Diterpene promptly executes a non-canonical autophagic cell death in doxorubicin-resistant lung cancer.

16-hydroxycleroda-3,13-dien-15,16-olide (HCD) has antitumor activity reported in numerous types of cancers. However, the efficacy of HCD treatment in non-small-cell lung cancer (NSCLC) cells and doxorubicin-resistant (Dox-R)-NSCLC cells remains to be unraveled. The underlying anti-cancer mechanism of HCD on Dox-R and Dox-sensitive (Dox-S) of A549 cells was also investigated. Cytotoxicity of HCD against two cell lines (Dox-S and Dox-R) were determined via MTT assay, flow cytometry, and Western blot. A further examination of its anti-cancer efficacy was performed in A549-bearing xenograft mice via orthotopic intratrachea (IT) inoculation, which showed that HCD could arrest both Dox-S and Dox-R cells at G2/M phase without altering the sub-G1 cycle along with increasing of cleaved-PARP. HCD downregulated the mTOR/Akt/PI3K-p85 and PI3K-ClassIII/Beclin-1 signals and upregulated p62/LC3-I/II expressions to further confirm that the cell autophagy of NSCLC cells after being HCD-induced. Morphological observations of mouse lung sections illustrated that fewer cancer cells accumulated close to the trachea while less neoplastic activities were found in HCD orthotopic treated mice without liver, kidney, and spleen toxicity. Lastly, Dox, HCD, and target therapy medicines of EGFR and ALK were nicely docked with EGFR, ALK, and mTOR. Conclusively, HCD was demonstrated the chemotherapeutic potential regardless of Dox-R and Dox-S cells, suggesting natural autophagic inducer HCD provides a promising lead compound for new drug discovery and development of lung cancer therapies.

Polyphenols, flavonoids and inflammasomes: the role of cigarette smoke in COPD.

COPD is predicted to become the third leading cause of morbidity and mortality worldwide by 2030. Cigarette smoking (active or passive) is one of its chief causes, with about 20% of cigarette smokers developing COPD from cigarette smoke (CS)-induced irreversible damage and sustained inflammation of the airway epithelium. Inflammasome activation leads to the cleavage of pro-interleukin (IL)-1ß and pro-IL-18, along with the release of pro-inflammatory cytokines via gasdermin D N-terminal fragment membrane pores, which further triggers acute phase pro-inflammatory responses and concurrent pyroptosis. There is currently intense interest in the role of nucleotide-binding oligomerisation domain-like receptor family, pyrin domain containing protein-3 inflammasomes in chronic inflammatory lung diseases such as COPD and their potential for therapeutic targeting. Phytochemicals including polyphenols and flavonoids have phyto-medicinal benefits in CS-COPD. Here, we review published articles from the last decade regarding the known associations between inflammasome-mediated responses and ameliorations in pre-clinical manifestations of CS-COPD via polyphenol and flavonoid treatment, with a focus on the underlying mechanistic insights. This article will potentially assist the development of drugs for the prevention and therapy of COPD, particularly in cigarette smokers.

In Silico Approaches to Identify Polyphenol Compounds as α-Glucosidase and α-Amylase Inhibitors against Type-II Diabetes.

Type-II diabetes mellitus (T2DM) results from a combination of genetic and lifestyle factors, and the prevalence of T2DM is increasing worldwide. Clinically, both α-glucosidase and α-amylase enzymes inhibitors can suppress peaks of postprandial glucose with surplus adverse effects, leading to efforts devoted to urgently seeking new anti-diabetes drugs from natural sources for delayed starch digestion. This review attempts to explore 10 families e.g., Bignoniaceae, Ericaceae, Dryopteridaceae, Campanulaceae, Geraniaceae, Euphorbiaceae, Rubiaceae, Acanthaceae, Rutaceae, and Moraceae as medicinal plants, and folk and herb medicines for lowering blood glucose level, or alternative anti-diabetic natural products. Many natural products have been studied in silico, in vitro, and in vivo assays to restrain hyperglycemia. In addition, natural products, and particularly polyphenols, possess diverse structures for exploring them as inhibitors of α-glucosidase and α-amylase. Interestingly, an in silico discovery approach using natural compounds via virtual screening could directly target α-glucosidase and α-amylase enzymes through Monte Carto molecular modeling. Autodock, MOE-Dock, Biovia Discovery Studio, PyMOL, and Accelrys have been used to discover new candidates as inhibitors or activators. While docking score, binding energy (Kcal/mol), the number of hydrogen bonds, or interactions with critical amino acid residues have been taken into concerning the reliability of software for validation of enzymatic analysis, in vitro cell assay and in vivo animal tests are required to obtain leads, hits, and candidates in drug discovery and development.

A nutraceutical combination of cinnamon, purple onion, and tea linked with key enzymes on treatment of type 2 diabetes.

Diabetes mellitus (DM) is concomitant with significant morbidity and mortality and its prevalence is accumulative worldwide. The conventional antidiabetic agents are known to mitigate the symptoms of diabetes; however, they may also cause adverse effects. This study was to explore the efficacy of polyherbal dietary supplement cinnamon, purple onion, and tea on the mediation of postprandial hyperglycemia in the search of combinations with a maximal response. A starch solution (3 g/kg Bwt) of oral starch tolerance test (OSTT) and glucose solution (4 g/kg Bwt) of oral glucose tolerance test (OGTT) with and without cinnamon, purple onion, tea extract (15 mg/kg Bwt), and mixture (each 5 mg/kg Bwt, 1:1:1), metformin (14 mg/kg Bwt), or acarbose (50 mg/kg Bwt) was administered to high fat plus high fructose-induced diabetic mice after an overnight fast. Postprandial plasma glucose levels were measured and changed areas under the response curve were calculated to find out the maximal efficacy of optimal polyherbal combinations. Compared with acarbose, the mixture of extracts (purple onion, cinnamon, and tea) indicated the decreasing blood glucose in OSTT. In OGTT, the mixture of extracts showed greater efficacy for hypoglycemia when compared with metformin. The molecular docking of α-amylase, α-glucosidase, and AMPK was further confirmed the putatively acting molecules from the extracts of purple onion, cinnamon, and tea. Overall, this investigation evidenced a beneficial mediation for the progression of lowering blood glucose with a combinatory extract of cinnamon, dietary onion, and tea, implicating their prospective as nutraceuticals that might ameliorate hyperglycemia in diabetes. PRACTICAL APPLICATIONS: Diabetes mellitus (DM), one of metabolic syndrome, attributes to risk factors like obesity, physical inactivity, ageing, life style, and genetic predisposition even with significant morbidity and mortality. DM is increasing and accounts for an estimated annual medical expenditure of US$ 827 billion worldwide. Therefore, maintaining blood glucose levels within the normal range is critical for preventing diabetes and its co-morbidities. The conventional antidiabetic agents are known to mitigate the symptoms of diabetes; nevertheless, they may also cause adverse or side effects. In an effort to design novel and well-tolerated solutions to halt the progression of DM, however evidence-base is extremely limited regarding the efficacy of polyherbal dietary supplement individual herbs for the management of glycemia. In this investigation evidenced a beneficial mediation for the progression of lowering blood glucose with a combinatory extract of cinnamon, dietary onion, and tea, implicating their prospective as nutraceuticals that might ameliorate hyperglycemia in diabetes.

Mangosteen xanthone γ-mangostin exerts lowering blood glucose effect with potentiating insulin sensitivity through the mediation of AMPK/PPARγ.

Diabetes mellitus (DM) is concomitant with significant morbidity and mortality and its prevalence is accumulative in worldwide. The conventional antidiabetic agents are known to mitigate the symptoms of diabetes; however, they may also cause side and adverse effects. There is an imperative necessity to conduct preclinical and clinical trials for the discovery of alternative therapeutic agents that can overcome the drawbacks of current synthetic antidiabetic drugs. This study aimed to investigate the efficacy of lowering blood glucose and underlined mechanism of γ-mangostin, mangosteen (Garcinia mangostana) xanthones. The results showed γ-Mangostin had a antihyperglycemic ability in short (2 h)- and long-term (28 days) administrations to diet-induced diabetic mice. The long-term administration of γ-mangostin attenuated fasting blood glucose of diabetic mice and exhibited no hepatotoxicity and nephrotoxicity. Moreover, AMPK, PPARγ, α-amylase, and α-glucosidase were found to be the potential targets for simulating binds with γ-mangostin after molecular docking. To validate the docking results, the inhibitory potency of γ-mangostin againstα-amylase/α-glucosidase was higher than Acarbose via enzymatic assay. Interestingly, an allosteric relationship between γ-mangostin and insulin was also found in the glucose uptake of VSMC, FL83B, C2C12, and 3T3-L1 cells. Taken together, the results showed that γ-mangostin exerts anti-hyperglycemic activity through promoting glucose uptake and reducing saccharide digestion by inhibition of α-amylase/α-glucosidase with insulin sensitization, suggesting that γ-mangostin could be a new clue for drug discovery and development to treat diabetes.

Pharmacological properties and underlying mechanisms of curcumin and prospects in medicinal potential.

Curcumin, isolated from Curcuma longa L., is a fat-soluble natural compound that can be obtained from ginger plant tuber roots, which accumulative evidences have demonstrated that it can resist viral and microbial infection and has anti-tumor, reduction of blood lipid and blood glucose, antioxidant and removal of free radicals, and is active against numerous disorders various chronic diseases including cardiovascular, pulmonary, neurological and autoimmune diseases. In this article is highlighted the recent evidence of curcuminoids applied in sevral aspects of medical problem particular in COVID-19 pandemics. We have searched several literature databases including MEDLINE (PubMed), EMBASE, the Web of Science, Cochrane Library, Google Scholar, and the ClinicalTrials.gov website via using curcumin and medicinal properties as a keyword. All studies published from the time when the database was established to May 2021 was retrieved. This review article summarizes the growing confirmation for the mechanisms related to curcumin's physiological and pharmacological effects with related target proteins interaction via molecular docking. The purpose is to provide deeper insight and understandings of curcumin's medicinal value in the discovery and development of new drugs. Curcumin could be used in the prevention or therapy of cardiovascular disease, respiratory diseases, cancer, neurodegeneration, infection, and inflammation based on cellular biochemical, physiological regulation, infection suppression and immunomodulation.

Garcinia linii extracts exert the mediation of anti-diabetic molecular targets on anti-hyperglycemia.

Different portions (stem GIS and leaf GIL) of Garcinia linii were extracted by ethanol/water and crude extracts were employed to investigate the contents of total phenol and flavonoids, antioxidation activities, and inhibitory activities of α-amylase and α-glucosidase via enzymatic assay and OGTT and OSTT for lowering glucose levels. The data revealed that GlS and GlL contained different levels of flavonoids and total phenol. Furthermore, the results showed the extracts exhibited remarkable antioxidation activities and inhibitory activities of α-amylase and α-glucosidase. In silico docking studies were done using Gold software and the probable molecules retrieved from PubChem were docked with several anti-diabetic relate targets, the results showed several components of G. linii could potentially inhibit diabetic molecules when compared with clinic drugs. The cell glucose uptake data also confirmed that GlL and GlS could retain the active component in the regulation of insulin, AMPK, PPARγ, and DPP4. In vivo, the evidence showed G. linii extracts including syringaldehyde suppressed effect of hyperglycemia on OSTT and OGTT assays. These results suggest that G. linii extract has a potential therapeutic value for the treatment of diabetes in humans.

Antrodia cinnamomea is a potentially effective complementary medicine for adjuvant therapy against breast cancer with bone metastasis: A case report.

RATIONALE: Palbociclib (PAL) is a first-in-class selective inhibitor of the cyclin-dependent kinases 4 (CDK4) and CDK6 and is indicated for the treatment of hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in combination with fulvestrant (FUL) in postmenopausal women. Antrodia cinnamomea (AC), a well-known Chinese folk medicine in Taiwan, possesses numerous biological capabilities, most notably an anti-tumor effect. However, the clinical use of AC as complementary medicine combined with adjuvant therapy is unexplored. In this case report, we evaluated AC combined with PAL plus FUL to reduce the tumor burden in an MBC patient. PATIENT CONCERNS: A Slovenian woman diagnosed with relapsed bone metastases of breast cancer (BC) was unable to undergo surgery and refused radiation therapy due to fear of side effects; she also feared the side effects of adjuvants. However, she was eager to live with a high quality of life. DIAGNOSIS: Stage IV, HR-positive/HER2-negative BC with relapse of bone metastases. INTERVENTIONS: After diagnosis of relapse of bone metastases, she received adjuvant with PAL plus FUL. Additionally, she chose to take AC orally (10 g/d). OUTCOMES: The pain was mostly relieved, and the side effects of adjuvant therapy reduced. Magnetic resonance imaging revealed reduction of tumor size at the fifth month of adjuvant therapy plus AC. After 14 months of adjuvant therapy plus AC, the tumors at the thoracic vertebrae T1 and T3 were found to have shrunk from 35.2 and 12.0 mm to 28.1 and 9.9 mm, respectively. Remarkably, no further metastases were observed. LESSONS: According to the circulating tumor cells (CTCs) test data, AC had better anti-tumor efficacy on active tumor cells than PAL plus FUL. Thus, AC could be an effective complementary medicine for adjuvant therapy in patients with HR-positive/HER2-negative MBC. Interestingly, continued elevation of carcinoma antigen 15-3 and lactate dehydrogenase levels but decreasing levels of alkaline phosphatase were observed, which may be indicative of the potent efficacy of treatment resulting in massive tumor cell death. The CTCs test may be a sensitive approach to monitor the progression of BC and subsequently evaluate the efficiency of therapy.

Optimization of Ultrasound-Assisted Extraction of Flavonoids from Celastrus hindsii Leaves Using Response Surface Methodology and Evaluation of Their Antioxidant and Antitumor Activities.

Celastrus hindsii is a potential source of flavonoids with biological activities. This study aimed to develop an ultrasound-assisted technique for extracting flavonoids from leaves of C. hindsii. Response surface methodology was employed to optimize the extraction conditions for maximizing the total flavonoid content (TFC). A maximum TFC of 23.6 mg QE/g was obtained under the extraction conditions of ultrasonic power of 130 W, extraction temperature of 40°C, extraction time of 29 min, and ethanol concentration of 65%. The flavonoid-rich extracts were then studied for their antioxidant and anticancer activities. The results showed that the C. hindsii leaf extract exhibited potent radical scavenging activities against DPPH (IC50 of 164.85 µg/mL) and ABTS (IC50 of 89.05 µg/mL). The extract also significantly inhibited the growth of 3 cancer cell lines MCF7, A549, and HeLa with the IC50 values of 88.1 µg/mL, 120.4 µg/mL, and 118.4 µg/mL, respectively. Notably, the extract had no cytotoxicity effect on HK2 normal kidney cell line. This study suggests that flavonoid-rich extract is a promising antioxidant and anticancer agent and that ultrasound-assisted extraction is an efficient method for extracting flavonoids from C. hindsii leaves.

Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence.

Traditional chemotherapy is being considered due to hindrances caused by systemic toxicity. Currently, the administration of multiple chemotherapeutic drugs with different biochemical/molecular targets, known as combination chemotherapy, has attained numerous benefits like efficacy enhancement and amelioration of adverse effects that has been broadly applied to various cancer types. Additionally, seeking natural-based alternatives with less toxicity has become more important. Experimental evidence suggests that herbal extracts such as Solanum nigrum and Claviceps purpurea and isolated herbal compounds (e.g., curcumin, resveratrol, and matairesinol) combined with antitumoral drugs have the potential to attenuate resistance against cancer therapy and to exert chemoprotective actions. Plant products are not free of risks: Herb adverse effects, including herb-drug interactions, should be carefully considered. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.

Clerodane Diterpene Ameliorates Inflammatory Bowel Disease and Potentiates Cell Apoptosis of Colorectal Cancer.

Inflammatory bowel disease (IBD) is general term for ulcerative colitis and Crohn's disease, which is chronic intestinal and colorectal inflammation caused by microbial infiltration or immunocyte attack. IBD is not curable, and is highly susceptible to develop into colorectal cancer. Finding agents to alleviate these symptoms, as well as any progression of IBD, is a critical effort. This study evaluates the anti-inflammation and anti-tumor activity of 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) in in vivo and in vitro assays. The result of an IBD mouse model induced using intraperitoneal chemical azoxymethane (AOM)/dextran sodium sulfate (DSS) injection showed that intraperitoneal HCD adminstration could ameliorate the inflammatory symptoms of IBD mice. In the in vitro assay, cytotoxic characteristics and retained signaling pathways of HCD treatment were analyzed by MTT assay, cell cycle analysis, and Western blotting. From cell viability determination, the IC50 of HCD in Caco-2 was significantly lower in 2.30 µM at 48 h when compared to 5-fluorouracil (5-FU) (66.79 µM). By cell cycle and Western blotting analysis, the cell death characteristics of HCD treatment in Caco-2 exhibited the involvement of extrinsic and intrinsic pathways in cell death, for which intrinsic apoptosis was predominantly activated via the reduction in growth factor signaling. These potential treatments against colon cancer demonstrate that HCD could provide a promising adjuvant as an alternative medicine in combating colorectal cancer and IBD.

Exploring a New Natural Treating Agent for Primary Hypertension: Recent Findings and Forthcoming Perspectives.

Primary hypertension describes abnormally-high systolic/diastolic blood pressure in a resting condition caused by various genetic or environmental risk factors. Remarkably, severe complications, such as ischemic cardiovascular disease, stroke, and chronic renal disease have led to primary hypertension becoming a huge burden for almost one-third of the total population. Medication is the major regimen for treating primary hypertension; however, recent medications may have adverse effects that attenuate energy levels. Hence, the search for new hypotensive agents from folk or traditional medicine may be fruitful in the discovery and development of new drugs. This review assembles recent findings for natural antihypertensive agents, extracts, or decoctions published in PubMed, and provides insights into the search for new hypotensive compounds based on blood-pressure regulating mechanisms, including the renin-angiotensin-aldosterone system and the sympathetic/adrenergic receptor/calcium channel system.

The Exploration of Natural Compounds for Anti-Diabetes from Distinctive Species Garcinia linii with Comprehensive Review of the Garcinia Family.

Approximately 400 Garcinia species are distributed around the world. Previous studies have reported the extracts from bark, seed, fruits, peels, leaves, and stems of Garcinia mangostana, G. xanthochymus, and G. cambogia that were used to treat adipogenesis, inflammation, obesity, cancer, cardiovascular diseases, and diabetes. Moreover, the hypoglycemic effects and underlined actions of different species such as G. kola, G. pedunculata, and G. prainiana have been elucidated. However, the anti-hyperglycemia of G. linii remains to be verified in this aspect. In this article, the published literature was collected and reviewed based on the medicinal characteristics of the species Garcinia, particularly in diabetic care to deliberate the known constituents from Garcinia and further focus on and isolate new compounds of G. linii (Taiwan distinctive species) on various hypoglycemic targets including α-amylase, α-glucosidase, 5'-adenosine monophosphate-activated protein kinase (AMPK), insulin receptor kinase, peroxisome proliferator-activated receptor gamma (PPARγ), and dipeptidyl peptidase-4 (DPP-4) via the molecular docking approach with Gold program to explore the potential candidates for anti-diabetic treatments. Accordingly, benzopyrans and triterpenes are postulated to be the active components in G. linii for mediating blood glucose. To further validate the potency of those active components, in vitro enzymatic and cellular function assays with in vivo animal efficacy experiments need to be performed in the near future.

Antrodia Cinnamomea Prolongs Survival in a Patient with Small Cell Lung Cancer.

Introduction: Antrodia cinnamomea (AC) is an extremely rare medicinal fungus native to forested regions of Taiwan. It possesses numerous biological activities, especially anti-tumor effects shown in various in vitro cancer cells and in vivo animal models. However, there are few clinical reports about AC as a treatment for cancer patients. This report attempts to demonstrate the therapeutic effect of dish-cultured AC (DAC) on a small cell lung cancer (SCLC) patient taken orally for an extended duration. Patient concerns: An 88-year-old male with a history of diabetes mellitus and hypertension visited the outpatient department with the symptoms of dyspnea and a cough for two weeks. After a diagnosis of SCLC, the patient declined both chemotherapy and radiotherapy because of the side effects and only accepted supportive care without additional therapy. Diagnosis: Limited-stage SCLC (T4N2M1a, stage IV) after the chest radiograph, computed tomography-guided biopsy, and pathological diagnosis. Interventions: The patient was prescribed DAC with an increasing dosage, from 5 g/d up to 10 g/d DAC, for six months, without radiation or chemotherapy treatment. Outcomes: DAC caused the tumor to shrink substantially. Surprisingly, the patient survived for 32 months without relapse after six months of DAC treatment. Laboratory examinations indicated that the patient's health had improved significantly, reverting to near normal levels. Notably, he had a good quality of life with a high Barthel index score. Unfortunately, this patient died of septic shock caused by acute cholangitis. Conclusion: DAC may exert an anti-cancer effect, which can lead to tumor regression. This is supposed to be achieved by the combined DAC's immunomodulatory, anti-angiogenic, anti-metastatic, anti-proliferative, and pro-apoptotic effects mediated through multiple signaling pathways. We propose that DAC can be used as a complementary medicine to prolong the life expectancy and improve the life quality of SCLC patients.

Effects of Sting Plant Extracts as Penetration Enhancers on Transdermal Delivery of Hypoglycemic Compounds.

Background and objectives: The percutaneous route is an interesting and inventive investigation field of drug delivery. However, it is challenging for drug molecules to pass through the skins surface, which is a characterized by its permeability barrier. The purpose of this study is to look at the effect of some penetration enhancers on in vivo permeation of insulin and insulin sensitizers (curcumin and rutin) through diabetes-induced mouse skin. Materials and Methods: Sting crude extracts of Dendrocnide meyeniana, Urtica thunbergiana Sieb. and Zucc, and Alocasia odora (Lodd.) Spach were used as the penetration enhancers. Mouse skin irritation was tested by smearing the enhancers for the measurements at different time points and the cell viability of the HaCaT human skin keratinocytes, which was determined by Trypan blue exclusion and MTT assays to evaluate human biosafety for these extracts after the mouse skin permeation experiments. Results: All enhancers induced a slight erythema without edema on the mouse skin that completely recovered after 6 h from the enhancer smears as compared with normal mouse skin. Furthermore, no damaged cells were found in the HaCaT keratinocytes under sting crude extract treatments. The blood sugar level in the diabetic mice treated with the insulin or insulin sensitizers, decreased significantly (p < 0.05) in the presence of enhancers. The area under the curve (AUC) values of transdermal drug delivery (TDD) ranged from 42,000 ± 5000 mg/dL x min without enhancers, to 30,000 ± 2000 mg/dL x min in the presence of enhancers. Conclusions: This study exhibited that natural plant extracts could be preferred over the chemically synthesized molecules and are safe and potent penetration enhancers for stimulating the transdermal absorption of drugs.

Plantago asiatica Seed Extracts Alleviated Blood Pressure in Phase I⁻Spontaneous Hypertension Rats.

Arterial pressure of each new breeding spontaneous Phase-1 hypertension (P1-HT) rat was recorded for 5 min by intravascular femoral artery catheter that served as a reference value prior to treatment. In the acute antihypertensive test, 0.36 g/kg Bwt of Plantago asiatica seed extract (PSE) was administered, via gavage feeding, to P1-HT rats, and the arterial pressures were continuously recorded for 1 h. The acute antihypertensive effects of PSE on P1-HT rats appeared within 15 min after PSE administration and lasted over 1 h with systolic pressure decreased 31.5 mmHg and diastolic pressure decreased 18.5 mmHg. The systolic pressure decreased 28 mmHg and diastolic pressure decreased 16 mmHg in P1-HT rats when simultaneously compared with verapamil hydrochloride (reference drug), whereas there were no significant differences in the pretreated reference values of acute PSE treatment and the untreated control. In the chronic test, P1-HT rats received 0.36 g/kg Bwt day of PSE or equal volume of water for 4 weeks via oral gavage, and the lower blood pressure tendencies of chronic PSE treatment were also found when compared with the controls. The antihypertensive values of PSE were also confirmed in spontaneously hypertensive rats (SHRs). Oral administration with PSE can effectively moderate blood pressure within an hour, while taking PSE daily can control the severity of hypertension, suggesting PSE is a potentially antihypertensive herb.

Polyalthia Clerodane Diterpene Potentiates Hypoglycemia via Inhibition of Dipeptidyl Peptidase 4.

Serine protease dipeptidyl peptidase 4 (DPP-4) is involved in self/non-self-recognition and insulin sensitivity. DPP-4 inhibitors are conventional choices for diabetic treatment; however, side effects such as headache, bronchus infection, and nasopharyngitis might affect the daily lives of diabetic patients. Notably, natural compounds are believed to have a similar efficacy with lower adverse effects. This study aimed to validate the DPP-4 inhibitory activity of clerodane diterpene 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) from Polyalthia longifolia, rutin, quercetin, and berberine, previously selected through molecular docking. The inhibitory potency of natural DPP-4 candidates was further determined by enzymatic, in vitro Caco-2, and ERK/PKA activation in myocyte and pancreatic cells. The hypoglycemic efficacy of the natural compounds was consecutively analyzed by single-dose and multiple-dose administration in diet-induced obese diabetic mice. All the natural-compounds could directly inhibit DPP-4 activity in enzymatic assay and Caco-2 inhibition assay, and HCD showed the highest inhibition of the compounds. HCD down-regulated LPS-induced ERK phosphorylation in myocyte but blocked GLP-1 induced PKA expression. For in vivo tests, HCD showed hypoglycemic efficacy only in single-dose administration. After 28-days administration, HCD exhibited hypolipidemic and hepatoprotective efficacy. These results revealed that HCD performed potential antidiabetic activity via inhibition of single-dose and long-term administrations, and could be a new prospective anti-diabetic drug candidate.

Nanoparticle-conjugated nutraceuticals exert prospectively palliative of amyloid aggregation.

Alzheimer's disease (AD), an age-related neurodegenerative disease, the most common causes of dementia is a multifactorial pathology categorized by a complex etiology. Numerous nutraceuticals have been clinically evaluated, but some of the trials failed. However, natural compounds have some limitations due to their poor bioavailability, ineffective capability to cross the blood-brain barrier, or less therapeutic effects on AD. To overcome these disadvantages, nanoparticle-conjugated natural products could promote the bioavailability and enhance the therapeutic efficacy of AD when compared with a naked drug. This application generates and implements new prospect for drug discovery in neurodegenerative diseases. In this article, we confer AD pathology, review natural products in clinical trials, and ascertain the importance of nanomedicine coupled with natural compounds for AD.

Natural Compounds from Herbs that can Potentially Execute as Autophagy Inducers for Cancer Therapy.

Accumulated evidence indicates that autophagy is a response of cancer cells to various anti-cancer therapies. Autophagy is designated as programmed cell death type II, and is characterized by the formation of autophagic vacuoles in the cytoplasm. Numerous herbs, including Chinese herbs, have been applied to cancer treatments as complementary and alternative medicines, supplements, or nutraceuticals to dampen the side or adverse effects of chemotherapy drugs. Moreover, the tumor suppressive actions of herbs and natural products induced autophagy that may lead to cell senescence, increase apoptosis-independent cell death or complement apoptotic processes. Hereby, the underlying mechanisms of natural autophagy inducers are cautiously reviewed in this article. Additionally, three natural compounds-curcumin, 16-hydroxycleroda-3,13-dien-15,16-olide, and prodigiosin-are presented as candidates for autophagy inducers that can trigger cell death in a supplement or alternative medicine for cancer therapy. Despite recent advancements in therapeutic drugs or agents of natural products in several cancers, it warrants further investigation in preclinical and clinical studies.

16-hydroxy-cleroda-3,13-dien-16,15-olide induced glioma cell autophagy via ROS generation and activation of p38 MAPK and ERK-1/2.

16-hydroxy-cleroda-3,13-dien-16,15-olide (HCD), a natural product isolated from medicinal plant Polyalthia longifolia exhibits anticancer activity through caspase-independent apoptosis in brain tumors, as previously reported. This study further attempted to investigate the involvement of HCD-induced autophagy in brain tumor cell lines neuroblastoma N18 and glioma C6 through the induction of reactive oxygen species (ROS) and the activation of p38 and ERK-1/2 pathway. The results demonstrated that HCD increased the hyper-generation of ROS and decreased cellular antioxidant enzymes, such as superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), and glutathione s transferase (GST). Furthermore, HCD increased the expressions of autophagic marker proteins LC3-II and Beclin-1 in a time- and dose-dependent manner. Additionally, HCD was found to significantly induce p-p38 MAPK and p-ERK-1/2 proteins by Western blot, which implies that HCD is a potential therapeutic anticancer agent that exerts its activity through inducing ROS-mediation for the autophagy of brain tumor cells.