Optimum tacrolimus trough levels for enhanced graft survival and safety in kidney transplantation: a retrospective multicenter real-world evidence study.

BACKGROUND: The current study aimed to determine the optimal tacrolimus trough levels for balancing graft survival and patient safety following kidney transplantation. MATERIALS AND METHODS: We conducted a retrospective cohort study involving 11,868 kidney transplant recipients from five medical centers. The association between tacrolimus exposures (periodic mean trough level, coefficient of variability, time in therapeutic range) and composite allograft outcome (de novo donor specific antibody, biopsy-proven rejection, kidney dysfunction, and graft failure), as well as safety outcomes (severe infection, cardiovascular events, malignancy, and mortality) were assessed. Data were sourced from Clinical Data Warehouses and analyzed using advanced statistical methods, including Cox marginal structural models with inverse probability treatment weighting. RESULTS: Tacrolimus levels of 5.0-7.9 ng/mL and 5.0-6.9 ng/mL during the 2-12 month and 12-72 month post-transplantation periods, respectively, were associated with reduced risks of composite allograft outcomes. During the first post-transplant year, the adjusted hazard ratios (aHR) for composite allograft outcomes were: 0.69 (95% CI 0.55-0.85, P<0.001) for 5.0-5.9 ng/mL; 0.81 (95% CI 0.67-0.98, P=0.033) for 6.0-6.9 ng/mL; and 0.73 (95% CI 0.60-0.89, P=0.002) for 7.0-7.9 ng/mL (compared to levels ≥8.0 ng/mL). For the 6-year composite outcomes, aHRs were 0.68 (95% CI 0.53-0.87, P=0.002) for 5.0-5.9 ng/mL and 0.65 (95% CI 0.50-0.85, P=0.001) for 6.0-6.9 ng/mL. These optimal ranges showed reduced rates of severe infection (6 y), malignancy (6 y), and mortality (1 y). CONCLUSION: This multicenter study provides robust evidence for optimal tacrolimus trough levels during the periods 2-12 and 12-72 months following kidney transplantation.

Structure and function of the pseudouridine 5'-monophosphate glycosylase PUMY from Arabidopsis thaliana.

Pseudouridine is a noncanonical C-nucleoside containing a C-C glycosidic linkage between uracil and ribose. In the two-step degradation of pseudouridine, pseudouridine 5'-monophosphate glycosylase (PUMY) is responsible for the second step and catalyses the cleavage of the C-C glycosidic bond in pseudouridine 5'-monophosphate (ΨMP) into uridine and ribose 5'-phosphate, which are recycled via other metabolic pathways. Structural features of Escherichia coli PUMY have been reported, but the details of the substrate specificity of ΨMP were unknown. Here, we present three crystal structures of Arabidopsis thaliana PUMY in different ligation states and a kinetic analysis of ΨMP degradation. The results indicate that Thr149 and Asn308, which are conserved in the PUMY family, are structural determinants for recognizing the nucleobase of ΨMP. The distinct binding modes of ΨMP and ribose 5'-phosphate also suggest that the nucleobase, rather than the phosphate group, of ΨMP dictates the substrate-binding mode. An open-to-close transition of the active site is essential for catalysis, which is mediated by two α-helices, α11 and α12, near the active site. Mutational analysis validates the proposed roles of the active site residues in catalysis. Our structural and functional analyses provide further insight into the enzymatic features of PUMY towards ΨMP.

Clinical features and molecular genetics associated with brain metastasis in suspected early-stage non-small cell lung cancer.

Introduction: Regarding whether brain magnetic resonance imaging (MRI) should be routine in patients with suspected early-stage lung cancer, guideline recommendations are inconsistent. Therefore, we performed this study to evaluate the incidence of and risk factors for brain metastasis (BM) in patients with suspected early-stage non-small-cell lung cancer (NSCLC). Methods: A review of the medical charts of consecutive NSCLC patients diagnosed between January 2006 and May 2020 was performed. We identified 1,382 NSCLC patients with clinical staging of T1/2aN0M0 (excluding BM), and investigated the incidence, clinical predictors, and prognosis of BM in the cohort. We also performed RNA-sequencing differential expression analysis using transcriptome of 8 patients, using DESeq2 package (version 1.32.0) with R (version 4.1.0). Results: Among 1,382 patients, nine hundred forty-nine patients (68.7%) underwent brain MRI during staging, and 34 patients (3.6%) were shown to have BM. Firth's bias-reduced logistic regression showed that tumor size (OR 1.056; 95% CI 1.009-1.106, p=0.018) was the only predictor of BM, and pathologic type was not a predictor of BM in our cohort (p>0.05). The median overall survival for patients with brain metastasis was 5.5 years, which is better than previously reported in the literature. RNA-sequencing differential expression analysis revealed the top 10 significantly upregulated genes and top 10 significantly downregulated genes. Among the genes involved in BM, Unc-79 homolog, non-selective sodium leak channel (NALCN) channel complex subunit (UNC79) was the most highly expressed gene in the lung adenocarcinoma tissues from the BM group, and an in vitro assay using A549 cells revealed that the NALCN inhibitor suppressed lung cancer cell proliferation and migration. Conclusions: Given the incidence and favorable outcome of BM in patients with suspected early-stage NSCLC, selective screening with brain MRI may be considered, especially in patients with high-risk features.

Resting Metabolic Rate for Diagnosing Tae-Eum Sasang Type and Unraveling the Mechanism of Type-Specific Obesity.

Increased resting metabolic rate (RMR), representing augmented energy expenditure, is a preferred physical characteristic; however, the Tae-Eum Sasang type, with a high incidence of obesity and metabolic diseases, has a higher RMR. This study scrutinized the physical characteristics of Sasang typology, a traditional Korean personalized medicine, to resolve this discrepancy, which can unravel the mechanism of Tae-Eum-type-specific obesity and improve the Tae-Eum Sasang-type diagnosis. A total of 395 healthy participants provided Sasang-type diagnosis using Sasang Constitutional Analysis Tool and physical features, including skeletal muscle mass, body fat mass, and RMR, along with those standardized using body weight. The Tae-Eum-type group showed significantly higher body weight, body mass index, body fat mass, and unstandardized RMR (kcal/day) than others, while their standardized measures of RMR per weigh (RMRw, kcal/day/kg) and percent skeletal muscle (PSM, %) were significantly lower. The logistic regression model revealed that the RMRw is pivotal for discriminating Tae-Eum type from others and explaining the developmental mechanism of Tae-Eum-type obesity. The aforementioned might provide a theoretical framework for Sasang-type diagnosis and Sasang-type-specific health promotion using bodily exercise and medical herbs.

Optogenetic fMRI for Brain-Wide Circuit Analysis of Sensory Processing.

Sensory processing is a complex neurological process that receives, integrates, and responds to information from one's own body and environment, which is closely related to survival as well as neurological disorders. Brain-wide networks of sensory processing are difficult to investigate due to their dynamic regulation by multiple brain circuits. Optogenetics, a neuromodulation technique that uses light-sensitive proteins, can be combined with functional magnetic resonance imaging (ofMRI) to measure whole-brain activity. Since ofMRI has increasingly been used for investigating brain circuits underlying sensory processing for over a decade, we systematically reviewed recent ofMRI studies of sensory circuits and discussed the challenges of optogenetic fMRI in rodents.

Role of anterior cingulate cortex inputs to periaqueductal gray for pain avoidance.

Although pain-related excessive fear is known to be a key factor in chronic pain disability, which involves the anterior cingulate cortex (ACC), little is known about the downstream circuits of the ACC for fear avoidance in pain processing. Using behavioral experiments and functional magnetic resonance imaging with optogenetics at 15.2 T, we demonstrate that the ACC is a part of the abnormal circuit changes in chronic pain and its downstream circuits are closely related to modulating sensorimotor integration and generating active movement rather than carrying sensory information. The projection from the ACC to the dorsolateral and lateral parts of the periaqueductal gray (dl/lPAG) especially enhances both reflexive and active avoidance behavior toward pain. Collectively, our results indicate that increased signals from the ACC to the dl/lPAG might be critical for excessive fear avoidance in chronic pain disability.

Protocol for mouse optogenetic fMRI at ultrahigh magnetic fields.

Mouse optogenetic functional magnetic resonance imaging (opto-fMRI) is critical for linking genes and functions and for mapping cell-type-specific neural circuits in the whole brain. Herein, we describe how opto-fMRI images can be reliably obtained in anesthetized mice with minimal distortions at ultrahigh magnetic fields. The protocol includes surgical and anesthesia procedures, animal cradle modification, animal preparation and setup, animal physiology maintenance, and pilot fMRI scanning. This protocol will enable reproducible mouse opto-fMRI experiments. For complete details on the use and execution of this protocol, please refer to Jung et al. (2021),1 Jung et al. (2022),2 and Moon et al. (2021).3.

Artificial intelligence in detecting temporomandibular joint osteoarthritis on orthopantomogram.

Orthopantomogram (OPG) is important for primary diagnosis of temporomandibular joint osteoarthritis (TMJOA), because of cost and the radiation associated with computed tomograms (CT). The aims of this study were to develop an artificial intelligence (AI) model and compare its TMJOA diagnostic performance from OPGs with that of an oromaxillofacial radiology (OMFR) expert. An AI model was developed using Karas' ResNet model and trained to classify images into three categories: normal, indeterminate OA, and OA. This study included 1189 OPG images confirmed by cone-beam CT and evaluated the results by model (accuracy, precision, recall, and F1 score) and diagnostic performance (accuracy, sensitivity, and specificity). The model performance was unsatisfying when AI was developed with 3 categories. After the indeterminate OA images were reclassified as normal, OA, or omission, the AI diagnosed TMJOA in a similar manner to an expert and was in most accord with CBCT when the indeterminate OA category was omitted (accuracy: 0.78, sensitivity: 0.73, and specificity: 0.82). Our deep learning model showed a sensitivity equivalent to that of an expert, with a better balance between sensitivity and specificity, which implies that AI can play an important role in primary diagnosis of TMJOA from OPGs in most general practice clinics where OMFR experts or CT are not available.

Influence of bolus size and chewing side on temporomandibular joint intra-articular space during mastication.

Previous studies suggested that, during mastication, magnitude and location of mechanical load in the temporomandibular joint (TMJ) might depend on chewing side and bolus size. Aim of this study was to dynamically measure the TMJ space while chewing on standardized boluses to assess the relationship among minimum intra-articular distances (MID), their location on the condylar surface, bolus size, and chewing side. Mandibular movements of 12 participants (6f, 24±1y.o.; 6 m, 28±6y.o.) were tracked optoelectronically while chewing unilaterally on rubber boluses of 15 × 15 × 5, 15 × 15 × 10, and 15 × 15 × 15 mm3 size. MID and their location along the main condylar axis were determined with dynamic stereometry. MID were normalized on the intra-articular distance in centric occlusion. Repeated measures ANOVA (α = 0.05) showed that MID were smaller on the balancing (0.74±0.19) than on the working condyle (0.89±0.16) independently of bolus size (p < 0.0001). MIDs did not differ between 5 and 10 mm bolus thicknesses (0.80±0.17) but increased for 15 mm (0.85±0.22, p = 0.024) and were located mostly laterally, close to the condylar center. This study confirmed higher reduction of TMJ space on the balancing than on the working condyle during mastication. Intra-articular distances increased significantly for the greatest bolus thickness. Loaded areas were located laterally, for both working and balancing joint.

Involvement of cannabinoid type 1 receptor in fasting-induced analgesia.

The endocannabinoid system (ECS) is known to modulate not only food intake but also pain, especially via the cannabinoid type 1 receptor (CB1R) expressed throughout the central nervous system and the peripheral tissues. Our previous study demonstrated that fasting produces an analgesic effect in adult male mice, which is reversed by intraperitoneal (i.p.) administration of CB1R antagonist (SR 141716). In the present study, we further examined the effect of CB1R expressed in the peripheral tissues. In the formalin-induced inflammatory pain model, i.p. administration of peripherally restricted CB1R antagonist (AM 6545) reversed fasting-induced analgesia. However, intraplantar administration of SR 141716 did not affect fasting-induced analgesia. Furthermore, mRNA expression of CB1R did not change in the formalin model by fasting in the dorsal root ganglia. The formalin-induced c-Fos expression at the spinal cord level was not affected by fasting, and in vivo recording from the superficial dorsal horn of the lumbar spinal cord revealed that fasting did not affect formalin-induced neural activity, which indicates minimal involvement of the spinal cord in fasting-induced analgesia. Finally, when we performed subdiaphragmatic vagotomy to block the hunger signal from the gastrointestinal (GI) system, AM 6545 did not affect fasting-induced analgesia, but SR 141716 still reversed fasting-induced analgesia. Taken together, our results suggest that both peripheral and central CB1Rs contribute to fasting-induced analgesic effects and the CB1Rs in the GI system which transmit fasting signals to the brain, rather than those in the peripheral sensory neurons, may contribute to fasting-induced analgesic effects.

Urinary Function of the Sasang Type and Cold-Heat Subgroup Using the Sasang Urination Inventory in Korean Hospital Patients.

INTRODUCTION: The Sasang type-specific pathophysiological symptom is pivotal for the Sasang type classification and pattern identification. The Sasang Urination and Defecation Inventory (SUDI) for urinary function analysis was developed; however, the clinical usefulness of urination-related subscales of SUDI in the Sasang type and Cold-Heat subgroup was not reported with acceptable validation analysis. METHODS: The clinical diagnosis of the Sasang type and Cold-Heat subgroup, responses to SUDI items, and weight and height of the 350 hospital patients were acquired retrospectively. The Sasang Urination Inventory (SUI) with SUI-CHR (problematic physical characteristics of urine), SUI-HSS (hypersensitivity of urinary urgency and high frequency), and SUI-DIS (urinary discomfort of hesitancy and residual urine sense) subscales using 12 items of SUDI were improvised. The item and construct validity of the SUI were examined using item response theory and confirmatory factor analysis, and the clinical usefulness of the SUI in Sasang type and Cold-Heat subgroup differentiation was attested. RESULTS: The SUI and its subscales showed acceptable structural validity and have clinical usefulness in the Tae-Eum type. The Tae-Eum type has a significantly higher SUI-CHR score than did the So-Yang type, and the Heat subgroup has a significantly higher SUI-HSS score than did the Cold subgroup in the Tae-Eum type. Discussion. The distinctive Sasang type- and Cold-Heat subscale-specific pathological symptoms in urinary function were revealed using the SUI. The SUI combined with objective Sasang typology measures might be useful for integrative precision medicine combining Eastern and Western practice and for evidence-based clinical education for medical professions.

The analgesic effect of refeeding on acute and chronic inflammatory pain.

Pain is susceptible to various cognitive factors. Suppression of pain by hunger is well known, but the effect of food intake after fasting (i.e. refeeding) on pain remains unknown. In the present study, we examined whether inflammatory pain behavior is affected by 24 h fasting and 2 h refeeding. In formalin-induced acute inflammatory pain model, fasting suppressed pain behavior only in the second phase and the analgesic effect was also observed after refeeding. Furthermore, in Complete Freund's adjuvant-induced chronic inflammatory pain model, both fasting and refeeding reduced spontaneous pain response. Refeeding with non-calorie agar produced an analgesic effect. Besides, intraperitoneal (i.p.) administration of glucose after fasting, which mimics calorie recovery following refeeding, induced analgesic effect. Administration of opioid receptor antagonist (naloxone, i.p.) and cannabinoid receptor antagonist (SR 141716, i.p.) reversed fasting-induced analgesia, but did not affect refeeding-induced analgesia in acute inflammatory pain model. Taken together, our results show that refeeding produce analgesia in inflammatory pain condition, which is associated with eating behavior and calorie recovery effect.

Hedonic drinking engages a supraspinal inhibition of thermal nociception in adult rats.

The taste of sucrose is commonly used to provide pain relief in newborn humans and is innately analgesic to neonatal rodents. In adulthood, sucrose remains a strong motivator to feed, even in potentially hazardous circumstances (ie, threat of tissue damage). However, the neurobiological mechanisms of this endogenous reward-pain interaction are unclear. We have developed a simple model of sucrose drinking-induced analgesia in Sprague-Dawley rats (6-10 weeks old) and have undertaken a behavioral and pharmacological characterization using the Hargreaves' test of hind-paw thermal sensitivity. Our results reveal an acute, potent, and robust inhibitory effect of sucrose drinking on thermal nociceptive behaviour that unlike the phenomenon in neonates is independent of endogenous opioid signalling and does not seem to operate through classical descending inhibition of the spinal cord circuitry. Experience of sucrose drinking had a conditioning effect whereby the apparent expectancy of sucrose enabled water alone (in euvolemic animals) to elicit a short-lasting placebo-like analgesia. Sweet taste alone, however, was insufficient to elicit analgesia in adult rats intraorally perfused with sucrose. Instead, the sucrose analgesia phenomenon only appeared after conditioning by oral perfusion in chronically cannulated animals. This sucrose analgesia was completely prevented by systemic dosing of the endocannabinoid CB1 receptor antagonist rimonabant. These results indicate the presence of an endogenous supraspinal analgesic circuit that is recruited by the context of rewarding drinking and is dependent on endocannabinoid signalling. We propose that this hedonic sucrose-drinking model may be useful for further investigation of the supraspinal control of pain by appetite and reward.

Analysis of Facial Features according to Sasang Types between Native Japanese and Native Korean Populations.

BACKGROUND: Facial diagnosis is a common practice and essential diagnostic method used in the Sasang Constitution Medicine (SCM). SCM is a kind of personalized medicine in Traditional Korean Medicine which categorizes people into four types, namely, Tae-Yang (TY) type, Tae-Eum type (TE), So-Yang (SY) type, and So-Eum (SE) type. This study was conducted to compare and analyze the differences in the facial feature across Sasang types among native Japanese and native Koreans. METHODS: A total of 843 subjects were recruited for this study, 127 native Japanese and 716 native Koreans, respectively. Facial feature points and the measurements of facial features were assigned and calculated automatically using a facial analysis program. Data of each Sasang type for both genders were also extracted and analyzed. Analysis of covariance was then used to examine the differences in facial feature variables among native Japanese and native Koreans and Sasang types. RESULTS: Significant differences were seen in the facial feature variables related to lower face area and eye shape. In males, TE types had wider mid-face and lower face as compared to other constitutions. Male TE types were also seen to have narrower eyes whereas male SY types had rounder eyes. In females, TE types had wider lower face width and area compared to SY types and SE types. Female SY types also had rounder eyes. CONCLUSIONS: This study presented distinctive feature in the lower face area and eye shape among the Sasang types in both native Japanese and native Koreans. This proposed that facial feature variables can also be used as an objective tool in distinguishing the Sasang types in native Japanese. Further studies are needed in the future to generalize these results.

Test-retest reliability of the questionnaire in the Sasang constitutional analysis tool (SCAT).

BACKGROUND: The Sasang constitutional analysis tool (SCAT) is an integrated Sasang constitutional analysis system developed by the Korea Institute of Oriental Medicine. This study aimed to evaluate the reliability of a questionnaire for measuring personality and pathophysiological symptoms that is one of the components of the SCAT. METHODS: In this study, data were collected from university students in their twenties. Tests were administered twice, with an interval of 4 weeks between tests. Test-retest data from 176 students were collected and used for analysis. Internal consistency reliability was analyzed by using Cronbach's alpha coefficient, and test-retest reliability was analyzed by using Spearman's rank correlation coefficient. RESULTS: Cronbach's alpha coefficient was 0.788 for personality, 0.511 for eating habits, 0.718 for digestion, 0.667 for heat- or cold-wise penchant, and 0.612 for water ingestion. Spearman's rank correlation coefficients, which were used to assess correlations between test and retest results, ranged from 0.444 to 0.828. CONCLUSION: The internal consistency and test-retest reliability of the SCAT questionnaire were found to be satisfactory.

Pharmacopuncture With Scolopendra subspinipes Suppresses Mechanical Allodynia in Oxaliplatin-Induced Neuropathic Mice and Potentiates Clonidine-induced Anti-allodynia Without Hypotension or Motor Impairment.

Chemotherapy-induced neuropathic pain is a common dose-limiting side effect of anticancerdrugs but lacks an effective treatment strategy. Scolopendra subspinipes has been used in traditional medicine to treat chronic neuronal diseases. Moreover, pharmacopuncture with S subspinipes (SSP) produces potent analgesia in humans and experimental animals. In this study, we examined the effect of SSP into the ST36 acupoint on oxaliplatin-induced mechanical allodynia in mice. Acupoint treatment with SSP (0.5%/20 µL) significantly decreased mechanical allodynia produced by a single oxaliplatin injection (10mg/kg i.p.), which was completely prevented by acupoint preinjection of lidocaine. Intrathecal treatment with yohimbine (25 µg/5 µL), an α2-adrenoceptor antagonist, prevented the anti-allodynic effect of SSP. In contrast, a high dose (0.1mg/kg i.p.) ofclonidine,an α2-adrenoceptor agonist, suppressed oxaliplatin-induced mechanical allodynia butproduced severe side effects including hypotension, bradycardia, and motor impairment. The combination of SSP with a lower dose of clonidine (0.03 mg/kg) produced a comparable analgesic effect without side effects. Collectively, our findings demonstrate that SSP produces an analgesic effect in oxaliplatin-induced pain via neuronal conduction at the acupoint and activation of spinal α2-adrenoceptors. Moreover, acombination of low-dose clonidine with SSP represents a novel and safe therapeutic strategy for chemotherapy-induced chronic pain. PERSPECTIVE: SSP can relieve oxaliplatin-induced mechanical allodynia. Moreover, SSP potentiates clonidine-induced anti-allodynia, allowing a lower dose of clonidine with no significant side effects. The combination of SSP and low-dose clonidine might provide a novel strategy for the management of chemotherapy-induced peripheral neuropathy.

Design of Dual-Mode Local Oscillators Using CMOS Technology for Motion Detection Sensors.

Recently, studies have been actively carried out to implement motion detecting sensors by applying radar techniques. Doppler radar or frequency-modulated continuous wave (FMCW) radar are mainly used, but each type has drawbacks. In Doppler radar, no signal is detected when the movement is stopped. Also, FMCW radar cannot function when the detection object is near the sensor. Therefore, by implementing a single continuous wave (CW) radar for operating in dual-mode, the disadvantages in each mode can be compensated for. In this paper, a dual mode local oscillator (LO) is proposed that makes a CW radar operate as a Doppler or FMCW radar. To make the dual-mode LO, a method that controls the division ratio of the phase locked loop (PLL) is used. To support both radar mode easily, the proposed LO is implemented by adding a frequency sweep generator (FSG) block to a fractional-N PLL. The operation mode of the LO is determined by according to whether this block is operating or not. Since most radar sensors are used in conjunction with microcontroller units (MCUs), the proposed architecture is capable of dual-mode operation by changing only the input control code. In addition, all components such as VCO, LDO, and loop filter are integrated into the chip, so complexity and interface issues can be solved when implementing radar sensors. Thus, the proposed dual-mode LO is suitable as a radar sensor.

Biopsychological and pathophysiological features of Cold-Heat subgroup of Sasang typology with Sasang Digestive Function Inventory, Sasang Personality Questionnaire and Body Mass Index.

BACKGROUND: The Sasang typology is a traditional Korean personalized medicine and its Cold-Heat subgroup identification is essential for effective use of medical herbs and acupuncture. The purpose of this study was to discover differences between Cold-Heat subgroups with objective clinical measures and to examine its clinical usefulness. METHODS: The pathophysiological symptoms of the digestive system, temperament and body shape of 241 patients were measured using the Sasang Digestive Function Inventory (SDFI), Sasang Personality Questionnaire (SPQ) and Body Mass Index (BMI). The differences between Cold and Heat subgroups of each Sasang types were tested by Analysis of Covariance considering age and sex, while the associations of SDFI, SPQ and BMI with Cold-Heat subgroup were examined by logistic regression analysis. RESULTS: There were significant differences between Cold and Heat subgroups in SDFI, SPQ and BMI for the So-Yang, SDFI and BMI for the Tae-Eum type and SDFI-Digestion subscale for the So-Eum type. Moreover, the SDFI-Digestion was a substantial predictor for Cold-Heat subgroup identification in three Sasang types. The logistic regression model with SDFI, SPQ and BMI correctly predicted 81.9%, 77% and 75.5% of the Cold-Heat subgroups in So-Yang, Tae-Eum and So-Eum types, respectively. CONCLUSION: The results of the present study showed that the objective and validated clinical measures of SDFI, SPQ and BMI would be useful for differentiating Cold-Heat subgroups of Sasang typology. Further clinical studies on pathophysiological mechanisms in Cold-Heat subgroup are required to generalize these results.

Pharmacognostic outlooks on medical herbs of Sasang typology.

The purpose of this study was to review the pharmacognostic characteristics of Sasang type-specific medical herbs and suggest biological mechanisms that might be related to the personalized treatment of the East. Major compounds and their pharmacological activities of medical herbs for each Sasang types were systematically reviewed. The pharmacognostic characteristics of its main compounds were systematically analyzed with previous studies and three web-based databases. Sasang type-specific medical herbs were selected, and biological effects of their phytochemicals were reviewed from the pathophysiological features of each Sasang types. Phenolics were dominant in Tae-Yang type-specific herbs, iridoids and triterpenes with antipyretic and diuretic effects were in So-Yang type-specific, saponins (triterpene saponins and steroidal saponins) with antitussive effects were in Tae-Eum type-specific, and monoterpene and sesquiterpenes with stomachic effect were in So-Eum type-specific herbs. Pharmacognostic understandings on Sasang type-specific medical herbs with consideration of type-specific pathophysiological features were provided for the first time. This study would contribute to in-depth understandings on the pathophysiology of Sasang typology and integration of East-Asian and Western personalized medicine.

Sinomenine produces peripheral analgesic effects via inhibition of voltage-gated sodium currents.

Sinomenium acutum has been used in traditional medicine to treat a painful disease such as rheumatic arthritis and neuralgia. Sinomenine, which is a main bioactive ingredient in Sinomenium acutum, has been reported to have an analgesic effect in diverse pain animal models. However little is known about the detailed mechanisms underlying peripheral analgesic effect of sinomenine. In the present study, we aimed to elucidate its cellular mechanism by using formalin-induced acute inflammatory pain model in mice. We found that intraperitoneal (i.p.) administration of sinomenine (50mg/kg) suppressed formalin-induced paw licking behavior in both the first and the second phase. Formalin-induced c-Fos protein expression was also suppressed by sinomenine (50mg/kg i.p.) in the superficial dorsal horn of spinal cord. Whole-cell patch-clamp recordings from small-sized dorsal root ganglion (DRG) neurons revealed that sinomenine reversibly increased the spike threshold and the threshold current intensity for evoking a single spike and decreased firing frequency of action potentials evoked in response to a long current pulse. Voltage-gated sodium currents (INa) were also significantly reduced by sinomenine in a dose-dependent manner (IC50=2.3±0.2mM). Finally, we confirmed that intraplantar application of sinomenine suppressed formalin-induced pain behavior only in the first phase, but not the second phase. Taken together, our results suggest that sinomenine has a peripheral analgesic effect by inhibiting INa.