Pulmonary delivery of forsythin-phospholipid complexes improves the lung anti-inflammatory efficacy in mice by enhancing dissolution and lung tissue affinity

Article

Author: Wei, Jia-Xing ; Yong-Hong, Liao ; Yu, Chen-Yang ; Yu-Zhuo, Li ; Jia-Xing, Wei ; Chen-Yang, Yu ; Li, Yu-Zhuo ; Liao, Yong-Hong ; Xiang, Fu ; Fu, Xiang

Forsythin, currently in phase II clinical trials in China for the treatment of the common cold and influenza, faces challenges in achieving adequate lung drug exposure due to its limited dissolution and permeability, thereby restricting its therapeutic efficacy. The objective of this work was to formulate a forsythin-phospholipid complex (FPC) to enhance its dissolution properties and lung affinity with a particular view to improving pulmonary drug exposure and anti-inflammatory response. The results revealed that forsythin reacted with dipalmitoyl-phosphatidylcholine to form a stable, nanosized FPC suspension. This formulation significantly improved the in vitro drug's dissolution, cellular uptake, and lung affinity compared to its uncomplexed form. Intratracheal administration of FPC in a mouse model of acute lung injury induced by lipopolysaccharide (LPS) resulted in a substantial increase in drug exposure to lung tissues (39.6-fold) and immune cells in the epithelial lining fluid (198-fold) compared to intraperitoneal injection. In addition, FPC instillation exhibited superior local anti-inflammatory effects, leading to improved survival rates among mice with LPS-induced acute respiratory distress syndrome, outperforming both instilled forsythin and injected FPC. Overall, this work demonstrated the potential of phospholipid complexes as a viable option for developing inhalation products for drugs with limited solubility and permeability properties.

01 Mar 2024·European Journal of Medicinal Chemistry

Design and synthesis of forsythin derivatives as anti-inflammatory agents for acute lung injury

Article

Author: Li, Xiaoting ; Quan, Zhe-Shan ; Guo, Hong-Yan ; Sang, Xiao-Tong ; Shen, Qing-Kun

Acute lung injury (ALI) is a clinically high mortality disease, which has not yet been effectively treated. The development of anti-ALI drugs is imminent. ALI can be effectively treated by inhibiting the inflammatory cascade and reducing the inflammatory response in the lung. Forsythia suspense is a common Chinese herbal medicine with significant anti-inflammatory activity. Using forsythin as the parent, 27 Forsythin derivatives were designed and synthesized, and the anti-AIL activity of these compounds was evaluated. Among them, compound B5 has the best activity to inhibit the release of IL-6, and the inhibition rate reaches 91.79% at 25 μM, which was 7.5 times that of the parent forsythin. In addition, most of the compounds have no significant cytotoxicity in vitro. Further studies showed that compound B5 had a concentration-dependent inhibitory effect on NO, IL-6 and TNF-α. And the IC₅₀ values of compound B5 for NO and IL-6 are 10.88 μM and 4.93 μM, respectively. We also found that B5 could significantly inhibit the expression of some immune-related cytotoxic factors, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition, B5 inhibits NF-κB/MAPK signaling pathway. In vivo experiments showed that B5 could alleviate lung inflammation in LPS-induced ALI mice and inhibit IL-6, TNF-α, COX-2 and iNOS. In summary, B5 has anti-inflammatory effects and alleviates ALI by regulating inflammatory mediators and inhibiting MAPK and NF-κB signaling pathways.

01 Jan 2024·Journal of Ethnopharmacology

Review of the therapeutic potential of Forsythiae Fructus on the central nervous system: Active ingredients and mechanisms of action

Review

Author: Zhang, Leying ; Lang, Fenglong ; Wang, Jue ; Feng, Juan

ETHNOPHARMACOLOGICAL RELEVANCETraditional Chinese medicine has gained significant attention in recent years owing to its multi-component, multi-target, and multi-pathway advantages in treating various diseases. Forsythiae Fructus, derived from the dried fruit of Forsythia suspensa (Thunb.) Vahl, is one such traditional Chinese medicine with numerous in vivo and ex vivo therapeutic effects, including anti-inflammatory, antibacterial, and antiviral properties. Forsythiae Fructus contains more than 200 chemical constituents, with forsythiaside, forsythiaside A, forsythiaside B, isoforsythiaside, forsythin, and phillyrin being the most active ingredients. Forsythiae Fructus exerts neuroprotective effects by modulating various pathways, including oxidative stress, anti-inflammation, NF-κB signaling, 2-AG, Nrf2 signaling, acetylcholinesterase, PI3K-Akt signaling, ferroptosis, gut-brain axis, TLR4 signaling, endoplasmic reticulum stress, PI3K/Akt/mTOR signaling, and PPARγ signaling pathway.AIM OF THE STUDYThis review aims to highlight the potential therapeutic effects of Forsythiae Fructus on the central nervous system and summarize the current knowledge on the active ingredients of Forsythiae Fructus and their effects on different pathways involved in neuroprotection.MATERIALS AND METHODSIn this review, we conducted a comprehensive search of databases (PubMed, Google Scholar, Web of Science, China Knowledge Resource Integrated, local dissertations and books) up until June 2023 using key terms such as Forsythia suspensa, Forsythiae Fructus, forsythiaside, isoforsythiaside, forsythin, phillyrin, Alzheimer's disease, Parkinson's disease, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, aging, and herpes simplex virus encephalitis.RESULTSOur findings indicate that Forsythiae Fructus and its active ingredients own therapeutic effects on the central nervous system by modulating various pathways, including oxidative stress, anti-inflammation, NF-κB signaling, 2-AG, Nrf2 signaling, acetylcholinesterase, PI3K-Akt signaling, ferroptosis, the gut-brain axis, TLR4 signaling, endoplasmic reticulum stress, PI3K/Akt/mTOR signaling, and PPARγ signaling pathway.CONCLUSIONForsythiae Fructus and its active ingredients have demonstrated promising neuroprotective properties. Future in vivo and clinical studies of Forsythiae Fructus and its active ingredients should be conducted to establish precise dosage and standard guidelines for a more effective application in the treatment of neurological disorders.

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Indication	Highest Phase	Country/Location	Organization	Date
Common Cold	Phase 2	CN	Zhejiang Yatai Pharmaceutical Co., Ltd.	-
Fever	Phase 2	CN	Zhejiang Yatai Pharmaceutical Co., Ltd.	-
Fever	Phase 2	CN	Dalian Fusheng Pharmaceutical Co., Ltd.	-
Influenza, Human	Phase 2	CN	Zhejiang Yatai Pharmaceutical Co., Ltd.	-
Pharyngitis	Phase 2	CN	Zhejiang Yatai Pharmaceutical Co., Ltd.	-
Pharyngitis	Phase 2	CN	Dalian Fusheng Pharmaceutical Co., Ltd.	-

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