Therapeutic Benefits of Piper nigrum: A Review

This manuscript aims to describe the various pharmacological activities of Piper nigrum. Pepper is a common spice of the plant which is used as spices in the kitchen to prepare various foods. Pepper production is centered in Kerela, followed by Karnataka and Maharashtra in India. Other big pepper-producing countries include Indonesia, Malaysia, Brazil, Vietnam, and Sri Lanka. It has various pharmacological activities used in the treatment of different diseases. The manuscript mainly describes the antituberculosis, anticonvulsant, analgesic, antipyretic, anti-inflammatory, antimicrobial, antioxidant, gastrointestinal and anticancer activity. The manuscript also describes the various studies related to the pharmacological activities of Piper nigrum. It is concluded from the manuscript that Piper nigrum has great efficacy in the treatment of various diseases.

Cytotopic (Cyto-) IL-15 as a New Immunotherapy for Prostate Cancer: Recombinant Production in Escherichia coli and Purification

Interleukin-15 (IL-15) is a cytokine previously suggested as a potential immunotherapy for cancer treatment. IL-15 can effectively reduce tumor growth in many preclinical tumor models including prostate cancer. This is due to its ability to expand and activate immune cells, such as CD8+ T cells and natural killer cells. To increase the potency of IL-15, we have engineered a protein variant that can be modified to localize and be retained in tissues where it is administered. However, the production of recombinant IL-15, the purity, and correct refolding of the final protein is not always ideal. In the current study, we aimed to optimize the methodology for production and purification of a modified recombinant human IL-15 and investigate the efficacy of the produced protein in the treatment of prostate tumors. Human IL-15 with its polypeptide sequence modified at the C-terminus to enable thiol conjugation with membrane localizing peptides, was produced in E. coli and purified using mild denaturing conditions (2M urea) from a washing step or from solubilization of inclusion bodies. The purified protein from the wash fraction was conjugated to a myristoylated peptide to form a membrane-localizing IL-15 (cyto-IL-15). The efficacy of cyto-IL-15 was investigated in subcutaneous TRAMP-C2 prostate tumors in mice and compared with cyto-IL-15 derived from protein purified from inclusion bodies (cyto-IL-15 Gen). When mild denaturing conditions were used for purification, the largest amount of IL-15 was collected from the wash fraction and a smaller amount from inclusion bodies. The protein from the wash fraction was mainly present as a monomer, whereas the one from inclusion bodies formed homodimers and higher complexes. After cytotopic modification, the purified IL-showed great efficacy in delaying prostate tumor growth (∼50%) and increased mice survival by ∼1.8-fold compared with vehicle. This study demonstrates an alternative, inexpensive and efficient method to produce and purify a modified version of IL-15 using mild denaturing conditions. This IL-15, when cytotopically modified, showed great efficacy as a monotherapy in prostate tumors in mice further highlighting the potential of IL-15 as a cancer immunotherapy.

MANAGEMENT OF HASHIMOTO'S THYROIDITIS THROUGH SHODHANA AND SHAMANA AUSHADHI: A CASE STUDY

Hashimoto's thyroiditis is chronic inflammation of the thyroid gland due to the formation of autoantibodies. It is an autoimmune disorder that would lead to hypothyroidism. Failures of host defense do occur, however, and fall into three broad categories: immune deficiencies, autoimmunity and hypersensitivities. Ayurveda has a unique approach in treating the auto immune disorders through Shodhana and Rasayana Therapies. Due to Nidana Sevana, Kapha - pitta vata dushti takes place leading to Jatharagni Vaishamya and Ama Utpatti. This causes Asamyak Ahara Pachana, Rasavaha Srotodushti, Rasa Dhatwagni Vaishamya leads to Uttarottara dhatwagni and Dhatu Vaishamya. When Agni becomes too low, metabolism is affected. Shodhana karma has a great efficacy in Sroto-shodhana and in turn it corrects the functioning of Jatharagni, dhatwagni Srotas and Doshas. The present case study includes a female patient of 26 years age suffering from Hashimoto's thyroiditis complaints of gradual increase in size of swelling over neck for 3 years She was treated with Shodhana and Shamana Aushadhis for 3 months and found effective in reducing the levels of antibodies.

Nanobiotechnology and Immunotherapy: Two Powerful and Cooperative Allies against Cancer

A number of novel cancer therapies have recently emerged that have rapidly moved from the bench to the clinic. Onco-immunotherapies, such as immune checkpoint blockade inhibitors and adoptive cell therapies, have revolutionized the field, since they provide a way to induce strong anti-tumor immune responses, which are able to fight cancer effectively. However, despite showing great efficacy in hematological and some solid tumors, unresponsiveness, development of therapy resistance and the development of serious adverse effects, limit their capacity to impact the vast majority of tumors. Nanoparticle-based delivery systems are versatile vehicles for a wide variety of molecular cargoes and provide an innovative strategy to improve conventional onco-immunotherapies. They can be finely tuned to release their contents in the tumor microenvironment, or to deliver combinations of adjuvants and antigens in the case of nanovaccines. In this review, we summarize the recent advancements in the field of nanobiotechnology, to remodel the tumor microenvironment and to enhance immunotherapies.

In silico Analysis of Quercetin and its Analogues Against Targeted Proteins

Quercetin is a flavonoid compound present in many plants such as onions, tomatoes, apples, green tea, flax seeds, etc. It possesses antioxidant and anti-inflammatory effects that help control inflammation, kill cancer cells, and prevent heart disease. Wide evidence reveals quercetin's antitumor property to inhibit various cancers like breast, lung, nasopharyngeal, kidney, colorectal, pancreatic, prostate, and ovarian cancer. In this study, quercetin was docked against proteins such as Apoptic protein (APAF-1, BAX, BCL-2), Heat shock protein, Cytochrome p45O, Actin, Tyrosine-protein kinase hck. From the Insilico research completed, we can infer that quercetin and the analogs show great efficacy in finding against cancer and can be used in cancer care. These findings will help us understand the quercetin's binding ability with proteins and know-how quercetin is involved in the anti-cancer, antioxidant role.

A novel antibody targeting TIM-3 resulting in receptor internalization for cancer immunotherapy

Background Strategies to reinvigorate exhausted T cells have achieved great efficacy in certain subpopulations of tumor patients. Blocking the antibodies that target programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 induces durable responses in Hodgkin’s lymphoma, melanoma, renal and lung cancers. T cell immunoglobulin mucin-3 (TIM-3) is another well-defined inhibitory receptor that is expressed in terminally differentiated Th1/Tc1 cells, which produces interferon gamma and cytotoxic molecules. It is also significantly expressed on forkhead box P3+ regulatory T cells and innate immune cells such as dendritic cells and macrophages. Methods By immunizing BALB/c mice with recombinant TIM-3 and screening of 20 000 hybridoma clones, we selected a monoclonal TIM-3-blocking antibody (IBI104), which shows great efficacy in vitro and in vivo. Results IBI104 blocks phosphatidylserine interaction with TIM-3 but does not interfere with the interaction of TIM-3 with galectin-9 in ELISA assays. However, in vitro administration of IBI104 induces the potent internalization of TIM-3 in activated T cells to the extent that it will shut down the entire TIM-3 mediated signaling regardless of the ligands. IBI104 shows potent anti-tumor efficacy when combined with anti-PD1 in vivo. Conclusions Our results suggest that IBI104 is a promising blocking antibody for TIM-3-mediated suppressive signaling and can serve as effective cancer immunotherapy, especially in combination with anti-PD1.

Composição química dos óleos essenciais de Schinus molle e atividade antifúngica em Sclerotinia sclerotiorum

Schinus molleis popularly known as aroeira-salsa, with aromaticleaves and branches. The present study wasto evaluate the chemical composition ofthe essential oils fromthe branches and leaves from S. molleand,antifungal activity on the isolate fromSclerotinia sclerotiorum(white mold).The branches and leaves were collected and processed to extractessential oils by hydrodistillation in a Clevenger type apparatus. The yields from essential oils extraction,and their chemical profiles were evaluated by gas chromatography with mass spectrometry.The essential oils yields were 0.21 and 0.37%, with 16 and 21 compounds identified for the essential oils of the branches and leaves, respectively. The major compounds were δ-cadiene 21.77%, viridiflorol 21.74, copaene 12.9% and caryophyllene 9.99% for the essential oil of the branches, for essential oil of the leavesgermacrene D 39.00%, α-pinene 14.77%,and germacrene B 6.25%.The antifungal activity had mycelial inhibition in S. sclerotiorumin allevaluatedconcentrations, with emphasis on 100 μLmL-1,which had inhibition from86.4 and 81.3% for branches and leaves, respectively. The essential oils fromS. mollehad good yields and are rich in monoterpenics and sesquiterpenicscompounds, and have great efficacy inantifungal activity.

Three Drug Regimens for Newly Diagnosed Multiple Myeloma Transplant-Ineligible Elderly Patients - a Systematic Review

Introduction: Patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT) tend to have comorbidities and/or advanced age that make this subset of patients difficult to manage with current drug regimens. Methods: A comprehensive literature search of PubMed, Embase, Clinicaltrials.gov and Web of Science was performed from inception and completed on 07/17/2019. Studies focusing on efficacy and tolerability of 3-drug regimens in patients with NDMM were included for the review. Results: Out of 3579 studies, a total of 10 (08 phase II and 03 phase III) clinical trials in last ten years (2010-2019) using 3-drug regimens in NDMM elderly pts (893M/807F) ineligible for ASCT (determined by investigators) were selected. A total of 1703/1740 NDMM pts were evaluated. Proteasome inhibitors (PIs) such as carfilzomib (C), bortezomib (V) and ixazomib (I) showed promising results in elderly transplant-ineligible NDMM pts. CLARION trial (phase III, n=955) compared two PIs (C and V) with melphalan (M) and prednisone. There was no statistically significant difference in progression-free survival (PFS) between two groups (median: 22.3 vs 22.1 months; HR: 0.91; 95% CI, 0.75-1.10, p = 0.159) as well as overall survival (OS) (HR: 1.08; 95% CI: 0.82-1.43). Difference in the least square means of the HR-QoL (Health related- quality of life) was 4.99 (p<.0001) favoring C-group. M may not be an ideal drug to combine with carfilzomib in this setting given more AEs.(Facon et al 2019). V as 3-drug regimen in combination with lenalidomide (L) in 242 pts achieved statistically significant prolonged PFS (median 43 mo) and OS (median 75 mo) with great efficacy and acceptable risk-benefit profile. (Durie et al 2017; phase III). Multinational phase II trial (n=70) by Dimopoulos et al (2019) evaluated I, with different fixed doses of cyclophosphamide (Cy). Median duration was 19 cycles, indicating the long-term tolerability of regimen. With favorable toxicity profile and maintained QoL scores, trial concluded that this therapy is tolerable in elderly transplant-ineligible NDMM pts. Tuchman et al (2017) in phase II trial (n=14) investigated (V-Cy-d) and achieved ORR of 64%, with ≥VGPR of 57%. Low dose V showed great efficacy with M yielding ORR of 86% and VGPR or better of 49% in phase II trial (n=101) that also evaluated Cy as 3-drug combination but results were more productive with M with longer PFS and OS which reduced when impact of frailty was examined on outcomes. Since toxicity was higher with M, trial suggested that 2-drug combination should be preferred in elderly frail patients. (Larocca et al 2015). Efficacy was quite promising when Bringhen et al (2014) trialed C with Cy-d; 87% OS and 76% PFS at 1 y in phase II trial (n=58) with much favorable safety profile. Monoclonal antibodies (mAb) such as elotuzumab (E) and pembrolizumab (Pe) are also tested in elderly. First study conducted on NDMM pts using humanized mAb; E, in phase II trial (n=40) by Takezako et al (2017) attained primary endpoint of the study (ORR) of (88%) and VGPR or better of 45% in Japanese pts with tolerable toxicities in elderly. No subjects on this study experienced severe peripheral neuropathy. KEYNOTE-185; a phase III multinational trial by Usmani et al (2019) evaluated Pe with Ld in 151 pts. FDA halted this study due to unfavorable benefit-risk profile; 19 deaths, 6 due to disease progression (PD), and 13 due to treatment-related AEs. Median PFS and median OS were not reached in either group. Immunomodulators such as L achieved one of the longest PFS reported in a trial of transplant ineligible patients (35 mo) by using LVd regimen in phase II multicenter trial (n=50). (O'Donnell et al 2018) Alkylating agents like bendamustine (ben) and M have been tested in different novel regimens. Decreasing intensity and increasing duration of ben resulted in better outcomes in phase II trial (n=59) by Berdeja et al (2016) and can be given as first line treatment. Ben yielded great results with low dose dexa as compared to high dose achieving 92% ORR. Original regimen was effective but relatively more toxic. Incidence of herpes and neuropathy decreased dramatically with the treatment modifications. Conclusion: Three-drug regimens having PIs, mABs, immunomodulators and alkylating agents have shown desirable results in NDMM transplant (ASCT)-ineligible elderly patients and are likely the emerging standard of care for NDMM. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.