Kaempferol attenuates liver fibrosis by inhibiting activin receptor-like kinase 5.

Liver fibrosis is a common public health problem. Patients with liver fibrosis are more likely to develop cirrhosis, or hepatocellular carcinoma (HCC) as a more serious consequence. Numerous therapeutic approaches have emerged, but the final clinical outcome remains unsatisfactory. Here, we discovered a flavonoid natural product kaempferol that could dramatically ameliorate liver fibrosis formation. Our data showed that intraperitoneal injection of kaempferol could significantly decrease the necroinflammatory scores and collagen deposition in the liver tissue. In addition, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), laminin (LN) and hyaluronic acid (HA) levels were significantly down-regulated in kaempferol treatment group compared with those in the control group. Our study also demonstrated that kaempferol markedly inhibited the synthesis of collagen and activation of hepatic stellate cells (HSCs) both in vivo and in vitro. Furthermore, the results of Western blotting revealed that kaempferol could down-regulate Smad2/3 phosphorylation dose-dependently. These bioactivities of kaempferol may result from its targeted binding to the ATP-binding pocket of activin receptor-like kinase 5 (ALK5), as suggested by the molecular docking study and LanthaScreen Eu kinase binding assay. Above all, our data indicate that kaempferol may prove to be a novel agent for the treatment of liver fibrosis or other fibroproliferative diseases.

In vivo and in vitro effects of microRNA-221 on hepatocellular carcinoma development and progression through the JAK-STAT3 signaling pathway by targeting SOCS3.

Hepatocellular carcinoma (HCC), as the third leading cancer-caused deaths, prevails with high mortality, and affects more than half a million individuals per year worldwide. A former study revealed that microRNA-221 (miR-221) was involved in cell proliferation of liver cancer and HCC development. The current study aims to evaluate whether miR-221 targeting SOCS3 affects HCC through JAK-STAT3 signaling pathway. A series of miR-221 mimic, miR-221 inhibitor, siRNA against SOCS3, and SOCS3 plasmids were introduced to SMMC7721 cells with the highest miR-221 expression assessed. The expression of JAK-STAT3 signaling pathway-related genes and proteins was determined by Western blot analysis. Cell apoptosis, viability, migration, and invasion were evaluated by means of flow cytometry, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide, and transwell assays, respectively. HCC xenograft in nude mice was performed to measure HCC tumor growth. miR-221 was found to be highly expressed but SOCS3 was poorly expressed in HCC tissues. miR-221 expression was correlated with lymph node metastasis (LNM) and tumor node metastasis (TNM) of HCC, and SOCS3 expression was correlated with LNM, differentiation and TNM of HCC. SOCS3 is a target gene of miR-221. MiR-221 mimic or si-SOCS3 exposure was found to induce cell viability, migration, and invasion, and reduce apoptosis. MiR-221 inhibitor was observed to have inhibitory effects on HCC cell proliferation, migration, and invasion. Moreover, the expression of JAK-STAT3 signaling pathway was suppressed by miR-221 inhibitor. Downregulated miR-221 expression could promote its target gene SOCS3 to inhibit the proliferation, invasion and migration of HCC cells by repressing JAK-STAT3 signaling pathway.

A20 rescues hepatocytes from apoptosis through the NF-κB signaling pathway in rats with acute liver failure.

Background: Acute liver failure (ALF) is a disease of acute derangements in the hepatic synthetic function with defects involving innate immune responses, which was reported to be negatively regulated by tumor necrosis factor α-induced protein 3 (A20). Herein, the present study was conducted to investigate the effects the A20 protein on the proliferation and apoptosis of hepatocytes through the nuclear factor (NF)-κB signaling pathway in the rat models simulating ALF.Methods: Male Wistar rats were used to simulate ALF in the model rats. Next, the positive expression of A20 and Caspase-3 proteins was measured in liver tissues. Rat hepatocytes were separated and subjected to pyrrolidine dithiocarbamate (PDTC, inhibitor of NF-κB pathway) or A20 siRNA. Additionally, both mRNA and protein levels of A20, NF-κB, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), and receptor-interacting protein 1 (RIP1) were determined. Finally, we detected the hepatocyte proliferation, cell cycle entry, and apoptosis.Results: ALF rats displayed a lower positive expression of A20 protein and a higher expression of Caspase-3 protein. Furthermore, A20 was down-regulated, while NF-κB, TRAF6, and RIP1 were all up-regulated in ALF rats. Notably, A20 inhibited activation of NF-κB signaling pathway. The blockade of NF-κB signaling pathway enhanced proliferation and cell cycle progression of hepatocytes, whereas inhibited apoptosis of hepatocytes. On the contrary, A20 siRNA reversed the above situation.Conclusion: A20 inhibits apoptosis of hepatocytes and promotes the proliferation through the NF-κB signaling pathway in ALF rats, potentially providing new insight into the treatment of ALF.

Sensory and sympathetic disorders in chronic non-specific neck pain.

The signs of sympathetic and sensory nerve-related disorders are not widely investigated in chronic nonspecific neck pain (NNP) patients. Thus, we performed skin temperature (Tsk), evaporation and touch threshold (TT) measurements to reveal possible dysfunctions at the fingertips of NNP patients (n=60) compared with healthy controls (n=11). Neck pain intensity was the main modifier of Tsk, and age the main modifier of TT in a multivariate model. On comparisons of the subgroups of NNP patients with unilateral (n=26) and bilateral (n=34) symptoms and controls, TT differed and Tsk tended to differ, the unilateral pain patients being found to demonstrate higher TT values on both sides. Interrelations between the measured parameters were found in the controls, but not in the patients. The NNP patients exhibited signs of functional impairment of innervation reflected in changes in tactile sensitivity and vasoactive sympathetic function. These changes may be based on both central and peripheral mechanisms, which possibly differ in patients with unilateral and bilateral symptoms.

Postoperative relieve of abnormal vasoregulation in carpal tunnel syndrome.

OBJECTIVE: To study the skin temperature changes as a sign of altered blood flow regulation due to abnormal sympathetic nerve function in carpal tunnel syndrome (CTS) and the efficacy of carpal tunnel release (CTR) operation in the alleviation of those signs and other symptoms of CTS. SUBJECTS AND METHODS: Forty-one healthy hands (n=41) of 22 volunteers and 22 hands (n=22) with clinically diagnosed carpal tunnel syndrome of 16 patients were examined. A series of infrared photos of the hands of each subject were taken and stored by using digital infrared thermography (DIRT) before and 6 months after the CTR. The temperatures of the finger tips from digit 1 (D1) to digit 5 (D5), the center point of thenar (Th) and hypothenar (Ht) eminences were measured, the median nerve index (MI=(D1-D2)+(D1-D3)+(D2-D3)) and the temperature differences between the median and the ulnar nerve distribution area (MED.ULN=(D1-D5)+(D2-D5)+(D3-D5)+(Th-Ht)) were calculated. Absolute values were used when calculating the temperature differences between different points. RESULTS: All the CTS patients were released from the CTS symptoms, i.e. numbness and pain after the operation, and the results of nerve conduction studies (NCS) were all back to normal. The MI and MED.ULN in CTS hands were significantly smaller before CTR compared to those of healthy control subjects (MI: p<0.001, MED.ULN: p<0.005), and those after CTR (p<0.005 for both parameters). The results also showed that all finger tips of the affected hand including those innervated by the ulnar nerve were cooler before but warmer after the operation. Before the operation, the non-CTS hands of the CTS patients, were also colder (although the difference was not significant) than the healthy control subjects but approached the same level after the CTR operation of the CTS hands. CONCLUSION: The results of DIRT measurements suggest that the blood flow regulation in CTS is abnormal possibly because of disturbed sympathetic vasomotor regulation and that the circulation gets normal together with the alleviation of the other symptoms of CTS as recorded 6 months after CTR operation.

Excessive texting in pathophysiology of first carpometacarpal joint arthritis.

A Case with isolated pain and swelling at the base of the left thumb is reported. The problem had lasted for 2 years, and it was getting worse with increasing pain also at the base of the right thumb. The X-ray showed a subluxation and an arthritis of the first CMCJ was diagnosed in left hand. An excision arthroplasty was successfully carried out. The excessive mobile phone use with active texting had been probably the main cause of the problem. Many, especially youngsters use their phones to text and play games a lot. The purpose of this report is to make the researchers and practitioners aware of this problem and to encourage them to record these cases that may be common in future.

Plantar infrared thermography measurements and low back pain intensity.

OBJECTIVE: To study the skin temperature disorders in low back pain (LBP) patients compared with reference persons without LBP and to evaluate the relationship between pain intensity and other clinical signs and temperature abnormalities. METHODS: Sixty-five patients with unilateral chronic LBP with or without referred nonradicular leg pain (29 men and 36 women; age range, 30-51 years) and 20 reference persons without LBP (7 men and 13 women; age range, 30-49 years) participated in this study. The pain level was recorded by the use of a visual analog scale (0-100). Questionnaires and a series of spinal mobility tests (the modified Schober, straight leg-raising test, finger-floor distance, side bending) were used. Thermographic images of the low back area and legs (anterior, lateral, and posterior surfaces and the plantar surfaces of feet) were taken with an infrared video camera. RESULTS: The temperature changes in the plantar surface correlated with LBP intensity. The pain levels differed in the groups with the different types of temperature changes. There were significant lower extremity regional skin temperature alterations (at least 1 regional interside difference more than 0.3 degrees C) in most cases both in LBP patients and in reference persons, but plantar interside temperature difference was significantly higher in LBP patients. CONCLUSION: Temperature changes of the plantar surface seem to be connected with LBP intensity. Temperature measurements may be useful as an adjunctive physiological test in the evaluation and documentation of autonomic dysfunction in LBP patients.

Sympathetic pathology evidenced by hand thermal anomalies in carpal tunnel syndrome.

OBJECTIVE: To clarify sympathetic pathology in carpal tunnel syndrome and the usefulness of digital infrared thermography as a diagnostic aid. MATERIAL AND METHODS: 38 clinically diagnosed carpal tunnel syndrome hands from 30 patients (confirmed by the standard nerve conduction studies) and 41 hands from 22 healthy volunteers (the hands having current finger inflammation were excluded) were studied. A series of hand infrared photos of each subject were taken and stored by using the technique of digital infrared thermography. We studied the infrared pictures and measured the temperatures of finger tips from digit 1 (D1) to digit 5 (D5), the center point of thenar (Th) and hypothenar eminences (Ht), then we calculated the temperature differences (absolute values) between each two of the 7 points, and median index (MI): (D1-D2)+(D2-D3)+(D1-D3). The means of D2 and Th (MD2+Th), D5 and Ht (MD5+Ht) were also calculated. RESULTS: The results showed that the temperatures of median nerve distribution area in the hands were highly significantly different (Th-Ht, p < 0.001, MI, p < 0.001) between carpal tunnel syndrome (CTS) and the control group. The differences between the median and ulnar nerve distribution area were also highly significantly different in CTS hands (MD2+Th compared to MD5+Ht, p < 0.01). The sensitivity and specificity of digital infrared thermography were 84 and 91%, respectively. CONCLUSION: Digital infrared thermography suggests sympathetic neural pathology in carpal tunnel syndrome. It may also be useful as an additional non-invasive tool in the diagnosis of CTS especially in the early stage.

Neck and shoulder pain related to computer use.

The neck and shoulder pain (NSP) symptoms are very common among intensive computer users. This paper reviews recent 20 years' research publications, which have focused on pathophysiology and other aspects of the neck and shoulder pain related to computer use (NSPRCU). The disorder is usually multidimensional, occupational, personal and social factors are among these evolved. Suggestions concerning the diagnostics, procedures of prevention, and treatment options have been discussed. As the details of pathophysiology of these disorders are not yet clear, further studies on NSPRCU are necessary.

Computer use related upper limb musculoskeletal (ComRULM) disorders.

Computer use has progressed fast in recent years. The symptoms and signs caused by repetitive computer use that is characterized by neck, shoulder, elbow, wrist and hand pain, paresthesia, and numbness can be called 'Computer Related Upper Limb Musculoskeletal (ComRULM) disorders'. Publications of recent 20 years have been reviewed. These disorders are usually multifactorial processes, caused by occupational, personal and social factors. Some suggestions concerning the diagnostics, procedures of prevention, and treatment options have been discussed. Further studies on 'ComRULM disorders' are necessary.