Melatonin modulate the expression of α1- and ß2-adrenoceptors in the hippocampus of rats subjected to unpredictable chronic mild stress.

OBJECTIVE: This study investigated the effects of chronic melatonin treatment on gene expression of α1-, α2-, ß1- and ß2-adrenoceptors in the hippocampus of rats subjected to chronic unpredictable mild stress (CUMS). BACKGROUND: Preclinical studies have also shown that melatonin prevented short- and long-term memory impairments and exhibited antidepressant-like actions. METHODS: For this study, we used 24 animals, which were divided into four groups, and the experiment lasted 4 weeks. We quantified the changes in mRNA and protein levels of α1-, α2-, ß1- and ß2-adrenoceptors in the hippocampus after melatonin treatment. RESULTS: Our results demonstrated a decreased gene expression of α1-, α2- and ß2-adrenoceptors in the hippocampus of rats subjected to unpredictable chronic mild stress, while there was no change in gene expression of ß1-adrenoceptors. Melatonin treatment in the CUMS rats prevented the stress-induced decrease in mRNA and protein levels of α1-and ß2-adrenoceptors, whereas did not affect either on mRNA or protein level of ß1-and α2-adrenoceptors. CONCLUSION: Our data suggest that melatonin, by increasing reduced levels of α1- and ß2-adrenoceptors mRNA and protein in the hippocampus of chronic stressed rats, may be beneficial in conditions such as chronic stress and provides an experimental opportunity to probe into further molecular mechanisms underlying the regulation of these receptor subtype (Fig. 2, Ref. 28).

Anxiety and Hyperlocomotion Induced by Chronic Unpredictable Mild Stress Can Be Moderated with Melatonin Treatment.

Preclinical studies have shown that melatonin exercised antidepressant-like and anxiolyticlike effects in animal models of anxiety. The aim of the present study was to correlate the changes in behaviour induced by melatonin treatment with the activity of the dopaminergic system in the hippocampus of Wistar rats exposed to chronic, unpredictable, mild stress (CUMS). Male Wistar rats, 11 weeks old, were subjected to chronic stress for 28 successive days. Separate groups of control and stressed rats were intraperitoneally injected daily either with melatonin (10 mg/kg/day, i.p.) or placebo (5% ethanol). The open-field and elevated plus-maze tests were used to assess locomotor activities and anxiety levels. The content of dopamine (DA) in the hippocampal tissues was determined using radioenzymatic assay, while changes in tyrosine hydroxylase (TH) mRNA and protein levels in the hippocampus were determined using real-time RT-PCR and Western immunoblotting. Chronic stress led to reduction in the hippocampal dopaminergic content without affecting the levels of TH protein. These changes were accompanied by increased locomotor activity and higher anxiety levels in the open-field test. Administration of melatonin for 28 days resulted in an increase in the hippocampal DA content as a result of elevated TH protein levels. Melatonin showed an improvement in anxiety-like behaviour along with significantly reduced exploration. We could conclude that melatonin may stimulate dopaminergic synthesis in the hippocampus in order to suppress stress-induced behaviour.

Regional cerebral arterial transit time hemodynamics correlate with vascular risk factors and cognitive function in men with coronary artery disease.

BACKGROUND AND PURPOSE: Arterial transit time is the time needed for blood to travel from large arteries to capillaries, as estimated from arterial spin-labeling MR imaging. The purpose of this study was to determine whether vascular risk factors and cognitive performance are related to regional differences in cerebral arterial transit time in patients with coronary artery disease who are at risk for cognitive decline. MATERIALS AND METHODS: Arterial transit time was estimated from multiple postlabel delay pseudocontinuous arterial spin-labeling images obtained from 29 men with coronary artery disease. Tests of memory, attention, processing speed, and executive function were administered. Principal component analysis was used to create separate models of cognition and vascular risk, which were related to brain regions through voxelwise analyses of arterial transit time maps. RESULTS: Principal component analysis identified 2 components of vascular risk: 1) "pressor" (age, systolic blood pressure, and pulse pressure) and 2) "obesity" (body fat percentage and body mass index). Obesity was inversely related to arterial transit time in the posterior cingulate, precuneus, lateral occipital cortices, middle temporal gyrus, and frontal pole (P corrected < .05), whereas pressor was not significant. Cognitive scores were factored into a single component. Poor performance was inversely related to precuneus arterial transit time (P corrected < .05). The average arterial transit time in regions identified by obesity was associated with poorer cognitive function (r(2) = 0.21, t = -2.65, P = .01). CONCLUSIONS: Altered cerebral hemodynamics, notably in nodal structures of the default mode network, may be one way that vascular risk factors impact cognition in patients with coronary artery disease.

Differential expression of tyrosine hydroxylase and transporters in the right and left stellate ganglion of socially isolated rats.

Chronic isolation stress of adult rat males acted increasing gene expression of tyrosine hydroxylase (TH) and neuronal norepinephrine transporter (NET) in the right stellate ganglia, while vesicular monoamine transporter 2 (VMAT2) level remained unchanged. The stress decreased protein level of TH, as well as mRNA levels for NET and VMAT2 in the left stellate ganglia, but expressed no effect on protein levels of these two transporters. These results demonstrate asymmetry in noradrenergic genes in the right and left stellate ganglia during stress and provide molecular evidence to help explain the difference in response to the stress.

Peripheral oxytocin treatment affects the rat adreno-medullary catecholamine content modulating expression of vesicular monoamine transporter 2.

The neuropeptide oxytocin has been shown to influence on neuroendocrine function. The aim of the present study was to investigate the effect of peripheral oxytocin treatment on the synthesis, uptake and content of adreno-medullary catecholamine. For this purpose oxytocin (3.6µg/100g body weight, s.c) was administrated to male rats once a day over 14 days. In order to assess the effect of peripheral oxytocin treatment on adreno-medullary catecholamine we measured epinephrine and norepinephrine content and gene expression of tyrosine hydroxylase (TH), norepinephrine transporter (NET) and vesicular monoamine transporter 2 (VMAT2) in the adrenal medulla. Our results show a significant increase of epinephrine (1.7-fold, p<0.05) and norepinephrine (1.5-fold, p<0.05) content in oxytocin treated animals compared to saline treated ones. Oxytocin treatment had no effect either on mRNA or protein level of TH and NET. Under oxytocin treatment the increase in VMAT2 mRNA level was not statistically significant, but it caused a significant increase in protein level of VMAT2 (3.7-fold, p<0.001). These findings indicate that oxytocin treatment increases catecholamine content in the rat adrenal medulla modulating VMAT2 expression.

Progress towards discovery of antifibrotic drugs targeting synthesis of type I collagen.

Type I collagen is the most abundant protein in human body. Fibrosis is characterized by excessive synthesis of type I collagen in parenchymal organs. It is a leading cause of morbidity and mortality worldwide, about 45% of all natural deaths are attributable to some fibroproliferative disease. There is no cure for fibrosis. To find specific antifibrotic therapy targeting type I collagen, critical molecular interactions regulating its synthesis must be elucidated. Type I and type III collagen mRNAs have a unique sequence element at the 5' end, the 5' stem-loop. This stem-loop is not found in any other mRNA. We cloned LARP6 as the protein which binds collagen 5' stem-loop with high affinity and specificity. Mutation of the 5' stem-loop or knock down of LARP6 greatly diminishes collagen expression. Mice with mutation of the 5' stem-loop are resistant to development of liver fibrosis. LARP6 associates collagen mRNAs with filaments composed of nonmuscle myosin; disruption of these filaments abolishes synthesis of type I collagen. Thus, LARP6 dependent collagen synthesis is the specific mechanism of high collagen expression seen in fibrosis. We developed fluorescence polarization (FP) method to screen for drugs that can inhibit binding of LARP6 to 5' stem-loop RNA. FP is high when LARP6 is bound, but decreases to low levels when the binding is competed out. Thus, by measuring decrease in FP it is possible to identify chemical compounds that can dissociate LARP6 from the 5' stem-loop. The method is simple, fast and suitable for high throughput screening.

Elimination of visually evoked BOLD responses during carbogen inhalation: implications for calibrated MRI.

Breathing a mixture of 10% CO(2) with 90% O(2) (referred to here as carbogen-10) increases blood flow due to the vasodilatory effect of CO(2), and raises blood O(2) saturation due to the enriched oxygen level. These effects both tend to reduce the level of deoxygenated hemoglobin in brain tissues, thereby reducing the potential for further increases in BOLD contrast. In the present study, blocks of intense visual stimulation (60s) were presented amid longer blocks (180s) during which subjects breathed various fractional concentrations (0-100%) of carbogen-10 diluted with medical air. When breathing undiluted carbogen-10, the BOLD response to visual stimulation was reduced below the level of noise against the background of the carbogen-10 response. At these concentrations, the total (visual+carbogen) BOLD response amplitude (7.5±1.0%, n=6) converged toward that seen with carbogen alone (7.5±1.0%, n=6). In spite of the almost complete elimination of the visual BOLD response, pseudo-continuous arterial spin-labeling on a separate cohort indicated a largely preserved perfusion response (89±34%, n=5) to the visual stimulus during inhalation of carbogen-10. The previously discussed observations suggest that venous saturation can be driven to very high levels during carbogen inhalation, a finding which has significant implications for calibrated MRI techniques. The latter methods involve estimation of the relative change in venous O(2) saturation by expressing activation-induced BOLD signal increases as a fraction of the maximal BOLD signal M that would be observed as venous saturation approaches 100%. While the value of M has generally been extrapolated from much smaller BOLD responses induced using hypercapnia or hyperoxia, our results suggest that these effects could be combined through carbogen inhalation to obtain estimates of M based on larger BOLD increases. Using a hybrid BOLD calibration model taking into account changes in both blood flow and arterial oxygenation, we estimated that inhalation of carbogen-10 led to an average venous saturation of 91%, allowing us to compute an estimated M value of 9.5%.

Effect of cold water immersion on repeated cycling performance and limb blood flow.

The purpose of the present study was to compare the effects of cold water immersion (CWI) and active recovery (ACT) on resting limb blood flow, rectal temperature and repeated cycling performance in the heat. Ten subjects completed two testing sessions separated by 1 week; each trial consisted of an initial all-out 35-min exercise bout, one of two 15-min recovery interventions (randomised: CWI or ACT), followed by a 40-min passive recovery period before repeating the 35-min exercise bout. Performance was measured as the change in total work completed during the exercise bouts. Resting limb blood flow, heart rate, rectal temperature and blood lactate were recorded throughout the testing sessions. There was a significant decline in performance after ACT (mean (SD) -1.81% (1.05%)) compared with CWI where performance remained unchanged (0.10% (0.71%)). Rectal temperature was reduced after CWI (36.8°C (1.0°C)) compared with ACT (38.3°C (0.4°C)), as was blood flow to the arms (CWI 3.64 (1.47) ml/100 ml/min; ACT 16.85 (3.57) ml/100 ml/min) and legs (CW 4.83 (2.49) ml/100 ml/min; ACT 4.83 (2.49) ml/100 ml/min). Leg blood flow at the end of the second exercise bout was not different between the active (15.25 (4.33) ml/100 ml/min) and cold trials (14.99 (4.96) ml/100 ml/min), whereas rectal temperature (CWI 38.1°C (0.3°C); ACT 38.8°C (0.2°C)) and arm blood flow (CWI 20.55 (3.78) ml/100 ml/min; ACT 23.83 (5.32) ml/100 ml/min) remained depressed until the end of the cold trial. These findings indicate that CWI is an effective intervention for maintaining repeat cycling performance in the heat and this performance benefit is associated with alterations in core temperature and limb blood flow.

[Liver injuries--personal experience with treatment].

BACKGROUND: Trauma is one of todays most serious and expensive health care problems, and it is the most common cause of mortality in young population. Non-operative tretment is standard strategi for menagment of blunt liver injuries in hemodynamically stable patiens in last decade. METHODS: Retrospective study included patiens with liver trauma, admitted in the period december 1995 - december 2005, in total 476. RESULTS: 392 of 476 patients presenting with liver trauma had blunt and only 84 had penetrating injury. Isolated liver injury was identified in 27.5% and 72.5% had associated injuries. Average ISS value was 24.06 (SD = 14.26).During the operation liver injury in patients was classified according to Moor. In 2% critical patients, due to hemodynamic unstability we performed "damage control surgery". Out of 476 patients 8.7% were successfully managet, 6.1% died as "mors in tabula" or during first 24 hours and 6.9% died during hospitalization. CONCLUSION: Higher proportion of nonoopertively treated is among patients with ISS less thanand those with injuries grade I end II.

[Evaluation of pulmonary and metabolic function in classic and laparoscopic cholecystectomy in patients with ASA I and ASA II scores].

This is a prospective study of patients treated at the Center for Urgent Surgery, Clinical Center of Serbia. The patients were divided into two groups; i.e., the controls consisted of 30 subjects, who underwent conventional cholecystectomy, and studied group with 30 patients who had laparoscopic cholecystectomy. The patients were homogenized by ASA score (ASA I and ASA II) and on population basis. Hemodynamic parameters and 4 time-point pulmonary function tests were monitored in both groups. Peritoneal insufflation resulted in significant increase of systemic arterial pressure (23%), mean arterial pressure (23.8%), systemic vascular resistance (65%), pulmonary vascular resistance (90%), and significant reduction of cardiac output (24%) and cardiac index (51%). Pneumoperitoneum caused transient restriction of pulmonary function by reducing the thoracic and lung compliance. Fall of pH concentration, increase of PaCO2 and ET CO2 without any changes of PaO2, SO2, base excess and bicarbonate ions concentrations were the sequelae of CO2 absorption from peritoneal cavity. Postoperative "hypothermi", i.e. lowering of body temperature for 0.3 degrees C was the consequence of sudden gas expansion (Joule-Thompson phenomenon), which implies continuous flow of dry gas under pressure over peritoneal surface. Tissue damage factors (D-dimer, C-reactive protein, Protein C) were significantly lower in laparoscopic group, meaning that such mode of treatment resulted in minor postoperative pain and shorter period of recovery. Laparoscopy is a revolution in surgery. Definite success of any laparoscopic intervention depends on anesthesia as its crucial factor, at the same time meeting the patient's wish and expectations to be free from pain and discharged in no time from hospital.

[Risk factors for bleeding from stress ulcer in severely injured and critically ill persons].

Bleeding stress ulcus is a mucosal stress induced lesion which appears as a result of mucosal damage in severely injured and critically ill persons. Prophylaxis treatment has dramatically reduced the incidence of bleeding in Intensive care units. We conducted a prospective study for the five years period. Of 954 patients (196 with acute necrotizing pancreatitis and 758 with severe injuries), 84 (8.5%) has clinically important bleeding. About 80% of these patients had more than one independent risk for acute bleeding from gastrointestinal tract. Prophylaxis treatment reduced bleeding in 90% risk patients (according Zinner score). Despite of prophylaxis, 13 patients required surgery. Overall mortality was 29 (34%) of 84 patients, including seven of 13 who required surgery. Sepsis and respiratory failure were identified as strong risk factors for bleeding in our group. The choice of the best prophylactic agens still remains the question.

[Surgical treatment of gastroduodenal ulcer bleeding-our experience].

INTRODUCTION: Acute bleeding from the upper gastrointestinal tract remains the commonest emergency in gastroen-terology, and is most often caused by gastroduodenal ulcer disease. Despite introduction of novel endoscopic techniques and pharmacological treatment, 6-15% patients have to be operated. The aim of our investigation is analyze data of patients treated for gastrointestinal ulcer bleeding in our institution, their treatment options and outcome. PATIENTS AND METHODS: We included 2237 patients admitted in the Department for Emergency medicine of Clinical center of Serbia during the period from January 1999 until December 2003. because of gastroduodenal ulcer bleeding. We analyzed age, gender treatment option, hospital stay and mortality. RESULTS: The mean age of our patients was 61.58 years, 1346 male and 891 female. The majority of patients were conservatively treated (84.5%). Operated patients mostly undergo Billroth II resection (57.8%). The mean hospital stay was 7.3 days. Average mortality was 14.4%. CONCLUSIONS: Despite adequate endoscopic management of bleeding gastroduodenal ulcer, surgeons will continue to treat this patients for emergency surgery.

[Orthopedic injuries in polytrauma].

Trauma is one of the leading causes of mortality in the world. Traumatic injury has a significant impact on the patient, socially, functionally and financially. Orthopaedic injuries are generally not life-threatening unless they result in significant hemodynamic instability. The outcome of the orthopaedic injuries might lead to mild or severe disability and lost quality of life. Therefore, the orthopaedic surgeon has significant role in treatment of trauma patient. In order to control and prevent traumatic injuries, to improve quality of trauma treatment and outcome, including the costs the National trauma registry is essential. The aim of the study was to collect the datas about the frequency of orthopaedic injuries in polytraumatised patients who were treated in intensive care unit of Emergency Center of Serbia in last two years. There were significant number of orthopaedic injuries (53.2%) in polytraumatised patients. The major cause of the injuries is traffic (78.6%) and most patients were between 30-50 years (30%).

[Massive hemorrhage and mechanisms of coagulopathy in trauma].

Trauma is disease of the young, mainly affecting people between 15-40 years of age. Uncontrolled massive bleeding is the leading cause of early in-hospital mortality, within 48h of admission, and the second leading cause of prehospital death in victims of both military and civilian trauma, accounting for 40-45% of the total fatalities. Coagulopathy develops early after injury and is present in 25-36% of trauma victims upon admission to the emergency department. Coagulopathy correlates to the severity of trauma and is associated with an increased risk of mortality. The aim of this paper is to explain pathophysiology of developing coagulopathy in trauma. The coagulopathy in the trauma patient is complex and multifactorial. It includes: dilutional coagulopathy, hypothermia, acidosis, hyperfibrinolysis, anemia and consumption coagulopathy. When the patient develops the so called "lethal triad" of hypothermia, acidosis and coagulopathy, surgical restoration of vascular integrity may be insufficient to achieve a deffinitive control of blood loss and non-mechanical bleeding from small vessels, usually terminated by spontaneous coagulation, becomes a life-threatening condition.

Detection of gastrointestinal and abdominal infections by 99mTc-ciprofloxacin.

BACKGROUND/AIMS: The aim of the study is detection and evaluation of the abdominal and gastrointestinal infective foci using 99mTc-ciprofloxacin (Laboratory for radioactive isotopes, Vinca). METHODOLOGY: In total 21 patients with clinical suspicion on abdominal or gastrointestinal infection were investigated. In all the patients, planar liver/spleen scintigraphy was performed. Ciprofloxacin chloride (3.5 mg) was mixed with 555 MBq of 99mTc in 3 mL of physiological solution and incubated for 20 min. After slow i.v. injection in a cubital vein, dynamic acquisition (1 f/min) was performed during the first 60 min in the position of interest, followed by static acquisition (500,000 imp) anterior and posterior view, abdomen and pelvis after 1 h and 4 h in all patients. When necessary, additional scintigrams were acquired after 24 h. In all the patients with negative or equivocal findings of planar scintigraphy, emission computerized tomography (SPECT) was performed (60 positions, 6 degrees). Interpretation was made by three independent observers. Additional data were provided using clinical findings, ultrasonography, computed tomography and magnetic resonance imaging, laboratory analyses, and surgical or microbiological confirmation of infection. RESULTS: There were eleven true-positive findings, seven true negative, two were false negative while one was false positive due to intestinal obstruction. Sensitivity was 79%, specificity 91%, positive predictive value 92%, negative predictive value 77%, accuracy 84%. CONCLUSIONS: According to our results, scintigraphy with radiolabeled ciprofloxacin is a useful method for detection and assessment of exact localization of abdominal and gastrointestinal infections.

[Determination of beta-endorphin plasma concentrations in surgical patients with acute abdominal pain]. / Odredjivanje plazma koncentracija opiodnog peptida beta-endorfina kod hirurskih bolesnika sa abdominalnim bolom.

Abdominal pain and surgery, frequently associated with this kind of pain, modify plasma levels of stress-hormones and iniciates the response of endogenous analgetic system. The aim of this study was to determine serum concentration of beta-endorphine in patients with acute abdominal pain (n=12), which were surgically treated. Serum concentration of beta-endorphin was measured on five data points: before, during and after surgery. During abdominal surgery serum concentration of beta-endorphin was increased by 7% compared to preoperative period; in postoperative period the concentration continued to rise and remained increased within next hours. The maximal levels of beta-endorphine were not observed during, and immediately after surgery. Postoperatively, between 6 and 8 p.m. on the day of surgery, maximal level of beta-endorphin was noted, which was even ten times higher than to preoperative value. Plasma level of beta-endorphin fell to the baseline values 24 hours after surgery. In conclusion, abdominal surgery induces a postponed (delayed) increase in serum beta-endorphine levels, which are associated with modulation of preoperative, intraoperative and postoperative pain perception.

[Advantages and disadvantages of planned staged relaparotomy using the zipper technique in surgical treatment of necrotizing pancreatitis]. / Prednosti i nedostaci planiranih etapnih relaparotomija "ziper tehnikom" kod hirurskog lecenja nekroticnog pankreatitisa.

The rationale of surgical intervention during acute necrotizing pancreatitis is to remove necrotic tissue preserving healthy glandular parenchyma and other adjacent structures, thus limiting severe complications. Necrosectomy and debridement are the crucial in surgical management, further treatment of pancreatic bed and peripancreatic tissue are still a matter of debate among pancreatic surgeons. Zipper technique is one of the three recognized methods [table: see text] for the surgical management of necrotizing pancreatitis. The aim this study was to review the literature data about treatment using this technique, as well to compare the results of treatment with other techniques, in order to present the advantage and disadvantage of zipper technique. The main advantage of this technique is a high level of control of intraabdominal infection and other septic complications associated with necrotizing pancreatitis and its surgical management. Increased risk of development of gastrointestinal and pancreatic fistulas as well of intraabdominal bleeding is probably the main disadvantage. A flexible approach focused on the individual patients is a reasonable solution in the surgical management of the necrotizing pancreatitis.

Fractal and nonfractal analysis of cell images: comparison and application to neuronal dendritic arborization.

Neurons of the rat spinal cord were stained using the Golgi impregnation method. Successfully impregnated neurons from laminae II, III, and VI were subjected to fractal and nonfractal analyses. Fractal analysis was performed using length-related techniques. Since an application of fractal methods to the analysis of dendrite arbor structures requires caution, we adopted as appropriate a nonfractal method proposing a generalized power-law model with two main nonfractal parameters: (i) the anfractuosity, characterizing the degree of dendritic deviation from straight lines; and (ii) an estimate of the total length of arbor dendrites. The anfractuosity can distinguish between two sets of drawings where the fractal methods failed. We also redefine some basic concepts of fractal geometry, present the ruler-counting method, and propose a new definition of fractal dimension.

[Second hemorrhage in patients with splenic injuries]. / Dvovremensko krvarenje kod bolesnika sa povredom slezine.

Although the diagnosis of spleen injuries is not a considerable clinical problem today, subsequent ruptures of this organ may occur in a smaller number of patients (2-5% of total proportion of spleen injuries) following the so-called "free interval". Such injuries are most commonly explained by present hematoma localized in the central spleen, which becomes larger in time, and eventually causes its rupture. This form of lesion may be found both in isolated blunt abdominal injuries and in associated injuries. When it is the question of delayed hemorrhage, our results as well as data obtained from foreign literature, suggest three basic rise factors of the etiology of this type of injury. These are as follows: a) spleen injuries in severe trauma or polytrauma, b) older patients (over 65 years of age), and c) in cases when more than a single blood unit had to be administered for the initial hemodynamic stabilization of a patient. Delayed hemorrhage, which is occult in polytraumatized patients since it is frequently "disguised" by severity of clinical picture and traumatic shock, may subsequently cause sudden fall of hemogram and hemodynamic parameter values, and if immediate surgery is not performed, it may lead to heavy bleeding and lethal outcome of the patient.

TAK1/JNK and p38 have opposite effects on rat hepatic stellate cells.

After liver injury, hepatic stellate cells (HSCs) undergo a process of activation with expression of smooth muscle alpha-actin (alpha-SMA), an increased proliferation rate, and a dramatic increase in synthesis of type I collagen. The intracellular signaling mechanisms of activation and perpetuation of the activated phenotype in HSCs are largely unknown. In this study the role of the stress-activated protein kinases, c-Jun N-terminal kinase (JNK) and p38, were evaluated in primary cultures of rat HSCs. The effect of JNK was assessed by using an adenovirus expressing a dominant negative form of transforming growth factor beta (TGF-beta)-activated kinase 1 (TAK1) (Ad5dnTAK1) and a new selective pharmacologic inhibitor SP600125. The effect of p38 was assessed with the selective pharmacologic inhibitor SB203580. These kinases were inhibited starting either in quiescent HSCs (culture day 1) or in activated HSCs (culture day 5). Although blocking TAK1/JNK and p38 decreased the expression of alpha-SMA protein in early stages of HSC activation, no effect was observed when TAK1/JNK or p38 were inhibited in activated HSCs. JNK inhibition increased and p38 inhibition decreased collagen alpha1(I) mRNA level as measured by RNase protection assays, with maximal effects observed in early stages of HSC activation. Furthermore, TAK1/JNK inhibition decreased HSC proliferation, whereas p38 inhibition led to an increased proliferation rate of HSCs, independently of its activation status. These results show novel roles for the TAK1/JNK pathway and p38 during HSC activation in culture. Despite similar activators of TAK1/JNK and p38, their functions in HSCs are distinct and opposed.