A Greater Increase in Complement C5a Receptor 1 Level at Onset and a Smaller Decrease in Immunoglobulin G Level after Recovery in Severer Coronavirus Disease 2019 Patients: A New Analysis of Existing Data with a New Two-Tailed t-Test.

(1) Background: It is our purpose to identify the differences in the changes in Complement C5a receptor 1 (C5aR1) levels showing the degree of inflammation at onset and Immunoglobulin G (IgG) levels showing the extent of survival of the virus fragments after recovery between coronavirus disease 2019 (COVID-19) and pneumonia coronavirus disease (non-COVID-19) for saving patients' lives. (2) Methods: First, the studies showing these markers' levels in individual patients before and after the passage of time were selected from the PubMed Central® databases with the keywords (((COVID-19) AND individual) NOT review) AND C5a/IgG. Then, no changes in these markers' levels with conventional analyses were selected from the studies. Finally, the no changes were reexamined with our new two-tailed t-test using the values on the regression line between initial levels and changed levels instead of the mean or median of changed levels as the expected values of changed levels. (3) Results: Not conventional analyses but our new t-test suggested a greater increase in C5aR1-levels at onset and a smaller decrease in IgG-levels after recovery in COVID-19 patients than non-COVID-19 patients. (4) Conclusion: Our new t-test also should be used in clinics for COVID-19 patients.

Antidepressant effects of acupuncture in a murine model: regulation of neurotrophic factors.

BACKGROUND: GV20 and Yintang are important targets in acupuncture treatment for depression. In this study, we examined the antidepressant effects of simultaneous acupuncture stimulation at GV20 and Yintang. METHODS: We compared the antidepressant effects of manual acupuncture (MA) stimulation at GV20 and Yintang, compared to acupuncture stimulation at two control point locations on the back of the mice (overlying the spinal column) and imipramine administration in a forced swimming (FS)-induced mouse model of depression, and examined the mRNA and protein expression of neurotrophic factors, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and NT-4/5 in the brains by real-time polymerase chain reaction in two different experimental schedules - preventive (MA given alongside FS modelling) and therapeutic (MA given after FS-induced depression was already established). RESULTS: MA at GV20 and Yintang significantly reduced the immobility time of mice with FS-induced depression in both preventive and therapeutic experimental designs, with effects that were comparable to those of imipramine administration. Immobility time following simultaneous acupuncture stimulation of the two control point locations overlying the spinal column was significantly suppressed only 2 weeks after the start of FS in the preventive effect experiment, and the suppressive effect was significantly lower than that of simultaneous acupuncture stimulation at GV20 and Yintang. In the therapeutic effect experiment, there was no change in the increase in immobility time after the end of FS. MA at GV20 and Yintang significantly increased the expression of BDNF and NT-3 in the preventive evaluation and NGF, BDNF, NT-3, and NT-4/5 in the therapeutic effect evaluation. CONCLUSION: Our findings suggest that simultaneous acupuncture stimulation at GV20 and Yintang is effective for the prevention and treatment of depression, and the effect likely involves modulation of the expression of multiple neurotrophic factors.

Observation of Acupuncture Effects on the Expression of Taurine Transporter and Taurine in the Senescence-Accelerated Mouse Brain: A Pilot Study.

In living organisms, taurine is important for homeostasis and is known to have preventive and inhibitory effects on various diseases. Taurine has been reported to play an important role in the development of the brain in newborns and in reducing the damage caused by cerebral ischemia. Previous studies indicated that acupuncture on a pair of acupoints of "DU16" and "DU20" can increase brain taurine transporter (TauT) expression in mice with penicillin-induced epilepsy and enhanced taurine anti-epilepsy effects. Our previous study reported that manual acupuncture stimulation of the head acupuncture points "Bai-Hui" (GV 20) and "Yintang" (Ex-HN3) could produce antidepressant effects. In this study, we investigated whether acupuncture stimulation of the head acupuncture points GV 20 and Ex-HN3 affects the expression of TauT and taurine in the cerebellum and hippocampus in senescence-accelerated mice. Acupuncture stimulation significantly increased the mRNA expression of TauT in the cerebellum and hippocampus. Immunohistochemical staining confirmed that the expression of TauT and taurine in the cerebellum and hippocampus increased. These results indicate that acupuncture stimulation might improve cognitive and behavioral abilities by increasing the expression of TauT and taurine.

Acupuncture Treatment for Social Defeat Stress.

Depression is a mood disorder characterized by disordered affect, thoughts, cognition, and behavior. Antidepressant therapy is often the primary treatment for depression. However, antidepressant therapy may cause unwanted side effects, and its effects are slow. Therefore, some patients are seeking alternative treatments for depression, such as acupuncture. However, there are many unclear points regarding the mechanism of the effect of acupuncture on depression. In recent years, we have reported that acupuncture improves the symptoms of mild depression induced by water-immersion stress in a rat model and depression induced by forced swimming in a mouse model. In this study, we examined the effect of acupuncture on the symptoms of social defeat stress (SDS)-induced depression in mice that most closely resemble human symptoms. In this study, we investigated the preventive and therapeutic effects of acupuncture as part of GV20 "Bai-Hui" and Ex-HN3 "Yintang" on model mice with depression induced by SDS. To examine the mechanism of the preventive and therapeutic effects of acupuncture on depression model mice, we examined the expression of neurotrophic factors in the brains of SDS mice. Two weeks of simultaneous acupuncture stimulation as part of GV20 and Ex-HN3 restored SDS-reduced brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and NT-4/5 expression, which was not observed with antidepressants. In contrast, acupuncture stimulation suppressed nerve growth factor (NGF) expression induced by SDS. These results suggest that acupuncture treatment could be effective in correcting the imbalance in the expression of neurotrophic factors. Furthermore, the effects of acupuncture on the expression of neurotrophic factors appear earlier than those of antidepressants, suggesting that it may be a useful treatment for depression.

Effect of Manual Acupuncture Stimulation at "Bai-Hui" (GV 20) or "Yintáng" (Ex-HN3) on Depressed Rats.

A previous study on rats showed that simultaneous acupuncture stimulation at the "Bai-Hui" (GV 20) and the "Yintáng" (Ex-HN3) acupoints alleviated the state of depression to an extent similar to that achieved by pharmacotherapy. This study investigated whether the alleviation of the depressed state required simultaneous acupuncture at these two acupuncture points. For the purposes of testing the effect of acupuncture on depressive symptoms, we treated a depression model rat, where depression had been induced by using a mild water-immersion stress technique, with either acupuncture stimulation at only one acupuncture point (GV 20 or Ex-HN3) or an antidepressant, and we measured the immobile time for evaluating the state of depression. Anxiety, as a symptom commonly associated with depression, was also evaluated by measuring the number of head dips. Neither the immobile time nor the number of head dips decreased upon acupuncture stimulation. From this study, single acupuncture stimulation at either "GV 20" or "Ex-HN3" alleviated neither the state of depression nor the anxiety. The water-immersion stress used to make the depression model rats was shown not to induce anxiety; however, the stress induced by immobilizing the rats for acupuncture stimulation did lead to anxiety.

Effect of acupuncture stimulation on rats with depression induced by water-immersion stress.

Depression is a kind of mood disorder. The incidence of depressed patients has demonstrated an upward trend in recent years. Symptoms may improve with treatments such as pharmacotherapy and cognitive-behavioral therapy, but such approaches may exert strong side effects, and therapeutic effects can be slow. We studied how acupuncture stimulation would affect depression as a method to reduce side effects. Mild depression was induced in rats by 1-week water-immersion stress. We treated these mildly depressed rats with either acupuncture stimulation at the "Bai-Hui" (GV 20) and "Yintáng" (Ex-HN3) points, or antidepressants. We then measured the immobile time and serum corticosterone level in rats. Immobile time and serum corticosterone level decreased on stimulation with acupuncture or antidepressants. These findings suggest that mild depression in rats was improved by stimulation with acupuncture The mechanisms underlying such improvement may effect HPA system activated by this stress, and inhibit the response to lead to the disorder of the hippocampal nerve cell.

Neuronal differentiation of human iPS cells induced by baicalin via regulation of bHLH gene expression.

Efficient differentiation is important for regenerative medicine based on pluripotent stem cells, including treatment of neurodegenerative disorders and trauma. Baicalin promotes neuronal differentiation of neural stem/progenitor cells of rats and mice. To evaluate the suitability of baicalin for neuronal differentiation of human iPS cells, we investigated whether it promotes neuronal differentiation in human iPS cells and monitored basic helix-loop-helix (bHLH) gene expression during neuronal differentiation. Baicalin promoted neuronal differentiation and inhibited glial differentiation, suggesting that baicalin can influence the neuronal fate decision in human iPS cells. Notch signaling, which is upstream of bHLH proteins, was not involved in baicalin-induced neuronal differentiation. Baicalin treatment did not down-regulate Hes1 gene expression, but it reduced Hes1 protein levels and up-regulated Ascl1 gene expression. Thus, baicalin promoted neuronal differentiation via modulation of bHLH transcriptional factors. Therefore, baicalin has potential to be used as a small-molecule drug for regenerative treatment of neurodegenerative disorders.

Management of Diabetes and Its Complications with Banaba (Lagerstroemia speciosa L.) and Corosolic Acid.

Banaba (Lagerstroemia speciosa L.) extracts have been used for many years in folk medicine to treat diabetes, with the first published research study being reported in 1940. This paper summarizes the current literature regarding Banaba and its constituents. The hypoglycemic effects of Banaba have been attributed to both corosolic acid as well as ellagitannins. Studies have been conducted in various animal models, human subjects, and in vitro systems using water soluble Banaba leaf extracts, corosolic acid, and ellagitannins. Corosolic acid has been reported to decrease blood sugar levels within 60 min in human subjects. Corosolic acid also exhibits antihyperlipidemic and antioxidant activities. The beneficial effects of Banaba and corosolic acid with respect to various aspects of glucose and lipid metabolism appear to involve multiple mechanisms, including enhanced cellular uptake of glucose, impaired hydrolysis of sucrose and starches, decreased gluconeogenesis, and the regulation of lipid metabolism. These effects may be mediated by PPAR and other signal transduction factors. Banaba extract, corosolic acid, and other constituents may be beneficial in addressing the symptoms associated with metabolic syndrome, as well as offering other health benefits.

Eucommia leaf extract (ELE) prevents OVX-induced osteoporosis and obesity in rats.

The cortex of Eucommia ulmoides Oliver is widely used to treat kidney deficiency in traditional Chinese medicine. Its leaves have recently been reported to have anti-obesity properties in metabolic syndrome-like rat models. Due to a sharp decline in estrogen production, obesity, together with osteoporosis, are common problems in postmenopausal women. In this study, we examined the potential effect of Eucommia leaf extract (ELE) in preventing osteoporosis and obesity induced by ovariectomy (OVX). Forty-six female Wistar rats were divided into six groups: Sham-Cont, OVX-Cont, and four OVX groups administered estradiol and different concentrations of ELE 1.25%, ELE 2.5%, and ELE 5%. Treatments were administered after ovariectomy at six weeks of age and continued for 12 weeks. OVX induced a significant decrease in the bone mineral density (BMD) of the lumbar, femora, and tibiae, together with a marked increase in body mass index (BMI). The administration of 5% ELE led to a significant increase in tibial and femoral BMD, as well as significantly increased bone-strength parameters when compared with OVX-Cont rats. According to the suppressed Dpd and increased osteocalcin concentrations in ELE 5% rats, we suggest that varying proportions of bone formation and bone absorption contributed to the enhanced BMD in the femora and tibiae. In addition, significant decreases in body weight, BMI and fat tissue in 5% ELE rats were also observed. These results suggest that ELE may have curative properties for BMD and BMI in OVX rats, and could provide an alternative therapy for the prevention of both postmenopausal osteoporosis and obesity.

Characteristics of diabetic osteopenia in KK-Ay diabetic mice.

We examined the bone mineral density (BMD) of the proximal region and the mid-diaphysis of the femur using dual energy X-ray absorption (DXA), the blood osteocalcin level and the blood glucose level every five weeks from 8 to 23 weeks old in KK-Ay diabetic mice. The BMD of the proximal region after 18 weeks old was significantly lower when compared with that at 8 weeks old (p<0.05), whereas there was no significant difference in the BMD of the mid-diaphysis at each week. The BMD of the proximal region at 18 weeks old was significantly lower than that in ddY mice, used as controls (p<0.05). The blood osteocalcin level at 18 weeks old was significantly lower than that at 8 weeks old and that in 18-week-old ddY mice (p<0.05). There was significant negative correlation between the blood glucose level and the BMD of the proximal region (r=-0.64, p<0.05). These results suggest that type 2 diabetes exerts an influence only on spongy bone, not on cortical bone, and that the BMD in the proximal region of the femur seems to be affected by blood glucose level, parallel with the progression of diabetes, through the blood osteocalcin level. In the present study, we show the characteristics of diabetic osteopenia in KK-Ay mice, an animal model of type 2 diabetes.

Effects of manual acupuncture at GB34 on carbon tetrachloride-induced acute liver injury in rats.

Manual acupuncture at Yanglingquan (GB34) is reported to have a beneficial effect on chronic liver damage. We, therefore, studied the effect of manual acupuncture at GB34 on acute liver damage. Rats were administered carbon tetrachloride (CCl(4)) or olive oil, and direct manual acupuncture was subsequently performed at GB34 or at a sham point (a nonacupoint). In rats administered with CCl(4), the serum levels of aspartate aminotransferase and alanine aminotransferase, the total cholesterol concentration, and the levels of hepatic thiobarbituric-acid-reactive substances were suppressed by acupuncture at GB34 when compared with acupuncture at the sham point. By contrast, there was little histological difference in the liver between acupuncture at GB34 and that at the sham point in rats administered with CCl(4). These results suggest that manual acupuncture at GB34 tends to improve acute liver damage but is not sufficient by itself to completely resolve the hepatic injury.

Demand for CAM Practice at Hospitals in Japan: A Population Survey in Mie Prefecture.

Complementary and alternative medicine (CAM) therapies have been provided at hospitals along with conventional medicine in industrialized nations. Previous studies conducted in Japan revealed high proportion of Japanese had experience of using CAM, but failed to discuss how it should be provided. The present study aims to clarify the demand for CAM practice at hospitals in Japan. A questionnaire consisting of 41 questions was mailed to 10 000 adults randomly selected from the electoral roll of Mie prefecture, Japan in January 2007. The questionnaire asked the subjects about demand for CAM practice at hospitals, types of CAM therapy to be provided and associated reasons. Sociodemographic characteristics, perceived health status, experience and purpose of CAM use, and information resource for CAM were also surveyed. Completed answers were collected from 2824 (28.6%) respondents. Two thousand and nineteen (71.5%) of the respondents demanded CAM practice at hospitals with the most likely reason of "patients can receive treatment under the guidance of a physicians". The three most popular CAM therapies were Kampo, acupressure/massage/Shiatsu and acupuncture/moxibustion. The demand was positively associated with gender, ages of 40-59 years, annual household incomes of 5-7 million yen, occupation of specialist and technical workers and sales workers and poor health status. Higher demand was observed among those who used both CAM and conventional medical therapies for curative purposes. In conclusion, Japanese show a high demand for CAM practice, hoping to use CAM for curative purposes with monitoring by physicians at hospitals.

Effect of corosolic acid on dietary hypercholesterolemia and hepatic steatosis in KK-Ay diabetic mice.

Corosolic acid (CA), contained in the leaves of the banaba plant (Lagerstroemia speciosa L.), is a pentacyclic triterpene, and has hypoglycemic effects. The effects of CA on dietary hypercholesterolemia and hepatic steatosis were assessed in KK-Ay mice, an animal model of type 2 diabetes. Two kinds of high cholesterol diet with or without 0.023% CA, were prepared for the study. KK-Ay mice were fed a normal diet (controls), the high cholesterol diet with CA (CA-mice) or that without CA (HC-mice) for 10 weeks. CA inhibited the mean blood cholesterol level by 32% (P<0.05) and the liver cholesterol content by 46% (P<0.05) compared with those of HC-mice 10 weeks after the start of dietary intake. Acutely, CA inhibited the mean blood cholesterol level 4 h after the administration of a high-cholesterol cocktail in an oral cholesterol-loading test, compared with that of control mice (P<0.05). These results suggest that CA has some direct effects on the cholesterol absorption process in the small intestine. CA may inhibit the activity of cholesterol acyltransferase, which acts in the re-esterification of cholesterol in the small intestine, in type 2 diabetes.

The effect of the major components of Fructus Cnidii on osteoblasts in vitro.

In traditional Chinese medicine, the cause of weak bones or bone loss is generally regarded as a result of kidney deficiency. Fructus Cnidii (FC), which is also known as She-Chuang-Zi, is a traditional herb that has been claimed to have kidney warming effects that invigorate Yang. In this study, we tried to determine the bone production-inducing effect of FC on osteoblastic cells in vitro using osthole, the main component of FC. Osteoblasts were isolated from neonatal Sprague-Dawley rat calvaria using the tissue piece culture method and treated with various concentrations of osthole ranging from 2.5 to 640 microg/mL, together with a blank control. Cell proliferation, alkaline phosphatase (ALP) activity, and bone nodules were measured. The cells were examined by hematoxylin-eosin staining, the Gomori Calcium-Cobalt method and immunofluorescent staining. The 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (or MTT) assay, ALP assay, and bone nodule results indicated significantly enhanced osteoblastic proliferation and differentiation at concentrations of osthole ranging from 40 to 320 microg/mL. Concentrations lower than 40 microg/ mL seemed less effective, and cytotoxicity to osteoblasts was observed at concentrations higher than 320 microg/mL. These results indicate that osthole is effective at inducing osteoblastic bone formation through the up-regulation of ALP activity. FC is a Chinese herb used to treat lumbar pain in clinical practice. Further studies concerning the effects and mechanism of osthole on osteoporotic patients and animals should be performed, as these studies may lead to the development of a drug treatment for osteoporosis in the future.

A pilot study exploring the effects of reflexology on cold intolerance.

Cold intolerance is an inability to tolerate cold temperatures and is accompanied by symptoms including headache, shoulder discomfort, dizziness and palpitations. The current study was performed to examine whether reflexology therapy affected cold intolerance in human subjects and whether the treatment was systemically effective. Ten female volunteer examinees with subjective feelings of cold were examined. After a 5-minute foot bath, 10 minutes of reflexology therapy was performed on their left foot. Skin temperature and blood flow were estimated before and after treatment, together with an interview concerning their feelings of cold and daily habits. In addition, how the recovery rate was affected by the application of a chilled-water load was also estimated. Along with significant increases in skin temperature and blood flow compared with pre-treatment at the bilateral points of KI-1, LR-3, and BL-60, a faster recovery after the application of the chilled-water load was also seen in the lower limbs on both sides. From these results, we conclude that reflexology has systemic effects and is an alternative method for treating cold intolerance.

Drinking hydrogen water ameliorated cognitive impairment in senescence-accelerated mice.

Hydrogen has been reported to have neuron protective effects due to its antioxidant properties, but the effects of hydrogen on cognitive impairment due to senescence-related brain alterations and the underlying mechanisms have not been characterized. In this study, we investigated the efficacies of drinking hydrogen water for prevention of spatial memory decline and age-related brain alterations using senescence-accelerated prone mouse 8 (SAMP8), which exhibits early aging syndromes including declining learning ability and memory. However, treatment with hydrogen water for 30 days prevented age-related declines in cognitive ability seen in SAMP8 as assessed by a water maze test and was associated with increased brain serotonin levels and elevated serum antioxidant activity. In addition, drinking hydrogen water for 18 weeks inhibited neurodegeneration in hippocampus, while marked loss of neurons was noted in control, aged brains of mice receiving regular water. On the basis of our results, hydrogen water merits further investigation for possible therapeutic/preventative use for age-related cognitive disorders.

Possible involvement of histamine, dopamine, and noradrenalin in the periaqueductal gray in electroacupuncture pain relief.

Acupuncture and electroacupuncture are used in pain relief; however, the mechanism underlying the analgesic effect of acupuncture is unclear. Several lines of evidence propose that the periaqueductal gray (PAG), which is one of the regions that contributes to the endogenous pain inhibitory system, is involved in the analgesic effect of acupuncture, and the region receives several neural projections such as histamine and noradrenalin and contains the dopamine cell bodies. The current study examined the effects of electroacupuncture at Zusanli (ST36) and Shangjuxu (ST37) acupoints, which are used for clinical pain control, on the release of neurotransmitters in the PAG in rats. Histamine and dopamine release was increased after pain stimulus, while the changes were completely abolished by electroacupuncture. Pain stimulus had no effect on noradrenalin release, but electroacupuncture increased its release. These findings indicate that acupuncture at Zusanli and Shangjuxu exerts an antinociceptive effect via the activation of neurons in the PAG and that the histaminergic, dopaminergic, and noradrenalinergic systems in the PAG are related to electroacupuncture-induced pain relief.

Tumoricidal effects of beta-glucans: mechanisms include both antioxidant activity plus enhanced systemic and topical immunity.

A study to evaluate the mechanisms of tumoricidal activity resulting from orally administered extract of Agaricus blazei Murill (A. blazei) was performed in mice bearing syngeneic and xenogeneic tumors. Tumor regression was comparably seen in both syngeneic and xenogeneic tumor-bearing mice when administered oral extract preparations. In addition, in a murine syngeneic tumor model, oral administration of water-soluble extracts of A. blazei resulted in significant production of cytokines such as IFN-gamma, and TNF-alpha in peritoneal exudate cells, in parallel with the marked regression of tumor development. The water-soluble extracts also induced pronounced antioxidant activity in in vitro and in vivo assays using two different methods. These results indicate the A. blazei extract may enhance not only the immnunomodulatory effects that promote activity of peritoneal exudate cells for tumor regression but also potentially result in the direct destruction of tumor cells through its antioxidant activity.

Effect of corosolic acid on the hydrolysis of disaccharides.

The banaba leaf (Lagerstroemia speciosa L.) has been used in traditional Oriental medicine to treat diabetes in the Philippines. It contains corosolic acid (CA), a compound which has a hypoglycemic effect. We examined the effect of CA on blood glucose levels and the hydrolysis of disaccharides in the small intestine in mice. CA (10 mg/kg body weight) improved hyperglycemia after an oral administration of sucrose, and significantly reduced the hydrolysis of sucrose in the small intestine. These results suggest that the hypoglycemic activity of CA is derived, at least in part, due to the inhibition of the hydrolysis of sucrose.

Effects of Fuscoporia obliqua on postprandial glucose excursion and endothelial dysfunction in type 2 diabetic patients.

Postprandial hyperglycemia has been reported to elicit endothelial dysfunction and provoke future cardiovascular complications. A reduction of postprandial blood glucose levels by the glucosidase inhibitor Fuscoporia obliqua was associated with a risk reduction of cardiovascular complications, but the effects of Fuscoporia obliqua on endothelial function have never been elucidated. This study is aimed to assess the efficacy of Fuscoporia obliqua on postprandial metabolic parameters and endothelial function in type 2 diabetic patients. Postprandial peak glucose (14.47 +/- 1.27 vs. 8.50 +/- 0.53 mmol/liter), plasma glucose excursion (PPGE), and change in the area under the curve (AUC) glucose after a single loading of test meal (total 450 kcal; protein 15.3%; fat 32.3%; carbohydrate 51.4%) were significantly higher in the diet-treated type 2 diabetic patients (n=14) than the age- and sex-matched controls (n=12). The peak forearm blood flow response and total reactive hyperemic flow (flow debt repayment) during reactive hyperemia, indices of resistance artery endothelial function on strain-gauge plethysmography, were unchanged before and after meal loading in the controls. But those of the diabetics were significantly decreased 120 and 240 min after the test meal. A prior administration of Fuscoporia obliqua decreased postprandial peak glucose, PPGE, and AUC glucose. The peak forearm blood flow and flow debt repayment were inversely well correlated with peak glucose, PPGE, and AUC glucose, but not with AUC insulin or the other lipid parameters. Even a single loading of the test meal was shown to impair the endothelial function in type 2 diabetic patients, and the postprandial endothelial dysfunction was improved by a prior use of Fuscoporia obliqua. Fuscoporia obliqua might reduce macrovascular complication by avoiding endothelial injury in postprandial hyperglycemic status.