PES; the increase was larger when CCK-8s was injected in the left side of the DVC. Protein secretion returned to baseline levels within 30 min. Microinjection of CCK-8s increased PES (although to a lower extent) also in rats that underwent complete vagal deafferentation. These data indicate that, as well as activating peripheral vagal afferents, CCK-8s increases pancreatic exocrine secretion via an action in the DVC. Our data suggest that the CCK-8s-induced increases in PES are due mainly to a paracrine effect of CCK; however, a relevant portion of the effects of CCK is due also to an effect of the peptide on brain stem vagal circuits.

Dopamine effects on identified rat vagal motoneurons.

Catecholaminergic neurons of the A2 area play a prominent role in brain stem vagal circuits. It is not clear, however, whether these neurons are noradrenergic or adrenergic, i.e., display tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DbetaH) immunoreactivity (-IR) or dopaminergic (i.e., TH- but not DbetaH-IR). Our aims were to investigate whether a subpopulation of neurons in the A2 area was dopaminergic and, if so, to investigate the effects of dopamine (DA) on the membrane of gastric-projecting vagal motoneurons. We observed that although the majority of A2 neurons were both TH- and DbetaH-IR, a small percentage of nucleus tractus solitarius neurons were TH-IR only, suggesting that DA itself may play role in these circuits. Whole cell recordings from thin brain stem slices showed that 71% of identified gastric-projecting motoneurons responded to DA (1-300 microM) with either an excitation (28%) or an inhibition (43%) of the membrane; the remaining 29% of the neurons were unresponsive. The DA-induced depolarization was mimicked by SK 38393 and prevented by pretreatment with SCH 23390. Conversely, the DA-induced inhibition was mimicked by bromoergocryptine and prevented by pretreatment with L741626. When tested on the same neuron, the effects of DA and NE were not always similar. In fact, in neurons in which DA induced a membrane depolarization, 77% were inhibited by NE, whereas 75% of neurons unresponsive to DA were inhibited by NE. Our data suggest that DA modulates the membrane properties of gastric-projecting motoneurons via D1- and D2-like receptors, and DA may play different roles than norepinephrine in brain stem vagal circuits.

Vagal afferent control of opioidergic effects in rat brainstem circuits.

We demonstrated recently that increasing the levels of cAMP allows opioids to modulate GABAergic synaptic transmission between the nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV). Using a combination of electrophysiological, immunohistochemical and biochemical approaches, we provide evidence that vagal afferent fibres dampen cAMP levels within the vagal brainstem circuits via tonic activation of group II metabotropic glutamate receptors (mGluRs). Whole-cell patch-clamp recordings were made from identified neurons of the rat DMV. Following chronic vagal deafferentation, the opioid agonist methionine-enkephalin (ME) inhibited the amplitude of evoked IPSC (eIPSC) in 32 of 33 neurons, without exogenous enhancement of cAMP levels. The ME-induced inhibition was prevented by the group II mGluR-selective agonist APDC. Following perfusion with the group II mGluR-selective antagonist EGLU, ME inhibited eIPSC amplitude in brainstem slices of control rats. Immunohistochemical experiments revealed that, following vagal deafferentation, mu-opioid receptors were colocalized on GABAergic profiles apposing DMV neurons; the number of colocalized profiles was significantly decreased by pretreatment with APDC. Radioimmunoassay and Western blot analysis showed that cAMP and phosphorylated cyclic AMP response element binding protein (pCREB) levels in the dorsal vagal complex were increased following vagal deafferentation. Our data show that by tonically dampening the levels of cAMP within the GABAergic synaptic contacts, activated group II mGluRs prevent the modulation of this synapse by endogenous opioids. These data suggest that the plasticity, hence the response, of central circuits controlling the vagal motor outflow to visceral organs is modulated and finely tuned by vagal afferent fibres.

In vitro analysis of the effects of cholecystokinin on rat brain stem motoneurons.

Using whole cell patch clamp in thin brain stem slices, we tested the effects of cholecystokinin (CCK) on identified gastric-projecting neurons of the rat dorsal motor nucleus of the vagus (DMV). Perfusion with the sulfated form of CCK octapeptide (CCK8s, 30 pM-300 nM, EC50 approximately 4 nM) induced a concentration-dependent inward current in 35 and 41% of corpus- and antrum/pylorus-projecting DMV neurons, respectively. Conversely, none of the fundus-projecting DMV neurons responded to perfusion with CCK8s. The CCK8s-induced inward current was accompanied by a 65 +/- 17% increase in membrane input resistance and reversed at 90 +/- 4 mV, indicating that the excitatory effects of CCK8s were mediated by the closure of a potassium conductance. Pretreatment with the synaptic blocker TTX (0.3-1 microM) reduced the CCK8s-induced current, suggesting that a portion of the CCK8s-induced current was mediated indirectly via an action on presynaptic neurons apposing the DMV membrane. Pretreatment with the selective CCK-A receptor antagonist lorglumide (0.3-3 microM) attenuated the CCK8s-induced inward current in a concentration-dependent manner, with a maximum inhibition of 69 +/- 12% obtained with 3 microM lorglumide. Conversely, pretreatment with the selective CCK-B antagonist triglumide did not attenuate the CCK8s-induced inward current; pretreatment with triglumide (3 microM) and lorglumide (1 microM) attenuated the CCK8s-induced current to the same extent as pretreatment with lorglumide alone. Immunohistochemical experiments showed that CCK-A receptors were localized on the membrane of 34, 65, and 60% of fundus-, corpus-, and antrum/pylorus-projecting DMV neurons, respectively. Our data indicate that CCK-A receptors are present on a subpopulation of gastric-projecting neurons and that their activation leads to excitation of the DMV membrane.