中医药的抗炎机制在治疗肝纤维化中的作用

肝脏是人体腹腔内最大的实体器官,对维持机体的基本生理功能起着至关重要的作用。肝脏疾病是威胁人类健康的常见病多发病。全球约有10%人口受到不同程度的肝脏疾病的危害,其中,肝纤维化往往成为这些疾病的晚期病理特征。由于肝纤维化的发病机制复杂,尚无有效的合成类药物能够治疗肝纤维化。中药治疗肝纤维化具有多靶点和副作用小的优势。本文综述了肝纤维化的病理特征与诱发炎症的关系,讨论了中药治疗肝纤维化的单味中药、传统配方及其化学活性成分的抗炎症机制。     

Migratory Disturbance Thresholds with Mule Deer and Energy Development

Fine-scale movement data has transformed our knowledge of ungulate migration ecology and now provides accurate, spatially explicit maps of migratory routes that can inform planning and management at local, state, and federal levels. Among the most challenging land use planning issues has been developing energy resources on public lands that overlap with important ungulate habitat, including the migratory routes of mule deer (Odocoileus hemionus). We generally know that less development is better for minimizing negative effects and maintaining habitat function, but we lack information on the amount of disturbance that animals can tolerate before reducing use of or abandoning migratory habitat. We used global positioning system data from 56 deer across 15 years to evaluate how surface disturbance from natural gas well pads and access roads in western Wyoming, USA, affected habitat selection of mule deer during migration and whether any disturbance threshold(s) existed beyond which use of migratory habitat declined. We used resource and step selection functions to examine disturbance thresholds at 3 different spatial scales. Overall, migratory use by mule deer declined as surface disturbance increased. Based on the weight of evidence from our 3 independent but complementary metrics, declines in migratory use related to surface disturbance were non-linear, where migratory use sharply declined when surface disturbance from energy development exceeded 3%. Disturbance thresholds may vary across regions, species, or migratory habitats (e.g., stopover sites). Such information can help with management and land use decisions related to mineral leasing and energy development that overlap with the migratory routes of ungulates. © 2020 The Wildlife Society.     

Differences Between Men and Women in Ambulatory Blood Pressure Thresholds for Diagnosis of Hypertension Based on Cardiovascular Outcomes

Previous studies have reported sex differences in the pathophysiology of hypertension and responses to blood pressure (BP)-lowering medications. Moreover, men exhibit typically higher BP than women, the differences being greater for systolic (SBP) than diastolic (DBP) BP. These differences become apparent during adolescence and remain significant at least until 55–60 yrs of age. Despite such significant sex-related differences in BP regulation, the current recommended ambulatory BP monitoring (ABPM) thresholds for diagnosis of hypertension do not differentiate between men and women. We aimed to derive separate male and female diagnostic thresholds for the awake and asleep SBP and DBP means based upon cardiovascular disease (CVD) outcome. We prospectively studied 3344 subjects (1718 men/1626 women), 52.6?±?14.5 yrs of age, during a median follow-up of 5.6 yrs. Those with hypertension at baseline were randomized to ingest all their prescribed hypertension medications upon awakening or the entire daily dose of ≥1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00?h and at 30-min intervals at night for 48?h, and physical activity was simultaneously monitored every minute by wrist actigraphy to accurately derive the awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Cox regression analysis was used to derive outcome-based reference thresholds for ABPM in men and women. Men exhibited greater event rates than women of CVD death, myocardial infarction, angina pectoris, coronary revascularization, and heart failure; however, event rates of non-CVD death and cerebrovascular events were comparable. The relationship between progressively higher ambulatory BP and CVD risk increased more rapidly in women than men for awake SBP/DBP means ≥125/75?mm Hg and asleep means ≥110/70?mm Hg. The derived outcome-based reference thresholds for men were 135/85?mm Hg for the awake and 120/70?mm Hg for the asleep SBP/DBP means. In terms of CVD outcome, the equivalent cutoff threshold values for women were 125/80?mm Hg for the awake and 110/65?mm Hg for the asleep SBP/DBP means. Outcome-based reference thresholds for the diagnosis of hypertension were 10/5?mm Hg lower for ambulatory SBP/DBP in women than men. This marked sex difference indicates the need for revision of current guidelines that propose diagnostic thresholds for ambulatory BP without differentiation between men and women. (Author correspondence: rhermida@uvigo.es)     

Vibrotactile difference thresholds: Effects of vibration frequency,vibration magnitude,contact area,and body location

It has not been established whether the smallest perceptible change in the intensity of vibrotactile stimuli depends on the somatosensory channel mediating the sensation. This study investigated intensity difference thresholds for vibration using contact conditions (different frequencies, magnitudes, contact areas, body locations) selected so that perception would be mediated by more than one psychophysical channel. It was hypothesized that difference thresholds mediated by the non-Pacinian I (NPI) channel and the Pacinian (P) channel would differ. Using two different contactors (1-mm diameter contactor with 1-mm gap to a fixed surround; 10-mm diameter contactor with 2-mm gap to the surround) vibration was applied to the thenar eminence and the volar forearm at two frequencies (10 and 125?Hz). The up-down-transformed-response method with a three-down-one-up rule provided absolute thresholds and also difference thresholds at various levels above the absolute thresholds of 12 subjects (i.e., sensation levels, SLs) selected to activate preferentially either single channels or multiple channels. Median difference thresholds varied from 0.20 (thenar eminence with 125-Hz vibration at 10?dB SL) to 0.58 (thenar eminence with 10-Hz vibration at 20?dB SL). Median difference thresholds tended to be lower for the P channel than the NPI channel. The NPII channel may have reduced difference thresholds with the smaller contactor at 125?Hz. It is concluded that there are large and systematic variations in difference thresholds associated with the frequency, the magnitude, the area of contact, and the location of contact with vibrotactile stimuli that cannot be explained without increased understanding of the perception of supra-threshold vibrotactile stimuli.     

Body Site Variation of Heat Pain Sensitivity

Thirty-two healthy human subjects provided thresholds for the perception of slight and moderate heat pain. Four body sites were tested bilaterally: thenar eminence of the hand, plantar surface of the foot, dorsolateral forearm, and lateral calf. Thresholds for the glabrous skin of the hand and foot were significantly greater than thresholds for the hairy skin of the arm and leg, the average difference being 1.3°c. Laterality was not a statistically significant factor. Thresholds increased progressively over 2–4 weeks of repeated testing, resulting in values averaging 0.6°c higher in the later sessions. The difference between moderate and slight pain thresholds averaged 1.1°c, and was consistent across body sites and with repeated testing.

The threshold values were normally distributed across subjects. Considerable intersubject variability was observed for both slight and moderate pain thresholds, more so on glabrous than on hairy skin sites. In comparison, the distribution of right-left difference values was narrower, demonstrating less intrasubject versus intersubject variability.

The highly significant difference in thresholds between glabrous and hairy skin sites demonstrates the importance of skin type for heat pain sensitivity. In contrast, there was no significant difference in heat pain sensitivity between comparable sites on the upper versus lower extremities, or between left and right sides.     

Effect of contact location on vibrotactile thresholds at the fingertip

Vibrotactile thresholds depend on the characteristics of the vibration, the location of contact with the skin, and the geometry of the contact with the skin. This experimental study investigated vibrotactile thresholds (from 8 to 250?Hz) at five locations on the distal phalanx of the finger with two contactors: (i) a 1-mm diameter circular probe (0.78-mm² area) with a 1-mm gap to a fixed circular surround (i.e., 7.1-mm² excitation area), and (ii) a 6-mm diameter circular probe (28-mm² area) with a 2-mm gap to a fixed circular surround (i.e., 79-mm² excitation area). With both contactors, especially the smaller contactor at low frequencies (i.e., 8, 16, and 31.5?Hz), thresholds decreased towards the tip of the finger, although there was little variation around the whorl. With low frequencies of vibration, and at all five locations on the finger, similar thresholds were obtained with both contactors, consistent with the NPI channel not changing in sensitivity with a change in the area of stimulation. At high frequencies (i.e., 63, 125, and 250?Hz), thresholds were lower with the larger area of stimulation at all locations, except at the extreme tip of the finger, consistent with spatial summation in the Pacinian channel. It is concluded that with a 6-mm diameter contactor, moderate variations in location around the whorl have little influence on the measured thresholds. With the 1-mm diameter contactor there were greater variations in thresholds and extreme locations, near the nail and the distal interphalangeal joint, may be unsuitable for investigating sensorineural disorders.     

Thermotactile thresholds at the fingertip: Effect of contact area and contact location

Thresholds for the detection of changes in temperature are used to indicate neuropathy, but a variety of different contact areas and contact locations are used. This study was designed to determine the effects of variations in contact area and contact location on both warm and cool thresholds at the fingertip. With 20 healthy subjects (10 females and 10 males aged 20–30 years), warm thresholds and cool thresholds were determined in two separate sessions using the method of limits. In the first part of each session, thresholds were determined around the centre of the whorl using circular contactors with five different diameters (3, 6, 9, 12, and 55 mm). In the second part of each session, thresholds were determined using two contactors (6- and 12-mm diameter) at three locations along the fingertip: (i) distal (5 mm from the nail), (ii) middle (centre of whorl), and (iii) proximal (3 mm from the distal interphalangeal joint). With increasing contact area, the warm thresholds decreased, the cool thresholds increased, and the inter-subject variability in both warm and cool thresholds decreased. Using the 6-mm diameter contactor, warm thresholds were independent of location but cool thresholds increased from distal to proximal locations. It is concluded that temperature sensitivity at the fingertip increases with increasing area of contact, with the variability in thresholds consistent with the existence of warm and cool “insensitive fields”. The findings show that the influence of contact area and contact location should be considered when assessing thermotactile thresholds at the fingertip.     

The Naphthoquinone Diospyrin Is an Inhibitor of DNA Gyrase with a Novel Mechanism of Action

Tuberculosis and other bacterial diseases represent a significant threat to human health. The DNA topoisomerases are excellent targets for chemotherapy, and DNA gyrase in particular is a well-validated target for antibacterial agents. Naphthoquinones (e.g. diospyrin and 7-methyljuglone) have been shown to have therapeutic potential, particularly against Mycobacterium tuberculosis. We have found that these compounds are inhibitors of the supercoiling reaction catalyzed by M. tuberculosis gyrase and other gyrases. Our evidence strongly suggests that the compounds bind to the N-terminal domain of GyrB, which contains the ATPase active site, but are not competitive inhibitors of the ATPase reaction. We propose that naphthoquinones bind to GyrB at a novel site close to the ATPase site. This novel mode of action could be exploited to develop new antibacterial agents.     

Inhibition of the First Step in Synthesis of the Mycobacterial Cell Wall Core,Catalyzed by the GlcNAc-1-phosphate Transferase WecA,by the Novel Caprazamycin Derivative CPZEN-45

Because tuberculosis is one of the most prevalent and serious infections, countermeasures against it are urgently required. We isolated the antitubercular agents caprazamycins from the culture of an actinomycete strain and created CPZEN-45 as the most promising derivative of the caprazamycins. Herein, we describe the mode of action of CPZEN-45 first against Bacillus subtilis. Unlike the caprazamycins, CPZEN-45 strongly inhibited incorporation of radiolabeled glycerol into growing cultures and showed antibacterial activity against caprazamycin-resistant strains, including a strain overexpressing translocase-I (MraY, involved in the biosynthesis of peptidoglycan), the target of the caprazamycins. By contrast, CPZEN-45 was not effective against a strain overexpressing undecaprenyl-phosphate–GlcNAc-1-phosphate transferase (TagO, involved in the biosynthesis of teichoic acid), and a mutation was found in the tagO gene of the spontaneous CPZEN-45-resistant strain. This suggested that the primary target of CPZEN-45 in B. subtilis is TagO, which is a different target from that of the parent caprazamycins. This suggestion was confirmed by evaluation of the activities of these enzymes. Finally, we showed that CPZEN-45 was effective against WecA (Rv1302, also called Rfe) of Mycobacterium tuberculosis, the ortholog of TagO and involved in the biosynthesis of the mycolylarabinogalactan of the cell wall of M. tuberculosis. The outlook for WecA as a promising target for the development of antituberculous drugs as a countermeasure of drug resistant tuberculosis is discussed.