Hip fracture is a major public health concern, with high incidence rates in the elderly worldwide. Hip fractures are associated with increased medical costs, patient dependency on families, and higher rates of morbidity and mortality. Chinese herbal medicine (CHM) is typically characterized as cost-effective and suitable for long-term use with few side effects. To better understand the effects of CHM on hip fracture patients, we utilized a population-based database to investigate the demographic characteristics, cumulative incidence of overall mortality, readmission, reoperation, and patterns of CHM prescription. We found that CHM usage was associated with a lower risk of overall mortality [P = 0.0009; adjusted hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.30-0.73], readmission (P = 0.0345; adjusted HR: 0.67, 95% CI: 0.46-0.97), and reoperation (P = 0.0009; adjusted HR: 0.57, 95% CI: 0.40-0.79) after adjustment for age, type of hip fracture, surgical treatment type, and comorbidities. We also identified the herbal formulas, single herbs, and prescription patterns for the treatment of hip fracture by using association rule mining and network analysis. For hip fracture patients, the most common CHM coprescription pattern was Du-Zhong (DZ) → Xu-Duan (XD), followed by Du-Huo-Ji-Sheng-Tang (DHJST) → Shu-Jing-Huo-Xue-Tang (SJHXT), and Gu-Sui-Bu (GSB) → Xu-Duan (XD). Furthermore, XD was the core prescription, and DZ, GSB, SJHXT, and DHJST were important prescriptions located in cluster 1 of the prescription patterns. This study provides evidence for clinical CHM use as an adjunctive therapy that offers benefits to hip fracture patients.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer involving epithelial squamous-cell carcinoma of the nasopharynx that mainly occurs in individuals from East and Southeast Asia. We investigated whether Chinese herbal medicine (CHM) as a complementary therapy offers benefits to these patients. We retrospectively evaluated the Taiwan Cancer Registry (Long Form) database for patients with advanced NPC, using or not using CHM, between 2007-2013. Cox proportional-hazard model and Kaplan‒Meier survival analyses were applied for patient survival. CHM-users showed a lower overall and cancer-related mortality risk than non-users. For advanced NPC patients, the overall mortality risk was 0.799-fold for CHM-users, after controlling for age, gender, and Charlson comorbidity index (CCI) score (Cancer stages 3 + 4: adjusted hazard ratio [aHR]: 0.799, 95% confidence interval [CI]: 0.676-0.943, p = 0.008). CHM-users also showed a lower cancer-related mortality risk than non-users (aHR: 0.71, 95% CI: 0.53-0.96, p = 0.0273). Association rule analysis showed that CHM pairs were Ban-Zhi-Lian (BZL; Scutellaria barbata D.Don) and For single herbs, Bai-Hua-She-She-Cao (Herba Hedyotis Diffusae; Scleromitrion diffusum (Willd.) R.J.Wang (syn. Hedyotis diffusa Willd.) and Mai-Men-Dong (MMD; Ophiopogon japonicus (Thunb.) Ker Gawl.), and Gan-Lu-Yin (GLY) and BHSSC. Network analysis revealed that BHSSC was the core CHM, and BZL, GLY, and Xin-Yi-Qing-Fei-Tang (XYQFT) were important CHMs in cluster 1. In cluster 2, ShengDH, MMD, Xuan-Shen (XS; Scrophularia ningpoensis Hensl.), and Gua-Lou-Gen (GLG; Trichosanthes kirilowii Maxim.) were important CHMs. Thus, as a complementary therapy, CHM, and particularly the 8 CHMs identified, are important for the treatment of advanced NPC patients.

Aplastic Anemia (AA) is a rare but fatal hematologic disease that may occur at any age and especially higher in Asia. We investigated whether Chinese herbal medicine (CHM) is beneficial to AA patients as a complementary therapy using a nationwide population-based database in Taiwan between 2000-2016. Patient survival was estimated by Kaplan‒Meier survival analyses and Cox proportional-hazard model. CHM-users presented lower risks of overall and anemia-related mortalities when compared to non-users. The risk of overall mortality for CHM-users in AA patients was 0.70-fold [adjusted hazard ratio (aHR): 0.70, 95% confidence interval (CI): 0.66-0.74, p < 0.001). The risk of anemia-related mortality was lower in CHM-users when compared to non-users (aHR: 0.46, 95% CI: 0.32-0.67, p < 0.001). The association rule analysis revealed that CHM pairs were Ban-Zhi-Lian (BZL; Scutellaria barbata D. Don)→Bai-Hua-She-She-Cao (BHSSC; Oldenlandia diffusa (Willd.) Roxb.), followed by Dang-Gui (DG; Angelica sinensis (Oliv.) Diels)→Huang-Qi (HQi; Astragalus membranaceus (Fisch.) Bunge), and Xian-He-Cao (XHC; Agrimonia pilosa f. borealis (Kitag.) Chu)→Gui-Pi-Tang (GPT). Network analysis showed that BZL, BHSSC, DG, HQi, XHC, GPT, and Dan-Shen (DanS; Salvia miltiorrhiza var. charbonnelii (H.Lév.) C.Y.Wu) were commonly used CHMs for AA patients. Therefore, further studies for these commonly prescribed herbs are needed in functional investigations in hematopoiesis-stimulating effect and large-scale randomized controlled trials (RCT) in bone marrow failure related diseases.

The survival of patients with HIV has greatly improved, due to Anti-Retroviral Therapy (ART). However, long-term HIV survivors often develop serious bone abnormalities, possibly due to the interplay of osteoblasts, osteoclasts, HIV ad ART. We evaluated in a nation-wide study in Taiwan the effect of Chinese herbal medicine (CHM) on overall mortality in HIV patients with osteoporosis or fractures. Enrollment period was between 1998 and 2011. Patients with osteoporosis or fractures before the HIV infection, and those with less than 14 days CHM use, were excluded. This left 498 patients, 160 CHM users, 338 without CHM. Univariate Kaplan-Meier and multivariate Cox regression analysis were used to compare the overall mortality in these 2 groups. Due to the nature of Chinese medicine, CHMs inevitably varied. We therefore also used rule mining and network analysis to determine which major CHM clusters were prescribed to the patients. CHM users had a much Lower mortality (hazard ratio (HR) = 0.43, 95% confidence interval (CI): 0.24-0.77, p < 0.005) and higher survival (p = 0.004, log-rank test). Although the CHMs greatly varied, network analysis identified one main cluster of strongly related CHM combinations (Chuan-Xiong-Cha-Tiao-San (CXCTS), Gan-Cao (GC; Glycyrrhiza uralensis Fisch.), Liu-He-Tang (LHT), Huang-Qin-Tang (HQT), Jia-Wei-Ping-Wei-San (JWPWS), and Dang-Gui-Long-Hui-Wan (DGLHuiW)). CHM as an additional treatment strongly improves overall survival in HIV-infected patients with osteoporosis and fractures.

Pemphigus is a life-threatening and skin-specific inflammatory autoimmune disease, characterized by intraepidermal blistering between the mucous membranes and skin. Chinese herbal medicine (CHM) has been used as an adjunct therapy for treating many diseases, including pemphigus. However, there are still limited studies in effects of CHM treatment in pemphigus, especially in Taiwan. To more comprehensively explore the effect of long-term CHM treatment on the overall mortality of pemphigus patients, we performed a retrospective analysis of 1,037 pemphigus patients identified from the Registry for Catastrophic Illness Patients database in Taiwan. Among them, 229 and 177 patients were defined as CHM users and non-users, respectively. CHM users were young, predominantly female, and had a lesser Charlson comorbidity index (CCI) than non-CHM users. After adjusting for age, sex, prednisolone use, and CCI, CHM users had a lower overall mortality risk than non-CHM users (multivariate model: hazard ratio (HR): 0.422, 95% confidence interval (CI): 0.242-0.735, p = 0.0023). The cumulative incidence of overall survival was significantly higher in CHM users than in non-users (p = 0.0025, log rank test). Association rule mining and network analysis showed that there was one main CHM cluster with Qi-Ju-Di-Huang-Wan (QJDHW), Dan-Shen (DanS; Radix Salviae miltiorrhizae; Salvia miltiorrhiza Bunge), Jia-Wei-Xiao-Yao--San (JWXYS), Huang-Lian (HL; Rhizoma coptidis; Coptis chinensis Franch.), and Di-Gu-Pi (DGP; Cortex lycii; Lycium barbarum L.), while the second CHM cluster included Jin-Yin-Hua (JYH; Flos lonicerae; Lonicera hypoglauca Miq.) and Lian-Qiao (LQ; Fructus forsythiae; Forsythia suspensa (Thunb.) Vahl). In Taiwan, CHMs used as an adjunctive therapy reduced the overall mortality to approximately 20% among pemphigus patients after a follow-up of more than 6 years. A comprehensive CHM list may be useful in future clinical trials and further scientific investigations to improve the overall survival in these patients.

The progression of acquired immunodeficiency syndrome is delayed in patients with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART). However, long-term ART is associated with adverse effects. Osteoporosis is one of the adverse effects and is a multifactorial systemic skeletal disease associated with bone fragility and an increased risk of fracture. We performed a longitudinal, comprehensive, nested case-control study to explore the effect of ART on the risk of osteoporosis in 104 osteoporotic and 416 non-osteoporotic patients with HIV infection at their average age about 29 years old in Taiwan. Patients with history of ART, current exposure to ART, higher cumulative defined daily doses (DDDs), or higher ART adherence were at a higher risk of osteoporosis (p < 0.05). Patients receiving nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-containing regimen (zidovudine-lamivudine combination, lamivudine-abacavir combination, and abacavir alone) and protease inhibitor (PI)-containing regimen (lopinavir-ritonavir combination, ritonavir, and atazanavir) had a higher risk of osteoporosis (p < 0.05). Especially, patients receiving high doses of the PIs lopinavir-ritonavir combination had an increased risk of osteoporosis (p < 0.05). In conclusion, history of ART, current exposure to ART, higher cumulative DDDs, and higher ART adherence were associated with an increased risk of osteoporosis. Furthermore, NRTI- and PI-containing regimens and high doses of PIs lopinavir-ritonavir combination may be associated with an increased risk of osteoporosis in patients with HIV infection in Taiwan.

Chinese herbal medicines (CHMs) are widely used in Asian countries. They show multiple pharmacological activities, including antiviral activities. The 5'-long terminal repeat (LTR) region of HIV-1, required for viral transcription, is a potential drug target for HIV-1 reactivation and intrinsic cell death induction of infected or latently infected cells. Modulation of HIV-1 reactivation requires interactions between host cell proteins and viral 5'-LTR elements. By evaluation of two CHMs- Xanthium strumarium and Pueraria montana, we found that 1) X. strumarium reactivated HIV-1 latently infected cells in J-Lat 8.4, J-Lat 9.2, U1, and ACH-2 cells in vitro; 2) 27 nuclear regulatory proteins were associated with HIV-1 5'-LTR using deoxyribonucleic acid affinity pull-down and LC-MS/MS analyses; and 3) among them, silencing of XRCC6 reactivated HIV-1 5'-LTR transcriptional activity. We found that X. strumarium inhibits the 5'-LTR associated XRCC6 nuclear regulatory proteins, increases its viral 5'-LTR promoter transcriptional activity, and reactivates HIV-1 latently infected cells in vitro. These findings may contribute to understanding the 5'-LTR activity and the host cell nuclear regulatory protein machinery for reactivating HIV-1 and for future investigations to eradicate and cure HIV-1 infection.

San-Huang-Xie-Xin-Tang (SHXXT), one of the most important traditional Chinese medicinal formulas, is comprised by three herbal medicines, the rhizome of Rheum officinale [or Rheum tanguticum (Polygonaceae) (Dahuang in Chinese)], the root of Scutellaria baicalensis (Labiatae) (Huangqin in Chinese), and the rhizome of Coptis chinensis (Ranunculaceae) (Huanglian in Chinese) in the ratios of 2:1:1 or 1:1:1. This study is aimed to quantitate and qualify of SHXXT, by a rapid, convenient, and effective HPLC-PDA approach associated with LC-MS technique. Of which method, nine chosen major bioactive components in SHXXT, including aloe-emodin (Ale), baicalin (Ba), berberine (Be), coptisine (Co), palmatine (Pa), resveratroloside (Res), rhein (Rh), sennoside A (Se-A), and wogonin (Wo), were evaluated within 30 min. The nine chemical markers were monitored in a high sensitivity with a low detection limit of 0.01-0.55 μg/mL and the correlation coefficient of the regression curve revealed a good linearity with R2 > 0.99. Moreover, the extraction solution system and the HPLC elution conditions were also optimized in the present study. This present developed protocol was then successfully applied to quantify nine chemical markers of 10 SHXXT products from eight Taiwanese TCM pharmaceutical companies. In quantitative results, Res was found as the major compound in SHXXT-1~5 and 8 with significantly higher amounts than those in other products, indicating the products SHXXT-1~5 and 8 may use R. tanguticum as the raw material, which possessed a higher concentration of the bioactive composition Res, instead of R. officinale. Simultaneously, Ale, Rh, and Wo were < 2% in these 10 products. Different chemical profiles of commercial products indicated that, probably, each product with the same named formula might be regarded as a sole medicine and need to be investigated individually. Importantly, it is never too much to emphasize the importance of quality control in TCM development.

Antiretroviral (ART) drugs has previously been associated with lipodystrophic syndrome, metabolic consequences, and neuropsychiatric complications. ART drugs include three main classes of protease inhibitors (PIs), nucleoside analog reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our previous work demonstrated that a high risk of hyperlipidemia was observed in HIV-1-infected patients who received ART drugs in Taiwan. Patients receiving ART drugs containing either Abacavir/Lamivudine (Aba/Lam; NRTI/NRTI), Lamivudine/Zidovudine (Lam/Zido; NRTI/NRTI), or Lopinavir/Ritonavir (Lop/Rit; PI) have the highest risk of hyperlipidemia. The aim of this study was to investigate the effects of Aba/Lam (NRTI/NRTI), Lam/Zido (NRTI/NRTI), and Lop/Rit (PI) on metabolic and neurologic functions in mice. Groups of C57BL/6 mice were administered Aba/Lam, Lam/Zido, or Lop/Rit, orally, once daily for a period of 4 weeks. The mice were then extensively tested for metabolic and neurologic parameters. In addition, the effect of Aba/Lam, Lam/Zido, and Lop/Rit on lipid metabolism was assessed in HepG2 hepatocytes and during the 3T3-L1 preadipocyte differentiation. Administration with Aba/Lam caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in leptin serum levels. Administration with Lop/Rit also caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in serum levels of total cholesterol, and HDL-c. Treatment of mice with Aba/Lam and Lop/Rit enhanced the lipid accumulation in the liver, and the decrease in AMP-activated protein kinase (AMPK) phosphorylation and/or its downstream target acetyl-CoA carboxylase (ACC) protein expression. In HepG2 hepatocytes, Aba/Lam, Lam/Zido, and Lop/Rit also enhanced the lipid accumulation and decreased phosphorylated AMPK and ACC proteins. In 3T3-L1 pre-adipocyte differentiation, Aba/Lam and Lop/Rit reduced adipogenesis by decreasing expression of transcription factor CEBPb, implicating the lipodystrophic syndrome. Our results demonstrate that daily oral administration of Aba/Lam and Lop/Rit may produce cognitive, motor, and metabolic impairments in mice, regardless of HIV-1 infection.

Increasing prevalence of allergic diseases with an inadequate variety of treatment drives forward search for new alternative drugs. Fatty acids, abundant in nature, are regarded as important bioactive compounds and powerful nutrients playing an important role in lipid homeostasis and inflammation. Phytochemical study on Typhonium blumei Nicolson and Sivadasan (Araceae), a folk anti-cancer and anti-inflammatory medicine, yielded four oxygenated fatty acids, 12R-hydroxyoctadec-9Z,13E-dienoic acid methyl ester (1) and 10R-hydroxyoctadec-8E,12Z-dienoic acid methyl ester (2), 9R-hydroxy-10E-octadecenoic acid methyl ester (3), and 12R*-hydroxy-10E-octadecenoic acid methyl ester (4). Isolated compounds were identified by spectroscopic methods along with GC-MS analysis. Isolated fatty acids together with a series of saturated, unsaturated and oxygenated fatty acids were evaluated for their anti-inflammatory and anti-allergic activities in vitro. Unsaturated (including docosahexaenoic and eicosapentaenoic acids) as well as hydroxylated unsaturated fatty acids exerted strong anti-inflammatory activity in superoxide anion generation (IC50 2.14-3.73 μM) and elastase release (IC50 1.26-4.57 μM) assays. On the other hand, in the anti-allergic assays, the unsaturated fatty acids were inactive, while hydroxylated fatty acids showed promising inhibitory activity in A23187- and antigen-induced degranulation assays (e.g., 9S-hydroxy-10E,12Z-octadecadienoic acid, IC50 92.4 and 49.7 μM, respectively). According to our results, the presence of a hydroxy group in the long chain did not influence the potent anti-inflammatory activity of free unsaturated acids. Nevertheless, hydroxylation of fatty acids (or their methyl esters) seems to be a key factor for the anti-allergic activity observed in the current study. Moreover, ChemGPS-NP was explored to predict the structure-activity relationship of fatty acids. The anti-allergic fatty acids formed different cluster distant from clinically used drugs. The bioactivity of T. blumei, which is historically utilized in folk medicine, might be related to the content of fatty acids and their metabolites.

Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib's angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected.