HIV/AIDS Curability Study, Different Approaches and Drug Combination.

AIM: HIV infection is currently an incurable disease characterized by life-long drug utility. Its incurable causality and mechanism are still unknown to us. METHODS: To overcome this therapeutic setback, some breakthroughs should be made by utilizing different approaches. How to plan some experimental and clinical novelty for HIV curability is a modern challenge. In this article, new ideas and approaches for global HIV/AIDS therapeutic strategies are proposed and represented by scientific insights. RESULTS: Pharmaceutical characteristics, herbal medicine, novel drug targets, cutting-edge biotherapy, drug combination, animal modalities, and immune-stimuli for HIV latency, as well as clearance, are highlighted. DISCUSSION: To elucidate our understanding of curative treatment for HIV/AIDS, many new pathological discoveries, expansion, technical advances, and potential drug targets are constructed. After the discovery of novel pathogenesis and therapeutic evolution, HIV/AIDS therapeutic curability may become achievable and a reality. CONCLUSION: Transformation from animal model investigation to widespread therapies for larger volume of human population is a necessity in modern medicine. In this infectious treatment scenario, major breakthroughs in medicine and drug development are anticipated.

Drug Sensitivity Testing for Cancer Therapy, Key Areas.

AIMS: Cancer is a high-mortality disease (9.6 million deaths in 2018 worldwide). Given various anticancer drugs, drug selection plays a key role in patient survival in clinical trials. METHODS: Drug Sensitivity Testing (DST), one of the leading drug selective systems, was widely practiced for therapeutic promotion in the clinic. Notably, DSTs assist in drug selection that benefits drug responses against cancer from 20-22% to 30-35% over the past two decades. The relationship between drug resistance in vitro and drug treatment benefits was associated with different tumor origins and subtypes. Medical theory and underlying DST mechanisms remain poorly understood until now. The study of the clinical scenario, sustainability and financial support for mechanism and technical promotions is indispensable. RESULTS: Despite the great technical advance, therapeutic prediction and drug selection by DST needs to be miniature, versatility and cost-effective in the clinic. Multi-parameters and automation of DST should be a future trend. Advanced biomedical knowledge and clinical approaches to translating oncologic profiles into drug selection were the main focuses of DST developments. With a great technical stride, the clinical architecture of the DST platform was entering higher levels (drug response testing at any stage of cancer patients and miniaturization of tumor samples). DISCUSSION: The cancer biology and pharmacology for drug selection mutually benefit the clinic. New proposals to reveal more therapeutic information and drug response prediction at genetic, molecular and omics levels should be estimated overall. CONCLUSION: By upholding this goal of non-invasive, versatility and automation, DST could save the life of several thousand annually worldwide. In this article, new insights into DST novelty and development are highlighted.

[Study on Ranunculaceae herbal decoction pieces using X-ray diffraction].

The powder X-ray diffraction(PXRD) technique was used to investigate fourteen kinds of Ranunculaceae herbal decoction pieces(RHDP) recorded in Chinese Pharmacopoeia and to explore a novel PXRD quality control method for RHDP. The results indicated that only three RHDP-Paeoniae Radix Alba, Paeoniae Radix Rubra, and Moutan Cortex, contained calcium oxalate monodydrate(COM), whereas no COM existed in other eleven kinds of RHDP. The difference in PXRD for Paeoniae Radix Alba and Paeoniae Radix Rubra from different growing areas were investigated. The quantitative analysis method for COM was discussed by considering the water-boiling manufacturing process of herbal decoction pieces. The water-boiling experiments revealed that the PXRD peaks from COM crystals in RHDP were enhanced significantly after boiling. Paeoniae Radix Alba, Paeoniae Radix Rubra, Moutan Cortex, Aconiti Lateralis Radix Praeparata, Aconiti Radix, Aconiti Kusnezoffii Radix, and Anemone Raddeanae Rhizoma exhibited a similar series of broader peaks in the 2θ region of 15° to 35°, whose origins were discussed on the basis of chemical constituents RHDP reported by other researchers. These diffraction broader peaks most likely originated from periodic orientation of benzene ring in organic molecular crystals of aconitine-and paeonolum-based alkaloids and glycosides chemical constituents, subsequently, possibly from some other organic constituents. The PXRD technique can be used to rapidly identify Cimicifuga heracleifolia with an amorphous dispersion peak and C. dahurica with a sharp-peak feature. Climatidis Radix et Rhizoma exhibited a series of sharp PXRD peaks. The PXRD method can provide a valuable quality control method for RHDP.

Ebola Therapeutic Study and Future Directions.

The constant Ebola epidemic outbreaks in Africa arisen in waves of panic worldwide. There is a high mortality rate (30-70%) among the Ebola-infected people in virus- stricken areas. Despite these horrors, the medical capabilities against this deadly viral disease were provided by limited therapeutic agents/options. As a result, several patented agents, biotherapies or prophylactic/therapeutic vaccines need to be reviving into the global markets-including patents of small molecular chemicals, short sequences or oligomers of DNA/RNA, linkages of chemicals with bio-molecules, herbal medicine and so on. In addition, the possible mechanisms of action of these therapeutic options are underway. To promote Ebola biomedical study, the multiple characters of Ebola infections-its origin, pathologic progress, genomic changes, therapeutic context and economic considerations are outlined in this review. Finally, a great difference can be expected after these types of efforts.

HIV/AIDS Curable Study: New Forms of Therapeutic Trinity.

BACKGROUND AND AIMS: AIDS (acquired immune deficient syndrome), a deadly human infectious disease is caused by HIV (human immunodeficiency viruses) infection. Patient's mortality was eventually reduced to one-fourth by combined chemotherapy (usually 3 chemical drugs simultaneously) than earlier HIV/AIDS treatments (single drug or vaccine) in the clinic. RESULTS: Combined treatments against HIV/AIDS are still incurable for all patients despite a high rate of patient's survival. Basic viral pathological study and advancing drug development systems for curable medications are indispensable nowadays and in the future. CONCLUSION: Up to date, therapeutic trinity (combined therapy) against HIV/AIDS is generally among chemical drugs. In this article, several forms of other therapeutic attempts for effectively curing efforts against HIV/AIDS are proposed-including the development of next generation therapeutic HIV vaccines and schedules, new categories of bio-therapy, different pathways of immune-modulation, herbal medicines in general (allopathic, Ayurveda and traditional Chinese medicines), high quality of physical exercises, and especially therapeutic combinations guided by latest medical discovery and principles (new forms of therapeutic trinity against HIV-induced pathogenesis and human mortality).

Drug Combination in Clinical Cancer Treatments.

AIM: The modality of anticancer drug combinations needs to be renovated from empirical into technical-supportive systems. METHODS: To challenge past therapeutic routines, the new landscape may be established. Among the different areas of anticancer drug combination study, research in the fields of medical study is the most important one-including disciplinary of therapeutics in different cancer stages, modern genetic/ molecular diagnostics, cancer bioinformatics, traditional Chinese medicine, mathematical data analysis, therapeutic toxicity monitor, personalized cancer medicine and so on. DISCUSSION: This article addresses these types of cancer therapeutic management systems for clinical anticancer drug combination utilities. CONCLUSION: Future cancer drug combinational studies and clinical optimums must be implemented.

Anthocyanins: Multi-Target Agents for Prevention and Therapy of Chronic Diseases.

Anthocyanins, a flavonoid class of polyphenols, are water soluble dark colored natural pigments found in fruits and vegetables. Owing to their wide distribution in plant materials, dietary consumption of anthocyanins is high compared to other flavonoids. Anthocyanins, due to their multifaceted medicinal properties are the active components in many herbal folk medicines. As in vitro and in vivo results, animal models, and clinical trials in various cell lines suggest, anthocyanins possess antioxidant, antidiabetic, antihyperlipidemic, anti-inflammatory, anticarcinogenic, antiulcer, and preventive activities against cardiovascular diseases. Additionally, anthocyanins exhibit chemotherapeutic, cardioprotective, hepatoprotective, and neuroprotective activities. In the diet, anthocyanins are absorbed in the stomach and intestinal cells and rapidly detected in the plasma. These promising properties of anthocyanins may well provide health benefits against chronic diseases.

Antimetastatic activities and mechanisms of bisdioxopiperazine compounds.

Bisdioxopiperazine (Biz) compounds, including ICRF-154 and razoxane (ICRF-159, Raz), are anticancer agents developed in the UK specifically targeting tumor metastases. Further three bisdioxopiperazine derivatives, bimolane (Bim), probimane (Pro) and MST-16, have been synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, PR China after 1980. Since metastases, the prevailing deadliest pathologic feature of cancer in clinics, have been the main obstacle in cancer therapy, antimetastatic effects and mechanisms of Biz compounds are interesting and significant topics of all time for researchers undergoing the investigations of metastases biology, treatments and patho-physiology. This review addresses and highlights the different inhibitions against metastases in vivo and molecular mechanisms in vitro of Biz compounds especially relating to the inhibitions of tumor metastasis including pathways of inhibitions against angiogenesis, topoisomerase II, calmodulin, sialic acid, fibrinogen, cell-movement and so on. We argue hererin that the systematic exploration of antimetastatic activity and mechanisms of Biz compounds seems to be a shortcut for a final solution of cancer therapy in the future.

Cell biological manifestations of bisdioxopiperazines treatment of human tumor cell lines in culture.

British developed Bisdioxopiperazine compound (Biz compounds) {ICRF-159 or ICRF-187 (razoxane, Raz)} which was the first agent ever to be observed inhibiting and controlling the spontaneous pulmonary metastases of murine Lewis Lung Carcinoma (LLC) tumor model worldwide. Since 1980, two new Biz compounds {probimane (Pro, AT-2153, MST-2) and MST-16} have been synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, PR China, based on structural modifications from British developed Biz compounds. Despite some similarities and differences of structural and pharmacological activities observed between Raz, Pro and MST-16, the systematic comparisons of their pharmacological activities and mechanisms, especially on neoplasm metastases, are still much needed. This work demonstrates that Biz compounds may inhibit tumor cell migration in vitro through a Matrigel-Coated Transwell plate assay and a wound-healing assay by using three human mammary tumor cell lines (MDA-MB-231, MDA-MB-435 and MDA-MB-468). Pro, ICRF-187 and MST-16 affect the network of actin assembly. We conclude that Biz compounds might inhibit neoplasm metastases via affecting a cascade of GTPases, cell skeleton polarizations and cell movements.

Anticancer activities and mechanisms of bisdioxopiperazine compounds probimane and MST-16.

Bisdioxopiperazine compounds, including ICRF-154 and razoxane (ICRF-159, Raz), are anticancer agents developed in the UK specifically targeting tumor metastases. Further two bisdioxopiperazine derivatives, probimane (Pro) and MST-16, have been synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, PR China after 1980. Anticancer activities and mechanisms of Pro and MST-16 compared with Raz, especially for antiproliferative and antimetastatic effects in vivo and in vitro, have been systematically evaluated in this lab as well as by other authors in China. Novel molecular mechanisms especially relating to the inhibition of tumor metastasis between probimane and razoxane have been especially explored and explained, including pathways of inhibitions against calmodulin, sialic acid, lipoperoxidation, fibrinogen, cell-movement and the cell-cycle arrest. The distributions and excretions of (14)[C]-Pro in mice have been carefully monitored long before for explaining the relationship of pharmacological data between in vitro and in vivo evaluations. Pro is more soluble in water and more strongly active against tumors than Raz. In our point of view, Pro seems to inherit and retain most of the targets and pathways of other bisdioxopiperazine compounds currently in use and is cytotoxically more potent than the rest of bisdioxopiperazine compounds. Therefore, there is a great potential and significance for further investigations.

Medicinal chemistry of probimane and MST-16: comparison of anticancer effects between bisdioxopiperazines.

Bisdioxopiperazines, including ICRF-154 and razoxane (ICRF-159, Raz), are a family of anticancer agents developed in the UK, specifically targeting neoplastic metastases. Two other bisdioxopiperazine derivatives, probimane (Pro) and MST-16, were synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. In order to determine the similarities and differences between these agents in medical chemistry, we evaluated the anti-tumor and anti-metastatic effects of Pro and MST-16 in vitro and in vivo against a number of human tumor cell lines and one of murine origin (Lewis lung carcinoma, LLC), and one human tumor xenograft (LAX-83) in nude mice. Our results show that Pro was cytotoxic to human tumor cell lines in vitro (IC50 < 50 microM for 48 h), approximately 3 to 20-fold more than MST-16. Pro and MST-16 manifested more prolonged cytotoxicity than some other first-line anticancer drugs including 5-fluorouacil, vincristine and doxorubicin, and maintain their cytotoxic effects for 4 days in vitro. In animal experiments, Pro and Raz were active against primary tumor growth (35-50 %) and significantly inhibited pulmonary metastasis of LLC (inhibition > 90 %) at dosage below LD(5). Both Raz and Pro were effective in administration schedules of 1, 5 and 9 days. Both Raz (25-32 %) and Pro (55-60 %) caused statistically significant inhibition of the growth of LAX 83 (a human lung adeno-carcinoma xenograft) in nude mice. In this model, Pro was more effective against LAX83 than Raz at equitoxic dosages. These findings suggest that Pro is active against more categories of tumors both in vivo and in vitro, which in some circumstances may make it superior to the currently-used anticancer bisdioxopiperazines, including razoxane and MST-16.

Individualized cancer chemotherapy integrating drug sensitivity tests, pathological profile analysis and computational coordination - an effective strategy to improve clinical treatment.

BACKGROUND: Most current cancer chemotherapy is unsatisfactory. There is a trend towards changing the norm for drug selection; one approach is to seek individualized cancer chemotherapy (ICC). METHODS AND RESULTS: ICC is an approach to maximizing the efficacy of chemotherapy and reducing its adverse effects to a minimum. It involves choosing anticancer drugs through the following critical steps: (i) performing drug sensitivity tests in vivo and/or in vitro; (ii) analyzing pathogenic information from morphology, histology and bioinformatics, so that targeted therapy can be offered to disrupt the escalating tumorigenic molecules and pathways; (iii) introducing mathematical and computational systems to assist in improving the quality of decision-making. CONCLUSION: Increasing clinical evidence indicates that drug sensitivity tests, pathological profile analyses and computational coordination are ways to improve therapeutic quality. In future, each patient should have his own unique chemotherapy protocol.

Anti-proliferative effects, cell cycle G2/M phase arrest and blocking of chromosome segregation by probimane and MST-16 in human tumor cell lines.

BACKGROUND: Anticancer bisdioxopiperazines, including ICRF-154, razoxane (Raz, ICRF-159) and ICRF-193, are a family of anticancer agents developed in the UK, especially targeting metastases of neoplasms. Two other bisdioxopiperazine derivatives, probimane (Pro) and MST-16, were synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Cytotoxic activities and mechanisms of Raz (+)-steroisomer (ICRF-187, dexrazoxane), Pro and MST-16 against tumor cells were evaluated by MTT colorimetry, flow cytometry and karyotyping. RESULTS: Pro was cytotoxic to human tumor cell lines in vitro (IC50<50 microM for 48 h). Four human tumor cell lines (SCG-7901, K562, A549 and HL60) were susceptible to Pro at low inhibitory concentrations (IC50 values < 10 microM for 48 h). Although the IC50 against HeLa cell line of vincristine (VCR, 4.56 microM), doxorubicin (Dox, 1.12 microM) and 5-fluoruouracil (5-Fu, 0.232 microM) are lower than Pro (5.12 microM), ICRF-187 (129 microM) and MST-16 (26.4 microM), VCR, Dox and 5-Fu shows a low dose-related - high cytotoxic activity. Time-response studies showed that the cytotoxic effects of Pro are increased for 3 days in human tumor cells, whereas VCR, Dox and 5-Fu showed decreased cytotoxic action after 24 h. Cell cycle G2/M phase arrest and chromosome segregation blocking by Pro and MST-16 were noted. Although there was similar effects of Pro and MST-16 on chromosome segregation blocking action and cell cycle G2/M phase arrest at 1- 4 microM, cytotoxicity of Pro against tumor cells was higher than that of MST-16 in vitro by a factor of 3- 10 folds. Our data show that Pro may be more effective against lung cancer and leukemia while ICRF-187 and MST-16 shows similar IC50 values only against leukemia. CONCLUSION: It suggests that Pro has a wider spectrum of cytotoxic effects against human tumor cells than other bisdioxopiperazines, especially against solid tumors, and with a single cytotoxic pathway of Pro and MST-16 affecting chromosome segregation and leading also to cell G2/ M phase arrests, which finally reduces cell division rates. Pro may be more potent than MST-16 in cytotoxicity. High dose- and time- responses of Pro, when compared with VCR, 5-Fu and Dox, were seen that suggest a selectivity of Pro against tumor growth. Compounds of bisdioxopiperazines family may keep up their cytotoxic effects longer than many other anticancer drugs.