Synthesis of novel pyrazole acetals of andrographolide and isoandrographolide as potent anticancer agents.

Globally, cancer is the most prevalent chronic disease-related cause of death. Although there are many anticancer drugs, some of them have adverse effects. Due to their limited side effects, natural products are preferred over synthetic drugs. Andrographolide and its derivatives are known to be potent anticancer agents. In this context, sixteen novel 3,19-(NH-3-aryl-pyrazole) acetals of andrographolide and isoandrographolide (1a-1h, 2a-2g, 2i) from 3-aryl-1-H-pyrazole-4-carboxaldehydes (a-i) were synthesized. All the synthesized compounds were characterized using 1H NMR, 13C NMR, HRMS, FT-IR, and UV-vis spectroscopy. All the compounds were evaluated against a panel of 60 different human cancer cell lines for their anticancer potential at NCI, USA. Four compounds, having promising GI50s (50% growth inhibitory activity) on all 60-cell lines were selected for further in vitro studies. Out of these four compounds, compound 1g exhibited the best IC50 (3.08 µM) against the colon cancer cell line, HCT-116. Cell cycle analysis, annexin V-FITC/PI, and ROS assays revealed that the apoptosis of HCT-116 cells induced by compound 1g could be mainly attributed to the elevated levels of intracellular ROS. Further, the structure-activity relationship revealed that the pyrazole moiety of andrographolide plays a key role in their anticancer properties. These compounds were further examined for in silico ADMET and Lipinski characteristics to assess their potential as lead compounds.

Engineered nanomicelles targeting proliferation and angiogenesis inhibit tumour progression by impairing the synthesis of ceramide-1-phosphate.

Tumour cells secrete various proangiogenic factors like VEGF, PDGF, and EGF that result in the formation of highly vascularized tumours with an immunosuppressive tumour microenvironment. As tumour growth and metastasis are highly dependent on angiogenesis, targeting tumour vasculature along with rapidly dividing tumour cells is a potential approach for cancer treatment. Here, we specifically engineered sub-100 sized nanomicelles (DTX-CA4 NMs) targeting proliferation and angiogenesis using an esterase-sensitive phosphocholine-tethered docetaxel conjugate of lithocholic acid (LCA) (PC-LCA-DTX) and a poly(ethylene glycol) (PEG) derivative of an LCA-combretastatin A4 conjugate (PEG-LCA-CA4). DTX-CA4 NMs effectively inhibit the tumour growth in syngeneic (CT26) and xenograft (HCT116) colorectal cancer models, inhibit tumour recurrence, and enhance the percentage survival in comparison with individual drug-loaded NMs. DTX-CA4 NMs enhance the T cell-mediated anti-tumour immune response and DTX-CA4 NMs in combination with an immune checkpoint inhibitor, anti-PDL1 antibody, enhance the anti-tumour response. We additionally showed that DTX-CA4 NMs effectively attenuate the production of ceramide-1-phosphate, a key metabolite of the sphingolipid pathway, by downregulating the expression of ceramide kinase at both transcriptional and translational levels. Therefore, this study presents the engineering of effective DTX-CA4 NMs for targeting the tumour microenvironment that can be explored further for clinical applications.

Engineered nanomicelles inhibit the tumour progression via abrogating the prostaglandin-mediated immunosuppression.

Cancer treatment is challenged due to immunosuppressive inflammatory tumour microenvironment (TME) caused by infiltration of tumour-promoting and inhibition of tumour-inhibiting immune cells. Here, we report the engineering of chimeric nanomicelles (NMs) targeting the cell proliferation using docetaxel (DTX) and inflammation using dexamethasone (DEX) that alters the immunosuppressive TME. We show that a combination of phospholipid-DTX conjugate and PEGylated-lipid-DEX conjugate can self-assemble to form sub-100 nm chimeric NMs (DTX-DEX NMs). Anti-cancer activities against syngeneic and xenograft mouse models showed that the DTX-DEX NMs are more effective in tumour regression, enhance the survival of mice over other treatment modes, and alter the tumour stroma. DTX-DEX NMs cause a significant reduction in myeloid-derived suppressor cells, alter the polarization of macrophages, and enhance the accumulation of cytotoxic CD4+ and CD8+ T cells in tumour tissues, along with alterations in cytokine expression. We further demonstrated that these DTX-DEX NMs inhibit the synthesis of prostaglandins, especially PGE2, by targeting the cyclooxygenase 2 that is partly responsible for immunosuppressive TME. Therefore, this study presents, for the first time, the engineering of lithocholic acid-derived chimeric NMs that affect the prostaglandin pathway, alter the TME, and mitigate tumour progression with enhanced mice survival.

A localized hydrogel-mediated chemotherapy causes immunogenic cell death via activation of ceramide-mediated unfolded protein response.

Treatment of triple-negative breast cancer (TNBC) is challenging because of its "COLD" tumor immunosuppressive microenvironment (TIME). Here, we present a hydrogel-mediated localized delivery of a combination of docetaxel (DTX) and carboplatin (CPT) (called DTX-CPT-Gel therapy) that ensured enhanced anticancer effect and tumor regression on multiple murine syngeneic and xenograft tumor models. DTX-CPT-Gel therapy modulated the TIME by an increase of antitumorigenic M1 macrophages, attenuation of myeloid-derived suppressor cells, and increase of granzyme B+CD8+ T cells. DTX-CPT-Gel therapy elevated ceramide levels in tumor tissues that activated the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-mediated unfolded protein response (UPR). This UPR-mediated activation of apoptotic cell death led to release of damage-associated molecular patterns, thereby activating the immunogenic cell death that could even clear the metastatic tumors. This study provides a promising hydrogel-mediated platform for DTX-CPT therapy that induces tumor regression and effective immune modulation and, therefore, can be explored further for treatment of TNBC.

Development of hyaluronic acid-anchored polycaprolactone nanoparticles for efficient delivery of PLK1 siRNA to breast cancer.

PlK1 has a significant role in the development of breast cancer. Thus, silencing of PlK1 gene may arrest the growth of breast cancer. However, the in vivo stability of PlK1 siRNA after injection remains a challenge to target the specific site. The delivery of siPlK1 RNA via viral vector and amine group-terminated dendrimer is associated with immune reaction and cellular cytotoxicity. Thus, in the present study, hyaluronic acid-functionalized and -thiolated polycaprolactone nanoparticles (SH-HPP NPs) were developed for enhancing the targeting capabilities of siRNA towards human breast cancer cells. NPs displayed size in the range of 180-217 nm, and with sustain and pH-dependent release of siRNA up to 120 h. The in vitro treatments with siRNA-containing NPs showed the high number of necrotic cells and the cell cycle arrest at the G2/M phase. The gene expression analysis depicts the decrease of endogenous PLK1 siRNA expression on MCF-7 cells upon PLK1 NPs treatment. In vitro cytotoxicity experiments demonstrated effective anticancer properties against MCF-7. Finally, in vivo results showed that substantial tumor inhibition was achieved with PLK1 siRNA-containing SH-HPP NPs in comparison of the control group. Hence, HPP NPs have enormous potential for the selective delivery of siRNA, i.e., breast cancer cells.

Targeting Vancomycin-Resistant Enterococci (VRE) Infections and Van Operon-Mediated Drug Resistance Using Dimeric Cholic Acid-Peptide Conjugates.

Emergence of vancomycin resistance in Gram-positive bacteria and the prevalence of vancomycin-resistant Enterococci (VRE) infections are highly alarming as very limited antibiotic options are available against VRE infections. Here, we present the synthesis of cholic acid-derived dimeric amphiphiles where two cholic acid moieties are tethered through carboxyl terminals using different alkylene spacers. Our investigations revealed that dimer 5 possessing a propylene spacer and glycine-valine peptides tethered on hydroxyl groups is the most effective antimicrobial against VRE. Dimer 5 can permeabilize bacterial membranes, generate reactive oxygen species, and clear preformed biofilms. We further demonstrate that dimer 5 downregulates vancomycin-mediated transcriptional activation of the vanHAX gene cluster and does not allow VSE to develop vancomycin resistance until 100 generations. Therefore, this study, for the first time, presents a bacterial membrane-targeting amphiphile that can mitigate VRE infections and inhibit the emergence of vancomycin resistance.

An exhaustive comprehension of the role of herbal medicines in Pre- and Post-COVID manifestations.

ETHNOPHARMACOLOGICAL RELEVANCE: The coronavirus disease (COVID-19) has relentlessly spread all over the world even after the advent of vaccines. It demands management, treatment, and prevention as well with utmost safety and effectiveness. It is well researched that herbal medicines or natural products have shown promising outcomes to strengthen immunity with antiviral potential against SARS-COV-2. AIM OF THE REVIEW: Our objective is to provide a comprehensive insight into the preventive and therapeutic effects of herbal medicines and products (Ayurvedic) for pre-and post-COVID manifestations. MATERIAL AND METHOD: The database used in the text is collected and compiled from Scopus, PubMed, Nature, Elsevier, Web of Science, bioRxiv, medRxiv, American Chemical Society, and clinicaltrials.gov up to January 2022. Articles from non-academic sources such as websites and news were also retrieved. Exploration of the studies was executed to recognize supplementary publications of research studies and systematic reviews. The keywords, such as "SARS-COV-2, coronavirus, COVID-19, herbal drugs, immunity, herbal immunomodulators, infection, herbal antiviral drugs, and WHO recommendation" were thoroughly searched. Chemical structures were drawn using the software Chemdraw Professional 15.0.0.160 (PerkinElmer Informatics, Inc.). RESULT: A plethora of literature supports that the use of herbal regimens not only strengthen immunity but can also treat SARS-COV-2 infection with minimal side effects. This review summarizes the mechanistic insights into herbal therapy engaging interferons and antibodies to boost the response against SARS-COV-2 infection, several clinical trials, and in silico studies (computational approaches) on selected natural products including, Ashwagandha, Guduchi, Yashtimadhu, Tulsi, etc. as preventive and therapeutic measures against COVID. We have also emphasized the exploitation of herbal medicine-based pharmaceutical products along with perspectives for unseen upcoming alike diseases. CONCLUSION: According to the current state of art and cutting-edge research on herbal medicines have showed a significant promise as modern COVID tools. Since vaccination cannot be purported as a long-term cure for viral infections, herbal/natural medicines can only be considered a viable alternative to current remedies, as conceived from our collected data to unroot recurring viral infections.

Hydrogel-mediated topical delivery of steroids can effectively alleviate psoriasis via attenuating the autoimmune responses.

Psoriasis is a systemic, relapsing, and chronic autoimmune inflammatory disease of the skin. Topical use of betamethasone, a glucocorticoid, in the form of creams is a common treatment for psoriasis. However, topical use of these creams is challenging due to the ineffective entrapment of steroids, burst release of the entrapped drugs, poor skin permeability, and high toxicity. Herein, we present the engineering of a betamethasone-loaded topical hydrogel (B-Gel) that can efficiently entrap steroids with high spreadability, and can also maintain the sustained release of drugs. We used an imiquimod (IMQ) induced ear psoriasis model, and demonstrated that topical application of B-Gel can mitigate the autoimmune inflammation reactions, and leads to a reduction in erythema, induration, scaling, and ear thickness. As interleukin 17 (IL-17) secreting T helper 17 (Th17) cells and γδ+ T cells are responsible for psoriasis, B-Gel treatment witnessed a reduction in the infiltration of leukocytes, CD4+ T cells, Th17 T cells, and dermal γδ+ T cells. We further demonstrated that B-Gel mediated reduction of IL-1ß, IL-17, and K16 (marker for keratinocyte proliferation) is responsible for alleviation of psoriasis. Therefore, the non-greasy nature of the hydrogel with a cooling effect provides an alternative for topical application of steroids.

An Insight into Anticancer Bioactives from Punica granatum (Pomegranate).

Cancer is one of the major reasons for mortality across the globe. Many side-effects are associated with the formulations available in the market, affecting the quality of life of the patients. This has caused the researchers to find an alternative source of medications, such as herbal medicine, showing a promising effect in anticancer treatment; one such source is Pomegranate, which belongs to the family Punicaceae. Punica granatum contains many polyphenols that have antioxidant, antidiabetic, and therapeutic effects in the treatment and management of metabolic and cardiovascular diseases, as well as a favourable effect on anticancer therapy. Polyphenols like punicalin, punicalagin, and ellagic acid are a few of the many compounds responsible for the anticancer activity of pomegranate. Many preparations of pomegranate, such as Pomegranate Juice (PJ), Pomegranate Seed Oil (PSO), Pomegranate peel extract (PoPx), etc. are used in various clinical studies. These polyphenols show anticancer activity by either arresting the cell cycle in the G2/M phase, inducing apoptosis or damaging the DNA of tumor cells. This review explicitly discusses the role and mechanism of bioactives obtained from the pomegranate in the treatment and management of cancer. The chemical structure, properties, and role of pomegranate in the treatment of breast, lung, thyroid, colon, and prostate cancer have been focused on in detail. This review also discusses various targeted drug delivery approaches for tumour treatment as well as patented preparation of pomegranate compounds along with the ongoing clinical trials.

Nonimmunogenic Hydrogel-Mediated Delivery of Antibiotics Outperforms Clinically Used Formulations in Mitigating Wound Infections.

Treatment of chronic wound infections caused by Gram-positive bacteria such as Staphylococcus aureus is highly challenging due to the low efficacy of existing formulations, thereby leading to drug resistance. Herein, we present the synthesis of a nonimmunogenic cholic acid-glycine-glycine conjugate (A6) that self-assembles into a supramolecular viscoelastic hydrogel (A6 gel) suitable for topical applications. The A6 hydrogel can entrap different antibiotics with high efficacy without compromising its viscoelastic behavior. Activities against different bacterial species using a disc diffusion assay demonstrated the antimicrobial effect of the ciprofloxacin-loaded A6 hydrogel (CPF-Gel). Immune profiling and gene expression studies after the application of the A6 gel to mice confirmed its nonimmunogenic nature to host tissues. We further demonstrated that topical application of CPF-Gel clears S. aureus-mediated wound infections more effectively than clinically used formulations. Therefore, cholic acid-derived hydrogels are an efficacious matrix for topical delivery of antibiotics and should be explored further.

A hydrogel-based implantable multidrug antitubercular formulation outperforms oral delivery.

We present a non-immunogenic, injectable, low molecular weight, amphiphilic hydrogel-based drug delivery system (TB-Gel) that can entrap a cocktail of four front-line antitubercular drugs, isoniazid, rifampicin, pyrazinamide, and ethambutol. We showed that TB-Gel is more effective than oral delivery of the combination of four drugs in reducing the mycobacterial infection in mice. Results show that half the dose of chemotherapeutic drugs is sufficient to achieve a comparable therapeutic effect to that of oral delivery.